U.S. patent application number 12/157712 was filed with the patent office on 2009-02-05 for azapeptide derivatives.
This patent application is currently assigned to CoNCERT Pharmaceuticals, Inc.. Invention is credited to Scott L. Harbeson, Roger D. Tung.
Application Number | 20090036357 12/157712 |
Document ID | / |
Family ID | 39730784 |
Filed Date | 2009-02-05 |
United States Patent
Application |
20090036357 |
Kind Code |
A1 |
Harbeson; Scott L. ; et
al. |
February 5, 2009 |
Azapeptide derivatives
Abstract
This invention relates to novel compounds that are azapeptides,
and pharmaceutically acceptable salts thereof. More specifically,
the invention relates to novel azapeptide compounds that are
derivatives of the HIV protease inhibitor atazanavir sulfate. This
invention also provides pyrogen-free compositions comprising one or
more compounds of the invention and a carrier, and the use of the
disclosed compounds and compositions in methods of treating
diseases and conditions that are treated by administering HIV
protease inhibitors. The invention also relates to the use of one
or more of the disclosed compounds as reagents in analytical
studies involving atazanavir.
Inventors: |
Harbeson; Scott L.;
(Cambridge, MA) ; Tung; Roger D.; (Lexington,
MA) |
Correspondence
Address: |
HAMILTON, BROOK, SMITH & REYNOLDS, P.C.
530 VIRGINIA ROAD, P.O. BOX 9133
CONCORD
MA
01742-9133
US
|
Assignee: |
CoNCERT Pharmaceuticals,
Inc.
Lexington
MA
|
Family ID: |
39730784 |
Appl. No.: |
12/157712 |
Filed: |
June 12, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60934201 |
Jun 12, 2007 |
|
|
|
61067627 |
Feb 29, 2008 |
|
|
|
Current U.S.
Class: |
514/1.1 ; 546/22;
546/335 |
Current CPC
Class: |
A61P 31/18 20180101;
C07D 213/42 20130101; C07F 9/58 20130101; A61P 31/00 20180101 |
Class at
Publication: |
514/7 ; 546/335;
514/19; 546/22 |
International
Class: |
A61P 31/18 20060101
A61P031/18; C07D 213/56 20060101 C07D213/56; C07F 9/58 20060101
C07F009/58; A61K 38/05 20060101 A61K038/05 |
Claims
1. A compound of the Formula Ib: ##STR00045## or a pharmaceutically
acceptable salt thereof, wherein: each of R.sup.1a and R.sup.1b is
independently selected from --CD.sub.3 and --CH.sub.3; R.sup.3 is
selected from --C(CD.sub.3).sub.3 and --C(CH.sub.3).sub.3; and
Y.sup.1a and Y.sup.1b are the same and are selected from H and
D.
2. The compound of claim 1, wherein the compound is selected from;
##STR00046## ##STR00047## acceptable salt of any of the
foregoing.
3. The compound of claim 2, wherein the compound is selected from
Compound 114, Compound 120, Compound 122 and Compound 131 or a
pharmaceutically acceptable salt of any of the foregoing.
4. A compound selected from: ##STR00048## pharmaceutically
acceptable salt of either of the foregoing.
5. The compound of any one of claims 1 to 4, wherein any atom not
designated as deuterium is present at its natural isotopic
abundance.
6. A pharmaceutical composition comprising a compound of Formula
Ib: ##STR00049## pharmaceutically acceptable salt thereof, wherein:
each of R.sup.1a and R.sup.1b is independently selected from
--CD.sub.3 and --CH.sub.3; R.sup.3 is selected from
--C(CD.sub.3).sub.3 and --C(CH.sub.3).sub.3; and Y.sup.1a and
Y.sup.1b are the same and are selected from H and D; and a
pharmaceutically acceptable carrier.
7. The composition of claim 6, wherein the compound is selected
from: Compound 131; Compound 122; Compound 114; Compound 106;
Compound 104; Compound 120; and Compound 123 or a pharmaceutically
acceptable salt of any of the foregoing.
8. The composition of claim 6, additionally comprising a second
therapeutic agent selected from a second HIV protease inhibitor, a
non-nucleoside reverse transcriptase inhibitor, a
nucleoside/nucleotide reverse transcriptase inhibitor, a viral
entry inhibitor, an integrase inhibitor, an immune based
antiretroviral agent, a viral maturation inhibitor, a cellular
inhibitor, or combinations of two or more of the above.
9. The composition of claim 8, wherein the second therapeutic agent
is selected from ritonavir, efavirenz, didanosine, tenofovir
disoproxil, nelfinavir mesilate, amprenavir, raltegravir potassium,
saquinavir, lopinavir, nevirapine, emtricitabine, abacavir,
lamivudine, zidovudine, maraviroc, stavudine, darunavir,
fosamprenavir, vicriviroc, a pharmaceutically acceptable salt of
any of the foregoing, and combinations thereof.
10. The composition of claim 9, wherein the second therapeutic
agent is selected from ritonavir, efavirenz, didanosine,
raltegravir, tenofovir disoproxil, lamivudine, abacavir,
zidovudine, emtricitabine, efavirenz, a pharmaceutically acceptable
salt of any of the foregoing, and combinations thereof.
11. The composition of claim 10, comprising two to three additional
second therapeutic agents independently selected from ritonavir,
efavirenz, didanosine, raltegravir, tenofovir disoproxil,
lamivudine, abacavir, zidovudine, emtricitabine, efavirenz, and a
pharmaceutically acceptable salt of any of the foregoing.
12. The composition of claim 11, comprising two additional second
agents independently selected from ritonavir, efavirenz,
didanosine, raltegravir, tenofovir disoproxil, lamivudine,
abacavir, zidovudine, emtricitabine, efavirenz, and a
pharmaceutically acceptable salt of any of the foregoing.
13. A method of treating HIV infection in a patient in need thereof
comprising the step of administering to the patient an effective
amount of a compound according to any one of Formula Ib:
##STR00050## pharmaceutically acceptable salt thereof, wherein:
each of R.sup.1a and R.sup.1b is independently selected from
--CD.sub.3 and --CH.sub.3; R.sup.3 is selected from
--C(CD.sub.3).sub.3 and --C(CH.sub.3).sub.3; and Y.sup.1a and
Y.sup.1b are the same and are selected from H and D.
14. The method of claim 13, further comprising administering to the
patient a second therapeutic agent selected from a second HIV
protease inhibitor, a non-nucleoside reverse transcriptase
inhibitor, a nucleoside/nucleotide reverse transcriptase inhibitor,
a viral entry inhibitor, an integrase inhibitor, an immune based
antiretroviral agent, a viral maturation inhibitor, a cellular
inhibitor, and combinations of two or more of the above.
15. The method of claim 14, wherein the second therapeutic agent is
selected from ritonavir, efavirenz, didanosine, tenofovir
disoproxil, nelfinavir mesilate, amprenavir, raltegravir potassium,
saquinavir, lopinavir, nevirapine, emtricitabine, abacavir,
lamivudine, zidovudine, maraviroc, stavudine, darunavir,
fosamprenavir, vicriviroc, a pharmaceutically acceptable salt of
any of the foregoing, and combinations thereof.
16. The method of claim 15, wherein the second therapeutic agent is
selected from ritonavir, efavirenz, didanosine, raltegravir,
tenofovir disoproxil, lamivudine, abacavir, zidovudine,
emtricitabine, efavirenz, a pharmaceutically acceptable salt of any
of the foregoing, and combinations thereof.
17. The method of claim 13, further comprising administering to the
patient two to three additional second therapeutic agents
independently selected from ritonavir, efavirenz, didanosine,
raltegravir, tenofovir disoproxil, lamivudine, abacavir,
zidovudine, emtricitabine, efavirenz, and a pharmaceutically
acceptable salt of any of the foregoing.
18. The method of claim 13, further comprising administering to the
patient two additional second therapeutic agents independently
selected from ritonavir, efavirenz, didanosine, raltegravir,
tenofovir disoproxil, lamivudine, abacavir, zidovudine,
emtricitabine, efavirenz, and a pharmaceutically acceptable salt of
any of the foregoing.
19. A pharmaceutical composition comprising a compound selected
from: ##STR00051## pharmaceutically acceptable salt of either of
the foregoing; and a pharmaceutically acceptable carrier.
20. A method of treating HIV infection in a patient in need thereof
comprising the step of administering to the patient an effective
amount of a compound selected from: ##STR00052## pharmaceutically
acceptable salt of either of the foregoing.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/934,201, filed on Jun. 12, 2007 and U.S.
Provisional Application No. 61/067,627, filed Feb. 29, 2008. The
entire teachings of the above applications are incorporated herein
by reference.
BACKGROUND OF THE INVENTION
[0002] Atazanavir sulfate, also known as
(3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenyl-
methyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecaned-
ioic acid dimethyl ester, sulfate, prevents the formation of mature
HIV virions in HIV-1 infected cells by selectively inhibiting the
virus-specific processing of certain polyproteins (viral Gag and
Gag-Pol). Atazanavir sulfate is currently approved for the
treatment of HIV infection.
[0003] Atazanavir is contraindicated for coadministration with
drugs that are highly dependent on CYP3A for clearance and for
which elevated plasma concentrations are associated with serious
and/or life-threatening events. Due to inhibition effects of
atazanavir on CYP3A, CYP2C8, and UGT1A1, caution is advised when
prescribing drugs primarily metabolized by CYP3A, CYP2C8, or UGT1A1
for patients receiving atazanavir. Common adverse events associated
with atazanavir include hyperbilirubinemia, rash, nausea, headache,
and jaundice/scleral icterus. Adverse events experienced by some
patients and for which a causal relationship has not been
established include diabetes mellitus/hyperglycemia, PR interval
prolongation, hemophilia, and fat redistribution.
[0004] Despite the beneficial activities of atazanavir, there is a
continuing need for new compounds to treat the aforementioned
diseases and conditions.
SUMMARY OF THE INVENTION
[0005] This invention relates to novel compounds that are
azapeptides, and pharmaceutically acceptable salts thereof. More
specifically, the invention relates to novel azapeptide compounds
that are derivatives of the HIV protease inhibitor atazanavir
sulfate. This invention also provides pyrogen-free compositions
comprising one or more compounds of the invention and a carrier,
and the use of the disclosed compounds and compositions in methods
of treating diseases and conditions that are treated by
administering HIV protease inhibitors. The invention also relates
to the use of one or more of the disclosed compounds as reagents in
analytical studies involving atazanavir.
[0006] The compounds of the invention are represented by Formula
A:
##STR00001##
or a salt, hydrate or solvate thereof, wherein:
[0007] each of R.sup.1a and R.sup.1b is independently selected from
C.sub.1-C.sub.3 alkyl, wherein one or more hydrogen atoms in the
alkyl is optionally replaced with a deuterium atom;
[0008] each of R.sup.2 and R.sup.3 is independently selected from
isopropyl, sec-butyl, and tert-butyl wherein one or more hydrogen
atoms in the isopropyl, sec-butyl, or tert-butyl is optionally
replaced with a deuterium atom;
[0009] R.sup.4 is selected from H, OH and
--O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8;
[0010] R.sup.5 is selected from H and
--(CR.sup.6R.sup.7--O).sub.n--R.sup.8, wherein: [0011] R.sup.6 and
R.sup.7 are each independently selected from H, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, and
C.sub.3-C.sub.7 cycloalkyl, or [0012] R.sup.6 and R.sup.7 are taken
together with the carbon to which they are attached to form a
3-7-membered cycloalkyl; [0013] each R.sup.5 is independently
selected from --C(O)H, --C(O)--(C.sub.1-C.sub.7 alkyl),
--P(O)--(OH).sub.2, --S(O)--OH, --S(O).sub.2--OH, and A-R.sup.11,
wherein [0014] A is an .alpha.-amino acid residue; and [0015]
R.sup.11 is selected from H, C.sub.1-C.sub.6 alkyl,
--C(O)--(C.sub.1-C.sub.7 alkyl), A-R.sup.12, [0016] wherein
R.sup.12 is selected from H, C.sub.1-C.sub.6 alkyl, and
--C(O)--(C.sub.1-C.sub.7 alkyl); and [0017] n is 0 or 1;
[0018] wherein any alkyl in R.sup.5 is optionally substituted;
[0019] each of Y.sup.1a and Y.sup.1b is independently selected from
H and D;
[0020] R.sup.9 is selected from 2-thienyl, 3-thienyl, thiazol-5-yl,
thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
pyrazin-2-yl, 2-methyl-2H-tetrazol-5-yl,
2-(d.sub.3-methyl)-2H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, and
1-(d.sub.3-methyl)-1H-tetrazol-5-yl; and
[0021] at least one of R.sup.1a, R.sup.1b, R.sup.2, R.sup.3 or Y
variable comprises a deuterium atom.
[0022] The compounds, pharmaceutically acceptable salts thereof and
compositions of the invention are useful for treating diseases that
are effectively treated by a compound that is an HIV protease
inhibitor. As such, the present invention includes a method of
treating a disease which is susceptible to treatment by a compound
that is an HIV protease inhibitor, comprising administering to a
subject in need thereof an effective amount of: (i) a compound or
pharmaceutically acceptable salt thereof; or (ii) a pyrogen-free
composition (e.g., a pharmaceutical composition) described
herein.
[0023] Diseases or conditions susceptible to treatment with a
compound having HIV protease inhibitory activity include, but are
not limited to, HIV infection.
[0024] The compounds and compositions of this invention are also
useful as reagents in methods for determining the concentration of
atazanavir sulfate in solution, examining the metabolism of
atazanavir sulfate and other analytical studies. An additional
utility of compounds of any of the formulae herein include their
use as internal standards to determine the true concentrations
atazanavir sulfate in biological matrices, such as plasma.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 is a graph showing the relative stability of
compounds of this invention in human liver microsomes as compared
to atazanavir.
[0026] FIG. 2 is a graph showing the relative stability of
compounds of this invention in human liver microsomes as compared
to atazanavir.
[0027] FIG. 3 is a graph showing the relative stability of
compounds of this invention in human liver microsomes as compared
to atazanavir.
[0028] FIG. 4 is a graph showing the relative plasma levels of
compounds of this invention following oral administration to chimps
as compared to atazanavir.
[0029] FIG. 5 is a graph showing the relative plasma levels of
compounds of this invention following oral administration to chimps
as compared to atazanavir.
DETAILED DESCRIPTION OF THE INVENTION
[0030] The terms "ameliorate" and "treat" are used interchangeably
and include both therapeutic treatment and prophylactic treatment
(reducing the likelihood of development). Both terms mean decrease,
suppress, attenuate, diminish, arrest, or stabilize the development
or progression of a disease (e.g., a disease or disorder delineated
herein), lessen the severity of the disease or improve the symptoms
associated with the disease.
[0031] "Disease" means any condition or disorder that damages or
interferes with the normal function of a cell, tissue, or
organ.
[0032] It will be recognized that some variation of natural
isotopic abundance occurs in a synthesized compound depending upon
the origin of chemical materials used in the synthesis. Thus, a
preparation of atazanavir will inherently contain small amounts of
deuterated isotopologues. The concentration of naturally abundant
stable hydrogen isotopes, notwithstanding this variation, is small
and immaterial as compared to the degree of stable isotopic
substitution of compounds of this invention. See, for instance,
Wada E et al., Seikagaku 1994, 66:15; Ganes L Z et al., Comp
Biochem Physiol Mol Integr Physiol 1998, 119:725.
[0033] Unless otherwise stated, when a position is designated
specifically as "H" or "hydrogen", the position is understood to
have hydrogen at its natural abundance isotopic composition. Also
unless otherwise stated, when a position is designated specifically
as "D" or "deuterium", the position is understood to have deuterium
at an abundance that is at least 3500 times greater than the
natural abundance of deuterium, which is 0.015% (i.e., at least
52.5% incorporation of deuterium).
[0034] The term "isotopic enrichment factor" as used herein means
the ratio between the isotopic abundance of D at a specified
position in a compound of this invention and the naturally
occurring abundance of that isotope. The natural abundance of
deuterium is 0.015%.
[0035] In other embodiments, a compound of this invention has an
isotopic enrichment factor for each deuterium present at a site
designated as a potential site of deuteration on the compound of at
least 4000 (60% deuterium incorporation), at least 4500 (67.5%
deuterium incorporation), at least 5000 (75% deuterium), at least
5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium
incorporation), at least 6333.3 (95% deuterium incorporation), at
least 6466.7 (97% deuterium incorporation), at least 6600 (99%
deuterium incorporation), or at least 6633.3 (99.5% deuterium
incorporation). It is understood that the isotopic enrichment
factor of each deuterium present at a site designated as a site of
deuteration is independent of other deuterated sites. For example,
if there are two sites of deuteration on a compound one site could
be deuterated at 52.5% while the other could be deuterated at 75%.
The resulting compound would be considered to be a compound wherein
the isotopic enrichment factor is at least 3500 (52.5%).
[0036] The term "isotopologue" refers to a species that differs
from a specific compound of this invention only in the isotopic
composition thereof. Isotopologues can differ in the level of
isotopic enrichment at one or more positions and/or in the
positions(s) of isotopic enrichment.
[0037] It will be understood that the term "compound," when
referring to the compounds of the invention, refers to a collection
of molecules having an identical chemical structure, except that
there may be isotopic variation among the constituent atoms of the
molecules. Thus, it will be clear to those of skill in the art that
a compound represented by a particular chemical structure
containing indicated deuterium atoms, will also contain lesser
amounts of isotopologues having hydrogen atoms at one or more of
the designated deuterium positions in that structure. The relative
amount of such isotopologues in a compound of this invention will
depend upon a number of factors including the isotopic purity of
deuterated reagents used to make the compound and the efficiency of
incorporation of deuterium in the various synthesis steps used to
prepare the compound. However, as set forth above the relative
amount of such isotopologues will be less than 47.5% of the
compound.
[0038] The term "compound" is also intended to include any solvates
or hydrates thereof.
[0039] A salt of a compound of this invention is formed between an
acid and a basic group of the compound, such as an amino functional
group, or a base and an acidic group of the compound, such as a
carboxyl functional group. According to another embodiment, the
compound is a pharmaceutically acceptable acid addition salt.
[0040] The term "pharmaceutically acceptable," as used herein,
refers to a component that is, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and other mammals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. A "pharmaceutically acceptable salt" means any
non-toxic salt that, upon administration to a recipient, is capable
of providing, either directly or indirectly, a compound of this
invention. A "pharmaceutically acceptable counterion" is an ionic
portion of a salt that is not toxic when released from the salt
upon administration to a recipient.
[0041] Acids commonly employed to form pharmaceutically acceptable
salts include inorganic acids such as hydrogen bisulfide,
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid
and phosphoric acid, as well as organic acids such as
para-toluenesulfonic acid, salicylic acid, tartaric acid,
bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric
acid, gluconic acid, glucuronic acid, formic acid, glutamic acid,
methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic
acid, succinic acid, citric acid, benzoic acid and acetic acid, as
well as related inorganic and organic acids. Such pharmaceutically
acceptable salts thus include sulfate, pyrosulfate, bisulfate,
sulfite, bisulfite, phosphate, monohydrogenphosphate,
dihydrogenphosphate, metaphosphate, pyrophosphate, chloride,
bromide, iodide, acetate, propionate, decanoate, caprylate,
acrylate, formate, isobutyrate, caprate, heptanoate, propiolate,
oxalate, malonate, succinate, suberate, sebacate, fumarate,
maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate,
chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate,
methoxybenzoate, phthalate, terephthalate, sulfonate, xylene
sulfonate, phenylacetate, phenylpropionate, phenylbutyrate,
citrate, lactate, .beta.-hydroxybutyrate, glycolate, maleate,
tartrate, methanesulfonate, propanesulfonate,
naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and
other salts. In one embodiment, pharmaceutically acceptable acid
addition salts include those formed with mineral acids such as
hydrochloric acid and hydrobromic acid, and especially those formed
with organic acids such as maleic acid.
[0042] For those compounds of the invention comprising
--P(O)--(OH).sub.2, --S(O)--OH, --S(O).sub.2--OH, suitable cationic
moieties to form pharmaceutically acceptable salts include, but are
not limited to, alkali metals such as sodium, potassium, and
lithium; alkaline earth metals such as calcium and magnesium; other
metals, such as aluminum and zinc; ammonia, and organic amines,
such as mono-, di-, or trialkylamines; dicyclohexylamine; tributyl
amine; pyridine; N-methyl, N-ethylamine; diethylamine;
triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines),
such as mono-, bis-, or tris-(2-hydroxyethyl)amine,
2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,
N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as
N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;
N-methyl-D-glucamine; amino acids such as arginine, lysine, and the
like, and zwitterions, such as glycine and the like.
[0043] As used herein, the term "hydrate" means a compound which
further includes a stoichiometric or non-stoichiometric amount of
water bound by non-covalent intermolecular forces.
[0044] As used herein, the term "solvate" means a compound which
further includes a stoichiometric or non-stoichiometric amount of
solvent such as water, acetone, ethanol, methanol, dichloromethane,
2-propanol, or the like, bound by non-covalent intermolecular
forces.
[0045] The disclosed compounds may exist in various stereoisomeric
forms. Stereoisomers are compounds which differ only in their
spatial arrangement. Enantiomers are pairs of stereoisomers whose
mirror images are not superimposable, most commonly because they
contain an asymmetrically substituted carbon atom that acts as a
chiral center. "Enantiomer" means one of a pair of molecules that
are mirror images of each other and are not superimposable.
Diastereomers are stereoisomers that are not related as mirror
images, most commonly because they contain two or more
asymmetrically substituted carbon atoms. "R" and "S" represent the
configuration of substituents around one or more chiral carbon
atoms.
[0046] When the stereochemistry of the disclosed compounds is named
or depicted by structure, the named or depicted stereoisomer is at
least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to
the other stereoisomers. When a single enantiomer is named or
depicted by structure, the depicted or named enantiomer is at least
60%, 70%, 80%, 90%, 99% or 99.9% optically pure. Percent optical
purity by weight is the ratio of the weight of the enantiomer over
the weight of the enantiomer plus the weight of its optical
isomer.
[0047] When a disclosed compound is named or depicted by structure
without indicating the stereochemistry, and has at least one chiral
center, it is to be understood that the name or structure
encompasses one enantiomer of the compound free from the
corresponding optical isomer, a racemic mixture of the compound and
mixtures enriched in one enantiomer relative to its corresponding
optical isomer ("scalemic mixtures").
[0048] When a disclosed compound is named or depicted by structure
without indicating the stereochemistry and has at least two chiral
centers, it is to be understood that the name or structure
encompasses a diastereomer free of other diastereomers, a pair of
diastereomers free from other diastereomeric pairs, mixtures of
diastereomers, mixtures of diastereomeric pairs, mixtures of
diastereomers in which one diastereomer is enriched relative to the
other diastereomer(s) and mixtures of diastereomeric pairs in which
one diastereomeric pair is enriched relative to the other
diastereomeric pair(s).
[0049] The term "substantially free of other stereoisomers" as used
herein means less than 25% of other stereoisomers, preferably less
than 10% of other stereoisomers, more preferably less than 5% of
other stereoisomers and most preferably less than 2% of other
stereoisomers, or less than "X" % of other stereoisomers (wherein X
is a number between 0 and 100, inclusive) are present.
[0050] The term "stable compounds," as used herein, refers to
compounds which possess stability sufficient to allow for their
manufacture and which maintain the integrity of the compound for a
sufficient period of time to be useful for the purposes detailed
herein (e.g., formulation into therapeutic products, intermediates
for use in production of therapeutic compounds, isolatable or
storable intermediate compounds, treating a disease or condition
responsive to therapeutic agents).
[0051] "D" refers to deuterium. "Stereoisomer" refers to both
enantiomers and diastereomers. "Tert", ".sup.t", and "t-" each
refer to tertiary. "US" refers to the United States of America.
"FDA" refers to Food and Drug Administration. "NDA" refers to New
Drug Application.
[0052] The term "optionally substituted" refers to the optional
replacement of one or more hydrogen atoms with another moiety.
Unless otherwise specified, any hydrogen atom including terminal
hydrogen atoms, can be optionally replaced.
[0053] The term "halo" refers to any of --Cl, --F, --Br, or
--I.
[0054] The term "oxo" refers to .dbd.O.
[0055] The term "alkoxy" refers to --O-alkyl.
[0056] The term "alkylamino" refers to --NH-alkyl.
[0057] The term "dialkylamino" refers to N(alkyl)-alkyl, wherein
the two alkyl moieties are the same or different.
[0058] The term "alkyl" refers to straight or branched alkyl chains
of from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms,
more preferably from 1 to 4 carbon atoms unless otherwise
specified. Examples of straight chained and branched alkyl groups
include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,
tert-butyl, pentyl, hexyl, heptyl and octyl. Alkyl may be
optionally substituted.
[0059] Alkyl or aryl groups that are optionally substituted will
typically contain one to four substituents that are independently
selected. Examples of optional substituents include C.sub.1-7
alkyl, halo, cyano, hydroxyl, carboxy, alkoxy, oxo, amino,
alkylamino, dialkylamino, cycloheteroalkyl, alkylcycloheteroalkyl,
aryl, alkylaryl, heteroaryl, and alkylheteroaryl.
[0060] The term "cycloheteroalkyl" refers to a non-aromatic
monocyclic, bicyclic, tricyclic, spirocyclic, or tetracyclic ring
system which includes one or more heteroatoms such as nitrogen,
oxygen or sulfur in at least one of the rings. Each ring can be
four, five, six, seven or eight-membered. Examples include
tetrahydrofuryl, tetrahydrothiophenyl, morpholino, thiomorpholino,
pyrrolidinyl, piperazinyl, piperidinyl, and thiazolidinyl, along
with the cyclic form of sugars.
[0061] The term "alkylcycloheteroalkyl" refers to a
cycloheteroalkyl group comprising an alkyl substituent. Examples
include 4-methylpiperazin-1-yl and 4-methylpiperidin-1-yl.
[0062] The term "aryl" refers carbocyclic aromatic groups such as
phenyl and naphthyl.
[0063] The term "alkylaryl" refers to an aryl group linked to the
rest of the molecule through an alkyl chain.
[0064] The term "heteroaryl" refers to monocyclic aromatic groups
comprising one or more heteroatoms such as nitrogen, oxygen or
sulfur in the ring, such as imidazolyl, thienyl, furyl, pyridyl,
pyrimidyl, pyranyl, pyrazolyl, pyrrolyl, pyrazinyl, thiazolyl,
oxazolyl, and tetrazolyl. Heteroaryl groups also include fused
polycyclic aromatic ring systems in which at least one ring
comprises one or more heteroatoms such as nitrogen, oxygen or
sulfur. Examples include benzothienyl, benzofuryl, indolyl,
quinolinyl, benzothiazole, benzoxazole, benzimidazole, quinolinyl,
isoquinolinyl and isoindolyl.
[0065] The term "alkylheteroaryl" refers to a heteroaryl group
linked to the rest of the molecule through an alkyl chain.
[0066] The term ".alpha.-amino acid residue" refers to a group of
the general formula --C(O)--CHR--NH-- and includes naturally
occurring and synthetic amino acids in either a D- or
L-configuration.
[0067] Unless otherwise specified, the term ".alpha.-amino acid"
includes .alpha.-amino acids having a (D)-, (L)- or racemic (D,L)
configuration. It is understood that when the variable R.sup.8 is
an .alpha.-amino acid, it is linked to the rest of the molecule
through the carbonyl carbon directly bonded to the .alpha.-carbon
of the amino acid. In accordance with the structure of Formula I,
such a linkage results in the formation of an ester
[0068] Throughout this specification, a variable may be referred to
generally (e.g., "each R") or may be referred to specifically
(e.g., R.sup.1, R.sup.2, R.sup.3, etc.). Unless otherwise
indicated, when a variable is referred to generally, it is meant to
include all specific embodiments of that particular variable.
[0069] The compounds of the invention are represented by Formula
A:
##STR00002##
or a salt, hydrate or solvate thereof, wherein:
[0070] each of R.sup.1a and R.sup.1b is independently selected from
C.sub.1-C.sub.3 alkyl, wherein one or more hydrogen atoms in the
alkyl is optionally replaced with a deuterium atom;
[0071] each of R.sup.2 and R.sup.3 is independently selected from
isopropyl, sec-butyl, and tert-butyl wherein one or more hydrogen
atoms in the isopropyl, sec-butyl, or tert-butyl is optionally
replaced with a deuterium atom;
[0072] R.sup.4 is selected from H, OH and
--O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8
[0073] R.sup.5 is selected from H and
--(CR.sup.6R.sup.7--O).sub.n--R.sup.8, wherein: [0074] R.sup.6 and
R.sup.7 are each independently selected from H, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, and
C.sub.3-C.sub.7 cycloalkyl, or [0075] R.sup.6 and R.sup.7 are taken
together with the carbon to which they are attached to form a
3-7-membered cycloalkyl; [0076] each R.sup.8 is independently
selected from --C(O)H, --C(O)--(C.sub.1-C.sub.7 alkyl),
--P(O)--(OH).sub.2, --S(O)--OH, --S(O).sub.2--OH, and A-R.sup.11,
wherein [0077] A is an .alpha.-amino acid residue; and [0078]
R.sup.11 is selected from H, C.sub.1-C.sub.6 alkyl,
--C(O)--(C.sub.1-C.sub.7 alkyl), A-R.sup.12, [0079] wherein
R.sup.12 is selected from H, C.sub.1-C.sub.6 alkyl, and
--C(O)--(C.sub.1-C.sub.7 alkyl); and n is 0 or 1;
[0080] wherein any alkyl in R.sup.5 is optionally substituted;
[0081] each of Y.sup.1a and Y.sup.1b is independently selected from
H and D;
[0082] R.sup.9 is selected from 2-thienyl, 3-thienyl, thiazol-5-yl,
thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
pyrazin-2-yl, 2-methyl-2H-tetrazol-5-yl,
2-(d.sub.3-methyl)-2H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, and
1-(d.sub.3-methyl)-1H-tetrazol-5-yl; and
[0083] at least one of R.sup.1a, R.sup.1b, R.sup.2, R.sup.3 or Y
variable comprises a deuterium atom.
[0084] Specific embodiments of Formula A include compounds
wherein:
[0085] a) one or both of R.sup.2 and R.sup.3 comprise a deuterium
atom;
[0086] b) each of R.sup.2 and R.sup.3 is independently selected
from --C(CH.sub.3).sub.3, --C(CD.sub.3).sub.3,
--CH(CH.sub.3).sub.2, --CD(CD.sub.3).sub.2,
--CH.sub.2CH.sub.2(CH.sub.3).sub.2, and
--CD.sub.2CD.sub.2(CD.sub.3).sub.2;
[0087] c) one or both of R.sup.1a and R.sup.1b comprise a deuterium
atom;
[0088] d) each of R.sup.1a and R.sup.1b is independently selected
from --CH.sub.3, --CD.sub.3, --CH.sub.2CH.sub.3,
--CD.sub.2CD.sub.3, --CD.sub.2CD.sub.2CD.sub.3, and
--CH.sub.2CH.sub.2CH.sub.3;
[0089] e) R.sup.5 is H, P(O)--(OH).sub.2,
--CH.sub.2--O--P(O)--(OH).sub.2, or a pharmaceutically acceptable
salt thereof;
[0090] f) R.sup.2 is selected from --C(CD.sub.3).sub.3,
--CD(CD.sub.3).sub.2, and --CD.sub.2CD.sub.2(CD.sub.3).sub.2;
or
[0091] g) two or more of the parameters set forth in a) through f)
are met.
[0092] In one embodiment, the compounds of the invention are
represented by Formula I:
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein:
[0093] each of R.sup.1a and R.sup.1b is independently selected from
CH.sub.3, CH.sub.2D, CHD.sub.2, and CD.sub.3;
[0094] each of R.sup.2 and R.sup.3 is independently
--C(CH.sub.3).sub.3, wherein from 1 to 9 hydrogen atoms are
optionally replaced with a deuterium atom;
[0095] R.sup.4 is selected from H, OH and
--O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8
[0096] R.sup.5 is selected from H and
--(CR.sup.6R.sup.7--O).sub.n--R.sup.8, wherein:
[0097] R.sup.6 and R.sup.7 are independently selected from H and
C.sub.1-C.sub.3 alkyl;
[0098] each R.sup.8 is independently selected from an .alpha.-amino
acid, --C(O)H, --C(O)--(C.sub.1-C.sub.7 alkyl), wherein said
C.sub.1-C.sub.7 alkyl is optionally substituted,
--P(O)--(OH).sub.2, and --S(O)--OH;
[0099] n is 0 or 1;
[0100] Y.sup.1a and Y.sup.1b are independently selected from H and
D; and
[0101] at least one of R.sup.1a, R.sup.1b, R.sup.2, R.sup.3 or Y
variable comprises a deuterium atom.
[0102] Specific embodiments of Formula I include a compound
wherein: [0103] i. each of R.sup.1a and R.sup.1b is independently
selected from CH.sub.3 and CD.sub.3; [0104] ii. each of R.sup.2 and
R.sup.3 is independently selected from --C(CH.sub.3).sub.3 and
--C(CD.sub.3).sub.3; [0105] iii. R.sup.2 is --C(CD.sub.3).sub.3;
[0106] iv. Y.sup.1a and Y.sup.1b are the same; [0107] v. each of
Y.sup.1a and Y.sup.1b is deuterium; [0108] vi. R.sup.4 is selected
from H and --O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8; [0109] vii.
R.sup.4 and R.sup.5 are simultaneously H; [0110] viii. each R.sup.6
and each R.sup.7 is H; [0111] ix. each R.sup.8 is independently
selected from an .alpha.-amino acid having (L)-configuration;
--C(O)H; --C(O)--(C.sub.1-C.sub.3 alkyl), wherein said
C.sub.1-C.sub.3 alkyl is optionally substituted with cyano,
hydroxyl, carboxy, alkoxy, amino, alkylamino, dialkylamino,
cycloheteroalkyl, alkyl cycloheteroalkyl, aryl, alkylaryl,
heteroaryl, and alkylheteroaryl; --P(O)--(OH).sub.2; a salt of
--P(O)--(OH).sub.2, wherein the cation is selected from Na.sup.+,
Mg.sup.2+, or ammonium; --S(O)--OH; and a salt of --S(O)--OH
wherein the cation is selected from Na.sup.+, Mg.sup.2+, or
ammonium; [0112] x. each R.sup.8 is independently selected from
L-Serine; L-Lysine; L-Tyrosine; L-Valine; L-Glutamic acid;
L-Aspartic acid; L-3-Pyridylalanine; L-Histidine; --C(O)H;
--C(O)--(C.sub.1-C.sub.3 alkyl); --C(O)CH.sub.2OCH.sub.3;
--C(O)CH.sub.2CH.sub.2OCH.sub.3; --C(O)CH.sub.2CH.sub.2C(O)OH;
--C(O)CH.sub.2CH.sub.2NH.sub.2; --C(O)CH.sub.2CH.sub.2NHCH.sub.3;
--C(O)CH.sub.2CH.sub.2N(CH.sub.3).sub.2;
##STR00004##
[0112] --P(O)--(OH).sub.2; a salt of --P(O)--(OH).sub.2, wherein
the cation is selected from Na.sup.+, K.sup.+ or Ca.sup.2+;
--S(O)--OH; and a salt of --S(O)--OH, wherein the cation is
selected from Na.sup.+, K.sup.+ or Ca.sup.2+; or [0113] xi. two or
more of the above parameters i. through x. are met.
[0114] Example embodiments where two or more of the above
parameters are met include, but are not limited to, the following
particular embodiments.
[0115] In one particular embodiment, R.sup.2 and R.sup.3 are
independently selected from --C(CH.sub.3).sub.3 and
--C(CD.sub.3).sub.3, and R.sup.1a and R.sup.1b are independently
selected from CH.sub.3 and CD.sub.3.
[0116] In another particular embodiment, R.sup.2 is
--C(CD.sub.3).sub.3, and R.sup.1a is CD.sub.3.
[0117] In another particular embodiment, R.sup.2 is
--C(CD.sub.3).sub.3, R.sup.1a is CD.sub.3, and R.sup.1b is
CD.sub.3.
[0118] In another particular embodiment, Y.sup.1a and Y.sup.1b are
the same (i.e., both are simultaneously deuterium or simultaneously
H), and either R.sup.1a and R.sup.1b are independently selected
from CH.sub.3 and CD.sub.3, or R.sup.2 and R.sup.3 are
independently selected from --C(CH.sub.3).sub.3 and
--C(CD.sub.3).sub.3. In a more particular embodiment, Y.sup.1a and
Y.sup.1b are the same (e.g., both are deuterium), R.sup.1a and
R.sup.1b are independently selected from CH.sub.3 and CD.sub.3, and
R.sup.2 and R.sup.3 are independently selected from
--C(CH.sub.3).sub.3 and --C(CD.sub.3).sub.3.
[0119] In yet another particular embodiment, R.sup.4 is selected
from H and --O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8, and either
R.sup.1a and R.sup.1b are independently selected from CH.sub.3 and
CD.sub.3, or R.sup.2 and R.sup.3 are independently selected from
--C(CH.sub.3).sub.3 and --C(CD.sub.3).sub.3. In a more particular
embodiment, R.sup.4 is selected from H and
--O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8, R.sup.1a and R.sup.1b are
independently selected from CH.sub.3 and CD.sub.3, and R.sup.2 and
R.sup.3 are independently selected from --C(CH.sub.3).sub.3 and
--C(CD.sub.3).sub.3.
[0120] In yet another particular embodiment, R.sup.4 is selected
from H and --O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8, and Y.sup.1a
and Y.sup.1b are the same. In a more particular embodiment, R.sup.4
is selected from H and --O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8,
and Y.sup.1a and Y.sup.1b are deuterium. In another more particular
embodiment, R.sup.4 is selected from H and
--O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8, Y.sup.1a and Y.sup.1b are
the same (i.e., both are simultaneously deuterium or simultaneously
H), and either R.sup.1a and R.sup.1b are independently selected
from CH.sub.3 and CD.sub.3 or R.sup.2 and R.sup.3 are independently
selected from --C(CH.sub.3).sub.3 and --C(CD.sub.3).sub.3. In a
most particular embodiment, R.sup.4 is selected from H and
--O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8, Y.sup.1a and Y.sup.1b are
the same (i.e., both are simultaneously deuterium or simultaneously
H), R.sup.1a and R.sup.1b are independently selected from CH.sub.3
and CD.sub.3, and R.sup.2 and R.sup.3 are independently selected
from --C(CH.sub.3).sub.3 and --C(CD.sub.3).sub.3.
[0121] In still another particular embodiment, R.sup.6 and R.sup.7
are each H, either R.sup.1a and R.sup.1b are independently selected
from CH.sub.3 and CD.sub.3, or R.sup.2 and R.sup.3 are
independently selected from --C(CH.sub.3).sub.3 and
--C(CD.sub.3).sub.3. In a more particular embodiment, R.sup.6 and
R.sup.7 are each H, R.sup.1a and R.sup.1b are independently
selected from CH.sub.3 and CD.sub.3, and R.sup.2 and R.sup.3 are
independently selected from --C(CH.sub.3).sub.3 and
--C(CD.sub.3).sub.3.
[0122] In yet another particular embodiment, R.sup.6 and R.sup.7
are each H, and Y.sup.1a and Y.sup.1b are the same. In a more
particular embodiment, R.sup.6 and R.sup.7 are each H, and Y.sup.1a
and Y.sup.1b are deuterium. In an even more particular embodiment,
R.sup.6 and R.sup.7 are each H, Y.sup.1a and Y.sup.1b are the same
(i.e., both are simultaneously deuterium or simultaneously H), and
either R.sup.1a and R.sup.1b are independently selected from
CH.sub.3 and CD.sub.3, or R.sup.2 and R.sup.3 are independently
selected from --C(CH.sub.3).sub.3 and --C(CD.sub.3).sub.3. In a
most particular embodiment, R.sup.6 and R.sup.7 are each H,
Y.sup.1a and Y.sup.1b are the same (e.g., both are deuterium),
R.sup.1a and R.sup.1b are independently selected from CH.sub.3 and
CD.sub.3, and R.sup.2 and R.sup.3 are independently selected from
--C(CH.sub.3).sub.3 and --C(CD.sub.3).sub.3.
[0123] In yet another particular embodiment, R.sup.6 and R.sup.7
are each H, and R.sup.4 is selected from H and
--O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8. In a more particular
embodiment, R.sup.6 and R.sup.7 are each H, R.sup.4 is selected
from H and --O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8, and either
R.sup.1a and R.sup.1b are independently selected from CH.sub.3 and
CD.sub.3 or R.sup.2 and R.sup.3 are independently selected from
--C(CH.sub.3).sub.3 and --C(CD.sub.3).sub.3. In a most particular
embodiment, R.sup.6 and R.sup.7 are each H, R.sup.4 is selected
from H and --O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8, R.sup.1a and
R.sup.1b are independently selected from CH.sub.3 and CD.sub.3, and
R.sup.2 and R.sup.3 are independently selected from
--C(CH.sub.3).sub.3 and --C(CD.sub.3).sub.3.
[0124] In yet another particular embodiment, R.sup.6 and R.sup.7
are each H, R.sup.4 is selected from H and
--O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8, and Y.sup.1a and Y.sup.1b
are the same. In a more particular embodiment, R.sup.6 and each
R.sup.7 are each H, R.sup.4 is selected from H and
--O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8, and Y.sup.1a and Y.sup.1b
are deuterium. In an even more particular embodiment, R.sup.6 and
R.sup.7 are each H, R.sup.4 is selected from H and
--O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8, Y.sup.1a and Y.sup.1b are
the same (i.e., both are simultaneously deuterium or simultaneously
H), and either R.sup.1a and R.sup.1b are independently selected
from CH.sub.3 and CD.sub.3, or R.sup.2 and R.sup.3 are
independently selected from --C(CH.sub.3).sub.3 and
--C(CD.sub.3).sub.3. In a most particular embodiment, R.sup.6 and
R.sup.7 are each H, R.sup.4 is selected from H and
--O--(CR.sup.6R.sup.7--O).sub.n--R.sup.8, Y.sup.1a and Y.sup.1b are
the same (i.e., both are simultaneously deuterium or simultaneously
H), R.sup.1a and R.sup.1b are independently selected from CH.sub.3
and CD.sub.3, and R.sup.2 and R.sup.3 are independently selected
from --C(CH.sub.3).sub.3 and --C(CD.sub.3).sub.3.
[0125] In another set of embodiments, for any one of the above
listed embodiments, R.sup.8 is independently selected from an
.alpha.-amino acid having (L)-configuration; --C(O)H;
--C(O)--(C.sub.1-C.sub.3 alkyl), wherein said C.sub.1-C.sub.3 alkyl
is optionally substituted with cyano, hydroxyl, carboxy, alkoxy,
amino, alkylamino, dialkylamino, cycloheteroalkyl, alkyl
cycloheteroalkyl, aryl, alkylaryl, heteroaryl, and alkylheteroaryl;
--P(O)--(OH).sub.2; a salt of --P(O)--(OH).sub.2 wherein the cation
is selected from Na.sup.+, K.sup.+, or Ca.sup.2+; --S(O)--OH; and a
salt of --S(O)--OH wherein the cation is selected from Na.sup.+,
K.sup.+, or Ca.sup.2+.
[0126] In a further set of embodiments, for any one of the above
listed embodiments, R.sup.8 is independently selected from
L-Serine; L-Lysine; L-Tyrosine; L-Valine; L-Glutamic acid;
L-Aspartic acid; L-3-Pyridylalanine; L-Histidine; --C(O)H;
--C(O)--(C.sub.1-C.sub.3 alkyl); --C(O)CH.sub.2OCH.sub.3;
--C(O)CH.sub.2CH.sub.2OCH.sub.3; --C(O)CH.sub.2CH.sub.2C(O)OH;
--C(O)CH.sub.2CH.sub.2NH.sub.2; --C(O)CH.sub.2CH.sub.2NHCH.sub.3;
--C(O)CH.sub.2CH.sub.2N(CH.sub.3).sub.2;
##STR00005##
--P(O)--(OH).sub.2; a salt of --P(O)--(OH).sub.2 wherein the cation
is selected from Na.sup.+, Mg.sup.2+, or ammonium; --S(O)--OH; and
a salt of --S(O)--OH wherein the cation is selected from Na.sup.+,
Mg.sup.2+, or ammonium; and
[0127] In yet another particular embodiment, R.sup.4 and R.sup.5
are simultaneously H, and either R.sup.1a and R.sup.1b are
independently selected from CH.sub.3 and CD.sub.3, or R.sup.2 and
R.sup.3 are independently selected from --C(CH.sub.3).sub.3 and
--C(CD.sub.3).sub.3. In a more particular embodiment, R.sup.4 and
R.sup.5 are simultaneously H, R.sup.1a and R.sup.1b are
independently selected from CH.sub.3 and CD.sub.3, and R.sup.2 and
R.sup.3 are independently selected from --C(CH.sub.3).sub.3 and
--C(CD.sub.3).sub.3.
[0128] In another particular embodiment, R.sup.4 and R.sup.5 are
simultaneously H, and Y.sup.1a and Y.sup.1b are the same. In a more
particular embodiment, R.sup.4 and R.sup.5 are simultaneously H,
and Y.sup.1a and Y.sup.1b are simultaneously deuterium. In an even
more particular embodiment, R.sup.4 and R.sup.5 are simultaneously
H, Y.sup.1a and Y.sup.1b are the same (i.e., both are
simultaneously deuterium or simultaneously H) and either R.sup.1a
and R.sup.1b are independently selected from CH.sub.3 and CD.sub.3,
or R.sup.2 and R.sup.3 are independently selected from
--C(CH.sub.3).sub.3 and --C(CD.sub.3).sub.3. In a most particular
embodiment, R.sup.4 and R.sup.5 are simultaneously H, Y.sup.1a and
Y.sup.1b are the same (i.e., both are simultaneously deuterium or
simultaneously H), R.sup.1a and R.sup.1b are independently selected
from CH.sub.3 and CD.sub.3, and R.sup.2 and R.sup.3 are
independently selected from --C(CH.sub.3).sub.3 and
--C(CD.sub.3).sub.3.
[0129] In yet another embodiment, the compound is a compound of the
Formula Ia:
##STR00006##
or a pharmaceutically acceptable salt thereof, and is selected from
any one of the compounds set forth in Table 1 below.
TABLE-US-00001 TABLE 1 Exemplary Embodiments of Formula Ia Compound
R.sup.1a R.sup.1b R.sup.2 R.sup.3 Y.sup.1a Y.sup.1b 101 CD.sub.3
CH.sub.3 C(CH.sub.3).sub.3 C(CH.sub.3).sub.3 H H 102 CH.sub.3
CD.sub.3 C(CH.sub.3).sub.3 C(CH.sub.3).sub.3 H H 103 CD.sub.3
CD.sub.3 C(CH.sub.3).sub.3 C(CH.sub.3).sub.3 H H 104 CH.sub.3
CH.sub.3 C(CD.sub.3).sub.3 C(CH.sub.3).sub.3 H H 105 CH.sub.3
CH.sub.3 C(CH.sub.3).sub.3 C(CD.sub.3).sub.3 H H 106 CH.sub.3
CH.sub.3 C(CD.sub.3).sub.3 C(CD.sub.3).sub.3 H H 107 CH.sub.3
CH.sub.3 C(CH.sub.3).sub.3 C(CH.sub.3).sub.3 D D 108 CD.sub.3
CH.sub.3 C(CH.sub.3).sub.3 C(CH.sub.3).sub.3 D D 109 CH.sub.3
CD.sub.3 C(CH.sub.3).sub.3 C(CH.sub.3).sub.3 D D 110 CD.sub.3
CD.sub.3 C(CH.sub.3).sub.3 C(CH.sub.3).sub.3 D D 111 CH.sub.3
CH.sub.3 C(CD.sub.3).sub.3 C(CH.sub.3).sub.3 D D 112 CH.sub.3
CH.sub.3 C(CH.sub.3).sub.3 C(CD.sub.3).sub.3 D D 113 CH.sub.3
CH.sub.3 C(CD.sub.3).sub.3 C(CD.sub.3).sub.3 D D 114 CD.sub.3
CH.sub.3 C(CD.sub.3).sub.3 C(CH.sub.3).sub.3 H H 115 CD.sub.3
CH.sub.3 C(CH.sub.3).sub.3 C(CD.sub.3).sub.3 H H 116 CD.sub.3
CH.sub.3 C(CD.sub.3).sub.3 C(CD.sub.3).sub.3 H H 117 CH.sub.3
CD.sub.3 C(CD.sub.3).sub.3 C(CH.sub.3).sub.3 H H 118 CH.sub.3
CD.sub.3 C(CH.sub.3).sub.3 C(CD.sub.3).sub.3 H H 119 CH.sub.3
CD.sub.3 C(CD.sub.3).sub.3 C(CD.sub.3).sub.3 H H 120 CD.sub.3
CD.sub.3 C(CD.sub.3).sub.3 C(CH.sub.3).sub.3 H H 121 CD.sub.3
CD.sub.3 C(CH.sub.3).sub.3 C(CD.sub.3).sub.3 H H 122 CD.sub.3
CD.sub.3 C(CD.sub.3).sub.3 C(CD.sub.3).sub.3 H H 123 CD.sub.3
CH.sub.3 C(CD.sub.3).sub.3 C(CH.sub.3).sub.3 D D 124 CD.sub.3
CH.sub.3 C(CH.sub.3).sub.3 C(CD.sub.3).sub.3 D D 125 CD.sub.3
CH.sub.3 C(CD.sub.3).sub.3 C(CD.sub.3).sub.3 D D 126 CH.sub.3
CD.sub.3 C(CD.sub.3).sub.3 C(CH.sub.3).sub.3 D D 127 CH.sub.3
CD.sub.3 C(CH.sub.3).sub.3 C(CD.sub.3).sub.3 D D 128 CH.sub.3
CD.sub.3 C(CD.sub.3).sub.3 C(CD.sub.3).sub.3 D D 129 CD.sub.3
CD.sub.3 C(CD.sub.3).sub.3 C(CH.sub.3).sub.3 D D 130 CD.sub.3
CD.sub.3 C(CH.sub.3).sub.3 C(CD.sub.3).sub.3 D D 131 CD.sub.3
CD.sub.3 C(CD.sub.3).sub.3 C(CD.sub.3).sub.3 D D
[0130] In yet another embodiment, the compound is a compound of the
Formula Ib:
##STR00007##
or a pharmaceutically acceptable salt thereof, wherein:
[0131] each of R.sup.1a and R.sup.1b is independently selected from
--CD.sub.3 and --CH.sub.3;
[0132] R.sup.3 is selected from --C(CD.sub.3).sub.3 and
--C(CH.sub.3).sub.3; and
[0133] Y.sup.1a and Y.sup.1b are the same and are selected from H
and D.
[0134] In yet another embodiment, the compound is represented by
Formula Ic:
##STR00008##
or a pharmaceutically acceptable salt thereof, wherein:
[0135] each of R.sup.1a and R.sup.1b is independently selected from
--CD.sub.3 and --CH.sub.3;
[0136] R.sup.3 is selected from --C(CD.sub.3).sub.3 and
--C(CH.sub.3).sub.3;
[0137] R.sup.5 is --P(O)--(OH).sub.2, --CH.sub.2--P(O)--(OH).sub.2,
or a pharmaceutically acceptable salt of either of the foregoing;
and
[0138] Y.sup.1a and Y.sup.1b are the same and are selected from H
and D.
[0139] In still another embodiment, the compound of this invention
is selected from the following:
##STR00009## ##STR00010## ##STR00011##
or a pharmaceutically acceptable salt of any of the foregoing.
[0140] In yet another embodiment, the compound of the invention is
selected from the following:
##STR00012##
pharmaceutically acceptable salt of either of the foregoing.
[0141] In an even more specific embodiment, the compound is
selected from Compound 114, Compound 120, Compound 122 and Compound
131.
[0142] In another set of embodiments, any atom not designated as
deuterium in any of the embodiments set forth above is present at
its natural isotopic abundance.
[0143] The synthesis of compounds of Formula I can be readily
achieved by synthetic chemists of ordinary skill. Relevant
procedures and intermediates are disclosed, for instance, in U.S.
Pat. No. 5,849,911; PCT Intl Publication WO 97/46514; Bold, G et
al., J Med Chem 1998, 41:3387; Xu, Z et al., Org Process Res Dev
2002, 6:323; and PCT Intl Publication WO 2006/014282.
[0144] Such methods can be carried out utilizing corresponding
deuterated and optionally, other isotope-containing reagents and/or
intermediates to synthesize the compounds delineated herein, or
invoking standard synthetic protocols known in the art for
introducing isotopic atoms to a chemical structure. Certain
intermediates can be used with or without purification (e.g.,
filtration, distillation, sublimation, crystallization,
trituration, solid phase extraction, and chromatography).
EXEMPLARY SYNTHESIS
[0145] A convenient method for synthesizing compounds of Formula Ia
is depicted in Scheme 1.
[0146] Scheme 1. General Route for Preparing Compounds of Formula
Ia where R.sup.1a=R.sup.1b, R.sup.2=R.sup.3.
##STR00013## ##STR00014##
[0147] Aldehyde X is treated with the commercially available
t-butoxycarbonylhydrazide (XI) to produce a BOC-protected hydrazone
intermediate XII, which is then reduced using either hydrogen or
deuterium gas to form the appropriate BOC-protected hydrazide XIII.
The BOC-protected hydrazide XIII is then treated with the
commercially available epoxide (XIV) to produce XV, which is then
deprotected with hydrochloric acid to produce XVI. The appropriate
carbamate derivative of tert-leucine XVII is treated with XVI in
the presence of
O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TPTU) to produce a compound of Formula Ia.
[0148] The use of a different protecting group on either XI or XIV
together with differential deprotection, as disclosed in Zhang, H
et al., J Labelled Compounds Radiopharm 2005, 48:1041-1047, allows
for the synthesis of compounds of Formula Ia that are not
symmetrically substituted. In this manner, different deuteration
patterns for R.sup.1a and R.sup.1b; and/or R.sup.2 and R.sup.3 can
be achieved, as depicted below in Schemes 1b and 1c.
[0149] Scheme 1b. General Route where R.sup.1a.noteq.R.sup.1b,
R.sup.2.noteq.R.sup.3.
##STR00015##
[0150] Scheme 1c. General Route for Incorporating Different R and Y
Groups.
##STR00016## ##STR00017##
[0151] The undeuterated aldehyde X useful in Schemes 1 and 1c above
is commercially available. The deuterated version of aldehyde X is
synthesized according to the procedure described in Thompson, A F
et al., JACS 1939, 61:1374-1376 or in Scott, C A et al., Syn Comm
1976, 6:135-139, as depicted below in Scheme 2.
[0152] Scheme 2. Preparation of Deuterated Intermediate X
##STR00018##
[0153] Alternatively, the undeuterated aldehyde X may be oxidized
to the carboxylic acid, converted to the Weinreb amide via the acyl
chloride, and reduced with LiAlD.sub.4 to afford the desired
deuterated aldehyde as set forth below in Scheme 2b.
[0154] Scheme 2b. Alternative Preparation of Deuterated
Intermediate X.
##STR00019##
[0155] Deuterated versions of the carbamate derivative of
tert-leucine XVII are produced according to Schemes 3 through
5.
[0156] Scheme 3. Route to Prepare Deuterated tert-Leucine
(XIII).
##STR00020##
[0157] As shown in Scheme 3, tert-leucine XXIII, wherein R.sup.2
and/or R.sup.3 are --C(CD.sub.3).sub.3, may be prepared starting
from the commercially available d.sub.9-pivalic acid (XX). XX is
reduced to the alcohol XXI with lithium aluminum hydride as
described in Brainard, R L et al., Organometallics 1986,
5:1481-1490. This alcohol XXI is oxidized to the aldehyde XXII by
any one of a number of mild conditions (see, for example,
Herrerias, C I et al., Tet Lett 2005, 47:13-17). The aldehyde XXII
is converted to the tert-leucine XXIII using an asymmetric Strecker
synthesis as disclosed by Boesten, W H J et al., Org Lett 2001,
3:1121-1124. An alternate asymmetric Strecker synthesis has been
disclosed by Davis, F A et al., J Org Chem 1996, 61:440-441.
[0158] Scheme 4. Conversion of Deuterated tert-Leucine to
Corresponding Carbamate.
##STR00021##
[0159] As shown in Scheme 4, deuterated tert-leucine XXV is reacted
with the appropriate chloromethylformate XXVI as described in
United States Patent Application Publication 2005131017, to produce
the desired carbamate derivative of tert-leucine XVII, which is
utilized in Scheme 1.
[0160] Scheme 5. Conversion of Deuterated t-Butyl Chloride to
Corresponding Pivalaldehyde (XXII).
##STR00022##
[0161] In Scheme 5, a deuterated t-butyl chloride is converted to
the corresponding pivalaldehyde (XXII) by refluxing in anhydrous
ether in the presence of magnesium and iodine, followed by addition
of anhydrous dimethylformamide (DMF). The pivalaldehyde (XXII) is
reacted with (R)-phenylglycine amide and NaCN in aqueous acetic
acid to produce nitrile (XXIIa). The nitrile (XXIIa) is hydrolyzed
with sulfuric acid to produce amide (XXIIb), which is then
hydrogenated over palladium on carbon to produce amide (XXIIc).
Amide (XXIIc) is hydrolyzed with hydrochloric acid to produce the
corresponding carboxylic acid (XXV), which is then reacted with a
deuterated methyl chloroformate in the presence of NaOH to produce
the deuterated intermediate XVII.
[0162] A number of novel intermediates can be used to prepare
compounds of Formula A. Thus, the invention also provides such a
compound which is selected from the following:
##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027##
##STR00028## ##STR00029## ##STR00030## ##STR00031##
##STR00032##
[0163] Under certain synthetic conditions, Compounds 103, 104, 106,
111, 113, 114, 120, 121, 122, 123, 129, and 131 have been prepared
with an isotopic abundance at each position indicated as "D" of at
least about 75%. Under other synthetic conditions, Compounds 103,
104, 106, 111, 113, 114, 120, 121, 122, 123, 129, and 131 have been
prepared with an isotopic abundance at each position indicated as
"D" of greater than about 95%.
[0164] Prodrugs of compounds of the invention represented by
Formula A where R.sup.5 is --P(O)--(OH).sub.2 or a salt thereof may
be prepared according to the procedure outlined in WO 2001000635A.
Prodrugs of the invention represented by Formula A where R.sup.5 is
--(CR.sup.6R.sup.7--O).sub.n--R.sup.8, wherein: R.sup.6 and R.sup.7
are H and each R.sup.8 is --P(O)--(OH).sub.2 or a salt thereof, may
be prepared according to the procedures of Safadi, M et al.,
Pharmaceutical Research, 1993, 10(9): 1350. Other suitable methods
for preparing prodrugs of the compounds of the invention can be
found in PCT Intl Publication WO 2006/014282.
[0165] In other embodiments, a compound of this invention has at
least 52.5% deuterium incorporation, at least 60% deuterium
incorporation, at least 67.5% deuterium incorporation, at least 75%
deuterium incorporation, at least 82.5% deuterium incorporation, at
least 90% deuterium incorporation, or at least 95% deuterium
incorporation at each position designated as deuterium in a
compound of this invention. The compound of the invention may be in
an amount of, for example, at least 100 mg, such as at least 200
mg, preferably at least 400 mg, more preferably at least 500 mg and
optionally up to 10 Kg.
[0166] The specific approaches and compounds shown above are not
intended to be limiting. The chemical structures in the schemes
herein depict variables that are hereby defined commensurately with
chemical group definitions (moieties, atoms, etc.) of the
corresponding position in the compound formulae herein, whether
identified by the same variable name (i.e., R.sup.1, R.sup.2,
R.sup.3, etc.) or not. The suitability of a chemical group in a
compound structure for use in the synthesis of another compound is
within the knowledge of one of ordinary skill in the art.
Additional methods of synthesizing compounds of Formula I and their
synthetic precursors, including those within routes not explicitly
shown in schemes herein, are within the means of chemists of
ordinary skill in the art. Methods for optimizing reaction
conditions and, if necessary, minimizing competing by-products, are
known in the art. In addition to the synthetic references cited
herein, reaction schemes and protocols may be determined by the
skilled artisan by use of commercially available
structure-searchable database software, for instance,
SciFinder.RTM. (CAS division of the American Chemical Society),
STN.RTM. (CAS division of the American Chemical Society), CrossFire
Beilstein.RTM. (Elsevier MDL), or internet search engines such as
Google.RTM. or keyword databases such as the US Patent and
Trademark Office text database.
[0167] The methods described herein may also additionally include
steps, either before or after the steps described specifically
herein, to add or remove suitable protecting groups in order to
ultimately allow synthesis of the compounds herein. In addition,
various synthetic steps may be performed in an alternate sequence
or order to give the desired compounds. Synthetic chemistry
transformations and protecting group methodologies (protection and
deprotection) useful in synthesizing the applicable compounds are
known in the art and include, for example, those described in
Larock R, Comprehensive Organic Transformations, VCH Publishers
(1989); Greene T W et al., Protective Groups in Organic Synthesis,
3rd Ed., John Wiley and Sons (1999); Fieser L et al., Fieser and
Fieser's Reagents for Organic Synthesis, John Wiley and Sons
(1994); and Paquette L, ed., Encyclopedia of Reagents for Organic
Synthesis, John Wiley and Sons (1995) and subsequent editions
thereof.
[0168] Combinations of substituents and variables envisioned by
this invention are only those that result in the formation of
stable compounds.
Compositions
[0169] The invention also provides pyrogen-free compositions
comprising an effective amount of a compound of any one of Formulae
A, I, Ia, Ib or Ic (e.g., including any of the formulae herein), or
a pharmaceutically acceptable salt of said compound; and an
acceptable carrier. Preferably, a composition of this invention is
formulated for pharmaceutical use ("a pharmaceutical composition"),
wherein the carrier is a pharmaceutically acceptable carrier. The
carrier(s) are "acceptable" in the sense of being compatible with
the other ingredients of the formulation and, in the case of a
pharmaceutically acceptable carrier, not deleterious to the
recipient thereof in an amount used in the medicament.
[0170] Pharmaceutically acceptable carriers, adjuvants and vehicles
that may be used in the pharmaceutical compositions of this
invention include, but are not limited to, ion exchangers, alumina,
aluminum stearate, lecithin, serum proteins, such as human serum
albumin, buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat.
[0171] If required, the solubility and bioavailability of the
compounds of the present invention in pharmaceutical compositions
may be enhanced by methods well-known in the art. One method
includes the use of lipid excipients in the formulation. See "Oral
Lipid-Based Formulations: Enhancing the Bioavailability of Poorly
Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences)," David
J. Hauss, ed. Informa Healthcare, 2007; and "Role of Lipid
Excipients in Modifying Oral and Parenteral Drug Delivery: Basic
Principles and Biological Examples," Kishor M. Wasan, ed.
Wiley-Interscience, 2006.
[0172] Another known method of enhancing bioavailability is the use
of an amorphous form of a compound of this invention optionally
formulated with a poloxamer, such as LUTROL.TM. and PLURONIC.TM.
(BASF Corporation), or block copolymers of ethylene oxide and
propylene oxide. See U.S. Pat. No. 7,014,866; and United States
patent publications 20060094744 and 20060079502.
[0173] The pharmaceutical compositions of the invention include
those suitable for oral, rectal, nasal, topical (including buccal
and sublingual), pulmonary, vaginal or parenteral (including
subcutaneous, intramuscular, intravenous and intradermal)
administration. In certain embodiments, the compound of the
formulae herein is administered transdermally (e.g., using a
transdermal patch or iontophoretic techniques). Other formulations
may conveniently be presented in unit dosage form, e.g., tablets,
sustained release capsules, and in liposomes, and may be prepared
by any methods well known in the art of pharmacy. See, for example,
Remington's Pharmaceutical Sciences, Mack Publishing Company,
Philadelphia, Pa. (17th ed. 1985).
[0174] Such preparative methods include the step of bringing into
association with the molecule to be administered ingredients such
as the carrier that constitutes one or more accessory ingredients.
In general, the compositions are prepared by uniformly and
intimately bringing into association the active ingredients with
liquid carriers, liposomes or finely divided solid carriers, or
both, and then, if necessary, shaping the product.
[0175] In certain embodiments, the compound is administered orally.
Compositions of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
sachets, or tablets each containing a predetermined amount of the
active ingredient; a powder or granules; a solution or a suspension
in an aqueous liquid or a non-aqueous liquid; an oil-in-water
liquid emulsion; a water-in-oil liquid emulsion; packed in
liposomes; or as a bolus, etc. Soft gelatin capsules can be useful
for containing such suspensions, which may beneficially increase
the rate of compound absorption.
[0176] In the case of tablets for oral use, carriers that are
commonly used include lactose and corn starch. Lubricating agents,
such as magnesium stearate, are also typically added. For oral
administration in a capsule form, useful diluents include lactose
and dried cornstarch. When aqueous suspensions are administered
orally, the active ingredient is combined with emulsifying and
suspending agents. If desired, certain sweetening and/or flavoring
and/or coloring agents may be added.
[0177] Compositions suitable for oral administration include
lozenges comprising the ingredients in a flavored basis, usually
sucrose and acacia or tragacanth; and pastilles comprising the
active ingredient in an inert basis such as gelatin and glycerin,
or sucrose and acacia.
[0178] Compositions suitable for parenteral administration include
aqueous and non-aqueous sterile injection solutions which may
contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents. The
formulations may be presented in unit-dose or multi-dose
containers, for example, sealed ampules and vials, and may be
stored in a freeze dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example water for
injections, immediately prior to use. Extemporaneous injection
solutions and suspensions may be prepared from sterile powders,
granules and tablets.
[0179] Such injection solutions may be in the form, for example, of
a sterile injectable aqueous or oleaginous suspension. This
suspension may be formulated according to techniques known in the
art using suitable dispersing or wetting agents (such as, for
example, Tween 80) and suspending agents. The sterile injectable
preparation may also be a sterile injectable solution or suspension
in a non-toxic parenterally-acceptable diluent or solvent, for
example, as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are mannitol, water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose, any bland fixed oil
may be employed including synthetic mono- or diglycerides. Fatty
acids, such as oleic acid and its glyceride derivatives are useful
in the preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions
or suspensions may also contain a long-chain alcohol diluent or
dispersant.
[0180] The pharmaceutical compositions of this invention may be
administered in the form of suppositories for rectal
administration. These compositions can be prepared by mixing a
compound of this invention with a suitable non-irritating excipient
which is solid at room temperature but liquid at the rectal
temperature and therefore will melt in the rectum to release the
active components. Such materials include, but are not limited to,
cocoa butter, beeswax and polyethylene glycols.
[0181] The pharmaceutical compositions of this invention may be
administered by nasal aerosol or inhalation. Such compositions are
prepared according to techniques well-known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons,
and/or other solubilizing or dispersing agents known in the art.
See, e.g.: Rabinowitz J D and Zaffaroni A C, U.S. Pat. No.
6,803,031, assigned to Alexza Molecular Delivery Corporation.
[0182] Topical administration of the pharmaceutical compositions of
this invention is especially useful when the desired treatment
involves areas or organs readily accessible by topical application.
For topical application topically to the skin, the pharmaceutical
composition should be formulated with a suitable ointment
containing the active components suspended or dissolved in a
carrier. Carriers for topical administration of the compounds of
this invention include, but are not limited to, mineral oil, liquid
petroleum, white petroleum, propylene glycol, polyoxyethylene
polyoxypropylene compound, emulsifying wax, and water.
Alternatively, the pharmaceutical composition can be formulated
with a suitable lotion or cream containing the active compound
suspended or dissolved in a carrier. Suitable carriers include, but
are not limited to, mineral oil, sorbitan monostearate, polysorbate
60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl
alcohol, and water. The pharmaceutical compositions of this
invention may also be topically applied to the lower intestinal
tract by rectal suppository formulation or in a suitable enema
formulation. Topically-transdermal patches and iontophoretic
administration are also included in this invention.
[0183] Application of the patient therapeutics may be local, so as
to be administered at the site of interest. Various techniques can
be used for providing the patient compositions at the site of
interest, such as injection, use of catheters, trocars,
projectiles, pluronic gel, stents, sustained drug release polymers
or other device which provides for internal access.
[0184] Thus, according to yet another embodiment, the compounds of
this invention may be incorporated into compositions for coating an
implantable medical device, such as prostheses, artificial valves,
vascular grafts, stents, or catheters. Suitable coatings and the
general preparation of coated implantable devices are known in the
art and are exemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and
5,304,121. The coatings are typically biocompatible polymeric
materials such as a hydrogel polymer, polymethyldisiloxane,
polycaprolactone, polyethylene glycol, polylactic acid, ethylene
vinyl acetate, and mixtures thereof. The coatings may optionally be
further covered by a suitable topcoat of fluorosilicone,
polysaccharides, polyethylene glycol, phospholipids or combinations
thereof to impart controlled release characteristics in the
composition. Coatings for invasive devices are to be included
within the definition of pharmaceutically acceptable carrier,
adjuvant or vehicle, as those terms are used herein.
[0185] According to another embodiment, the invention provides a
method of coating an implantable medical device comprising the step
of contacting said device with the coating composition described
above. It will be obvious to those skilled in the art that the
coating of the device will occur prior to implantation into a
mammal.
[0186] According to another embodiment, the invention provides a
method of impregnating an implantable drug release device
comprising the step of contacting said drug release device with a
compound or composition of this invention. Implantable drug release
devices include, but are not limited to, biodegradable polymer
capsules or bullets, non-degradable, diffusible polymer capsules
and biodegradable polymer wafers.
[0187] According to another embodiment, the invention provides an
implantable medical device coated with a compound or a composition
comprising a compound of this invention, such that said compound is
therapeutically active.
[0188] According to another embodiment, the invention provides an
implantable drug release device impregnated with or containing a
compound or a composition comprising a compound of this invention,
such that said compound is released from said device and is
therapeutically active.
[0189] Where an organ or tissue is accessible because of removal
from the patient, such organ or tissue may be bathed in a medium
containing a composition of this invention, a composition of this
invention may be painted onto the organ, or a composition of this
invention may be applied in any other convenient way.
[0190] In another embodiment, a composition of this invention
further comprises a second therapeutic agent. In one embodiment,
the second therapeutic agent is one or more additional compounds of
the invention. In a particular embodiment, each of the two or more
compounds of the invention present in such compositions differs
from all others in the positions of isotopic enrichment. Commonly,
such a composition comprises three, four, five or more different
compounds of this invention.
[0191] In another embodiment, the second therapeutic agent may be
selected from any compound or therapeutic agent known to have or
that demonstrates advantageous properties when administered with a
compound having the same mechanism of action as atazanavir. Such
agents include those indicated as being useful in combination with
atazanavir, including but not limited to, those described in PCT
publications WO 2003020206, WO 2005058248, WO 2006060731 and WO
2005027855.
[0192] Preferably, the second therapeutic agent is an agent useful
in the treatment or prevention of HIV infection (i.e., an
antiretroviral agent).
[0193] In one embodiment, the second therapeutic agent is selected
from other anti-retroviral agents including, but not limited to, a
second HIV protease inhibitor (e.g., amprenavir, fosamprenavir,
tipranavir, indinavir, saquinavir, lopinavir, ritonavir, darunavir,
or nelfinavir), a non-nucleoside reverse transcriptase inhibitor
("NNRTI") (e.g., etravirine, delavirdine, efavirenz, nevirapine, or
rilpivirine), a nucleoside/nucleotide reverse transcriptase
inhibitor ("NRTI") (e.g., zidovudine, lamivudine, emtricitabine,
tenofovir disoproxil fumarate, didanosine, stavudine, abacavir,
racivir, amdoxovir, apricitabine, entecavir, adefovir or
elvucitabine) a viral entry inhibitor (e.g., enfuvirtide,
maraviroc, vicriviroc, PRO 140, or TNX-355), an integrase inhibitor
(e.g., raltegravir, or elvitegravir), an immune based
antiretroviral agent (e.g., immunitin, proleukin, remune, BAY
50-4798 or IR103), a viral maturation inhibitor (e.g., bevirimat),
a cellular inhibitor (e.g., droxia or hydroxyurea), or combinations
of two or more of the above.
[0194] In a more specific embodiment, the second therapeutic agent
is selected from ritonavir, efavirenz, didanosine, tenofovir
disoproxil, nelfinavir mesilate, amprenavir, raltegravir,
saquinavir, lopinavir, nevirapine, emtricitabine, abacavir,
lamivudine, zidovudine, maraviroc, stavudine, darunavir,
fosamprenavir, vicriviroc, pharmaceutically acceptable salts of any
of the foregoing, and combinations thereof.
[0195] In an even more specific embodiment, the second therapeutic
agent is selected from ritonavir, efavirenz, didanosine,
raltegravir, tenofovir disoproxil lamivudine, abacavir, zidovudine,
emtricitabine, efavirenz, pharmaceutically acceptable salts of any
of the foregoing, and combinations thereof. In another specific
embodiment, the compositions of this invention comprise a compound
of any one of Formulae A, I, Ia, Ib, or Ic, and two to three of the
second therapeutic agents set forth above in this paragraph. In an
even more specific embodiment, the compositions of this invention
comprise a compound of any one of Formulae A, I, Ia, Ib, or Ic, and
two of the second therapeutic agents set forth above in this
paragraph.
[0196] In another embodiment, the invention provides separate
dosage forms of a compound of this invention and one or more of any
of the above-described second therapeutic agents, wherein the
compound and second therapeutic agent are associated with one
another. The term "associated with one another" as used herein
means that the separate dosage forms are packaged together or
otherwise attached to one another such that it is readily apparent
that the separate dosage forms are intended to be sold and
administered together (within less than 24 hours of one another,
consecutively or simultaneously).
[0197] In yet another embodiment the invention provides a
pharmaceutical composition comprising an effective amount of a
compound of any one of Formulae A, I, Ia, Ib or Ic, the
administration of which to a test subject results in a serum
terminal elimination half-life of the compound that is greater than
the serum terminal elimination half-life of atazanavir when
atazanavir is administered to an equivalent test subject in a
pharmaceutical composition comprising a molar equivalent amount of
atazanavir and that is administered in the same dosing regimen as
the compound of any one of Formulae A, I, Ia, Ib or Ic. In other
embodiments, the serum terminal elimination half-life of a compound
of any one of Formulae A, I, Ia, Ib or Ic is at least 110%, 120%,
130%, 140%, 150% or 160% or more of the serum terminal elimination
half-life of atazanavir produced by a molar equivalent atazanavir
composition administered in the same dosing regimen. In a more
specific embodiment, the compound of any one of Formulae A, I, Ia,
Ib or Ic is administered in a single dose.
[0198] In a related embodiment, the invention provides a
pharmaceutical composition comprising an effective amount of a
compound of any one of Formulae A, I, Ia, Ib or Ic, or a
pharmaceutically acceptable salt thereof, wherein the serum
terminal elimination half-life of the compound following
administration of a single dose of the composition to a test
subject is greater than 5.0 hours, greater than 6.0 hours, greater
than 7.0 hours or greater than 8.0 hours.
[0199] In another embodiment, the invention provides a
pharmaceutical composition comprising an effective amount of a
compound of any one of Formulae A, I, Ia, Ib or Ic, the
administration of which to a test subject results in an
AUC.sub.0-.tau. (where .tau.=dosing interval) of the compound that
is greater than the AUC.sub.0-.tau. of atazanavir when atazanavir
is administered to an equivalent test subject in a molar equivalent
pharmaceutical composition and that is administered in the same
dosing regimen as the compound of any one of Formulae A, I, Ia, Ib
or Ic. In other embodiments, the AUC.sub.0-.tau. produced by a
composition of this invention is at least 120%, 130%, 140%, 150%,
160% or more of the AUC.sub.0-.tau. produced by a molar equivalent
atazanavir composition administered in the same dosing regimen. In
a more specific embodiment, the compound of any one of Formulae A,
I, Ia, Ib or Ic is administered once-daily.
[0200] In another embodiment, the invention provides a
pharmaceutical composition comprising an effective amount of a
compound of any one of Formulae A, I, Ia, Ib or Ic, the oral
administration of which to a test subject results in a maximum
serum concentration of the compound (C.sub.max) that is greater
than the maximum serum concentration of atazanavir when atazanavir
is orally administered to an equivalent test subject in a molar
equivalent pharmaceutical composition and that is administered in
the same dosing regimen as the compound of any one of Formulae A,
I, Ia, Ib or Ic. In a related embodiment, the maximum serum
concentration a compound of any one of Formulae A, I, Ia, Ib or Ic
produced by oral administration of a composition of this invention
is at least 120%, 125%, 130%, 135%, or more than the maximum serum
concentration of atazanavir produced by oral administration of a
molar equivalent atazanavir composition administered in the same
dosing regimen. In a more specific embodiment, the compound of any
one of Formulae A, I, Ia, Ib or Ic is administered once daily. In
another embodiment, the invention provides a pharmaceutical
composition comprising an effective amount of a compound of any one
of Formulae A, I, Ia, Ib or Ic, the oral administration of which to
a test subject results in a minimum serum concentration of the
compound (C.sub.min) that is greater than the minimum serum
concentration of atazanavir when atazanavir is orally administered
to an equivalent test subject in a molar equivalent pharmaceutical
composition and that is administered in the same dosing regimen as
the compound of any one of Formulae A, I, Ia, Ib or Ic. In a
related embodiment, the minimum serum concentration a compound of
any one of Formulae A, I, Ia, Ib or Ic produced by oral
administration of a composition of this invention is at least 125%,
150%, 175%, 200%, or more than the minimum serum concentration of
atazanavir produced by oral administration of a molar equivalent
atazanavir composition administered in the same dosing regimen. In
a more specific embodiment, the compound of any one of Formulae A,
I, Ia, Ib or Ic is administered once daily.
[0201] The compounds of the present invention also demonstrate
greater resistance to certain metabolism as compared to atazanavir.
Thus, in another embodiment, the invention provides a
pharmaceutical composition comprising an effective amount of a
compound of any one of Formulae A, I, Ia, Ib or Ic, the oral
administration of which to a test subject results in a rate of
serum clearance of the compound following oral dosing that is less
than the rate of serum clearance of atazanavir following oral
administration of atazanavir to an equivalent test subject in a
molar equivalent pharmaceutical composition and that is
administered in the same dosing regimen as the compound of any one
of Formulae A, I, Ia, Ib or Ic. In other embodiments, the rate of
serum clearance of a compound following oral administration of a
composition of this invention is less than 90%, less than 80%, less
than 70%, or less than 60% of the serum clearance rate of
atazanavir following oral administration of a molar equivalent
atazanavir composition administered in the same dosing regimen. In
a more specific embodiment, the compound of any one of Formulae A,
I, Ia, Ib or Ic is administered once daily.
[0202] In a related embodiment, the invention provides a
pharmaceutical composition comprising 150 mg of a compound of any
one of Formulae A, I, Ia, Ib or Ic, or a pharmaceutically
acceptable salt thereof, wherein the rate of serum clearance of the
compound following oral administration of a single dose of the
composition to a chimpanzee is less than 90 ml/h/kg, less than 80
ml/h/kg, less than 75 ml/h/kg, or less than 70 ml/h/kg.
[0203] In another related embodiment, the invention provides a
pharmaceutical composition comprising 50 mg of a compound of any
one of Formulae A, I, Ia, Ib or Ic, or a pharmaceutically
acceptable salt thereof, wherein the rate of serum clearance of the
compound following oral administration of a single dose of the
composition to a chimpanzee is less than 350/h/kg, less than
325/h/kg, less than 300/h/kg, or less than 275/h/kg.
[0204] In still another related embodiment, the invention provides
a pharmaceutical composition comprising an effective amount of a
compound of any one of Formulae A, I, Ia, Ib or Ic, the oral
administration of which to a test subject results in an amount of
compound excreted intact in 24 hours following administration that
is greater than the amount of atazanavir excreted intact in 24
hours following oral administration of atazanavir to an equivalent
test subject in a molar equivalent pharmaceutical composition and
that is administered in the same dosing regimen as the compound of
any one of Formulae A, I, Ia, Ib or Ic. In other embodiments, the
amount of a compound of any one of Formulae A, I, Ia, Ib or Ic
excreted intact in 24 hours following oral administration of a
composition of this invention is greater than 140%, greater than
160%, greater than 180%, greater than 200%, or greater than 250% or
more of the amount of atazanavir excreted intact 24 hours following
oral administration of a molar equivalent atazanavir composition
administered in the same dosing regimen. In a more specific
embodiment, the compound of any one of Formulae A, I, Ia, Ib or Ic
is administered once daily.
[0205] In yet another embodiment, the invention provides a
pharmaceutical composition comprising an effective amount of a
compound of any one of Formulae A, I, Ia, Ib or Ic, the
administration of which to a test subject results in either a) a
similar AUC.sub.0-12, b) a similar C.sub.max, or c) a similar
C.sub.min (the lowest concentration within the dosing interval) as
atazanavir when atazanavir is administered to an equivalent test
subject in a pharmaceutical composition comprising an amount of
atazanavir that is greater than the amount of the compound of any
one of Formulae A, I, Ia, Ib or Ic on a mole basis of active
ingredient and that is administered in the same dosing regimen as
the compound of any one of Formulae A, I, Ia, Ib or Ic. In other
embodiments, the effective amount of a compound of any one of
Formulae A, I, Ia, Ib or Ic is no more than 80%, 70%, 60%, 50%,
40%, or less of the amount of atazanavir required to produce a
similar AUC.sub.0-12, a similar C.sub.min and/or a similar
C.sub.max when administered in the same dosing regimen as the
compound of any one of Formulae A, I, Ia, Ib or Ic. In a more
specific embodiment, the compound of any one of Formulae A, I, Ia,
Ib or Ic is administered once daily.
[0206] In another embodiment, the invention provides a
pharmaceutical composition comprising between 250 mg and 275 mg of
a compound of any one of Formulae A, I, Ia, Ib or Ic, the
administration of which once a day to a test subject in the absence
of co-administration of ritonavir results in a C.sub.min of between
275 and 625 ng/mL of plasma and/or a mean plasma concentration at
steady state ("C.sub.ss," also defined as AUC.sub.0-.tau., where
.tau. is the time of the dosing interval) of between 925 and 1425
ng/mL of plasma.
[0207] In another embodiment, the invention provides a
pharmaceutical composition comprising between 275 mg and 300 mg of
a compound of any one of Formulae A, I, Ia, Ib or Ic, the
administration of which once a day to a test subject results in a
C.sub.min of between 300 and 675 ng/mL of plasma and/or a C.sub.ss
of between 1000 and 1550 ng/mL of plasma.
[0208] In another embodiment, the invention provides a
pharmaceutical composition comprising between 300 mg and 325 mg of
a compound of any one of Formulae A, I, Ia, Ib or Ic, the
administration of which once a day to a test subject results in a
C.sub.min of between 350 and 750 ng/mL of plasma and/or a C.sub.ss
of between 1100 and 1675 ng/mL of plasma.
[0209] In another embodiment, the invention provides a
pharmaceutical composition comprising between 325 mg and 350 mg of
a compound of any one of Formulae A, I, Ia, Ib or Ic, the
administration of which once a day to a test subject in the absence
of co-administration of ritonavir results in a C.sub.min of between
375 and 800 ng/mL of plasma and/or a C.sub.ss of between 1200 and
1800 ng/mL of plasma.
[0210] In another embodiment, the invention provides a
pharmaceutical composition comprising between 350 mg and 375 mg of
a compound of any one of Formulae A, I, Ia, Ib or Ic, the
administration of which once a day to a test subject in the absence
of co-administration of ritonavir results in a C.sub.min of between
400 and 850 ng/mL of plasma and/or a C.sub.ss of between 1300 and
1925 ng/mL of plasma.
[0211] In another embodiment, the invention provides a
pharmaceutical composition comprising between 375 mg and 400 mg of
a compound of any one of Formulae A, I, Ia, Ib or Ic, the
administration of which once a day to a test subject in the absence
of co-administration of ritonavir results in a C.sub.min of between
425 and 900 ng/mL of plasma and/or a C.sub.ss of between 1400 and
2050 ng/mL of plasma.
[0212] In another embodiment, the invention provides a
pharmaceutical composition comprising between 400 mg and 425 mg of
a compound of any one of Formulae A, I, Ia, Ib or Ic, the
administration of which once a day to a test subject in the absence
of co-administration of ritonavir results in a C.sub.min of between
450 and 975 ng/mL of plasma and/or a C.sub.ss of between 1500 and
2175 ng/mL of plasma.
[0213] In another embodiment, the invention provides a
pharmaceutical composition comprising between 425 mg and 450 mg of
a compound of any one of Formulae A, I, Ia, Ib or Ic, the
administration of which once a day to a test subject in the absence
of co-administration of ritonavir results in a C.sub.min, of
between 500 and 1025 ng/mL of plasma and/or a C.sub.ss of between
1575 and 2300 ng/mL of plasma.
[0214] In each of the above embodiments, a pharmaceutically
acceptable salt of a compound of any one of Formulae A, I, Ia, Ib
or Ic, and/or atazanavir may be used instead of the free base
form.
[0215] In a more specific embodiment, in each of the compositions
set forth above, the compound is a compound of Formula I. In an
even more specific embodiment, in each of the compositions set
forth above, the compound is a compound of Formula Ib. In a still
more specific embodiment, in each of the compositions set forth
above, the compound selected from Compound 114, Compound 120,
Compound 122, and Compound 131.
[0216] The term "molar equivalent amount" as used herein means an
amount present in a first composition that is the same as the
amount present in a second composition on a mole basis of active
ingredient.
[0217] A "test subject" is any mammal, preferably a chimpanzee or a
human.
[0218] An "equivalent test subject" is defined herein as being of
the same species and sex as the test subject, and which shows no
more than 10% variability as compared to the test subject in the
pharmacokinetic parameter being tested after administration of an
equal amount of atazanavir to both the test subject and the
equivalent subject. The skilled artisan will recognize that one way
of reducing variability is to co-dose the compound of the invention
along with atazanavir.
[0219] In the pharmaceutical compositions of the invention, the
compound of the present invention is present in an effective
amount. As used herein, the term "effective amount" refers to an
amount which, when administered in a proper dosing regimen, is
sufficient to treat (therapeutically or prophylactically) the
target disorder. For example, and effective amount is sufficient to
reduce or ameliorate the severity, duration or progression of the
disorder being treated, prevent the advancement of the disorder
being treated, cause the regression of the disorder being treated,
or enhance or improve the prophylactic or therapeutic effect(s) of
another therapy. Preferably, the compound is present in the
composition in an amount of from 0.1 to 50 wt. %, more preferably
from 1 to 30 wt. %, most preferably from 5 to 20 wt. %.
[0220] The interrelationship of dosages for animals and humans
(based on milligrams per meter squared of body surface) is
described in Freireich et al., (1966) Cancer Chemother. Rep 50:
219. Body surface area may be approximately determined from height
and weight of the patient. See, e.g., Scientific Tables, Geigy
Pharmaceuticals, Ardsley, N.Y., 1970, 537.
[0221] In one embodiment, an effective amount of a compound of this
invention can range from about 200 to about 800 mg per treatment.
In more specific embodiments, the range is from about 250 mg to
about 600 mg, or from about 250 mg to about 400 mg, or from about
300 mg to about 500 mg, or most specifically from about 325 mg to
about 450 mg. Treatment is typically administered from one to two
times daily. Effective doses will also vary, as recognized by those
skilled in the art, depending on the diseases treated, the severity
of the disease, the route of administration, the sex, age and
general health condition of the patient, excipient usage, the
possibility of co-usage with other therapeutic treatments such as
use of other agents and the judgment of the treating physician. For
example, guidance for selecting an effective dose can be determined
by reference to the prescribing information for atazanavir.
[0222] For pharmaceutical compositions that comprise a second
therapeutic agent, an effective amount of the second therapeutic
agent is between about 20% and 100% of the dosage normally utilized
in a monotherapy regime using just that agent. Preferably, an
effective amount is between about 70% and 100% of the normal
monotherapeutic dose. The normal monotherapeutic dosages of these
second therapeutic agents are well known in the art. See, e.g.,
Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton
and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon
Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing,
Loma Linda, Calif. (2000), each of which references are
incorporated herein by reference in their entirety.
[0223] It is expected that some of the second therapeutic agents
referenced above will act synergistically with the compounds of
this invention. When this occurs, it will allow the effective
dosage of the second therapeutic agent and/or the compound of this
invention to be reduced from that required in a monotherapy. This
has the advantage of minimizing toxic side effects of either the
second therapeutic agent of a compound of this invention,
synergistic improvements in efficacy, improved ease of
administration or use and/or reduced overall expense of compound
preparation or formulation.
Methods of Treatment
[0224] In another embodiment, the invention provides a method of
treating HIV infection in a patient in need thereof comprising the
step of administering to the patient an effective amount of
compound of any one of Formulae A, I, Ia, Ib or Ic or a
pharmaceutically acceptable composition comprising a compound of
any one of Formulae A, I, Ia, Ib or Ic.
[0225] Methods delineated herein also include those wherein the
patient is identified as in need of a particular stated treatment.
Identifying a patient in need of such treatment can be in the
judgment of a patient or a health care professional and can be
subjective (e.g. opinion) or objective (e.g. measurable by a test
or diagnostic method).
[0226] In another embodiment, any of the above methods of treatment
comprises the further step of co-administering to said patient one
or more second therapeutic agents. The choice of second therapeutic
agent may be made from any second therapeutic agent known to be
useful for co-administration with atazanavir. The choice of second
therapeutic agent is also dependent upon the particular disease or
condition to be treated. Examples of second therapeutic agents that
may be employed in the methods of this invention are those set
forth above for use in combination compositions comprising a
compound of this invention and a second therapeutic agent.
[0227] In particular, the combination therapies of this invention
include co-administering a compound of any one of Formulae A, I,
Ia, Ib or Ic and a second HIV protease inhibitor (e.g., amprenavir,
fosamprenavir, tipranavir, indinavir, saquinavir, lopinavir,
ritonavir, darunavir, or nelfinavir), a non-nucleoside reverse
transcriptase inhibitor ("NNRTI") (e.g., etravirine, delavirdine,
efavirenz, nevirapine, or rilpivirine), a nucleoside/nucleotide
reverse transcriptase inhibitor ("NRTI") (e.g., zidovudine,
lamivudine, emtricitabine, zidovudine, tenofovir disoproxil
fumarate, didanosine, stavudine, abacavir, racivir, amdoxovir,
apricitabine, or elvucitabine) a viral entry inhibitor (e.g.,
enfuvirtide, maraviroc, vicriviroc, PRO 140, or TNX-355), an
integrase inhibitor (e.g., raltegravir, or elvitegravir), an immune
based antiretroviral agent (e.g., immunitin, proleukin, remune, BAY
50-4798 or IR103), a viral maturation inhibitor (e.g., bevirimat),
a cellular inhibitor (e.g., droxia or hydroxyurea), or combinations
of two or more of the above.
[0228] In a more specific embodiment, the combination therapies of
this invention include co-administering a compound of any one of
Formulae A, I, Ia, Ib or Ic and a second therapeutic agent selected
from ritonavir, efavirenz, didanosine, tenofovir disoproxil,
nelfinavir mesilate, amprenavir, raltegravir, saquinavir,
lopinavir, nevirapine, emtricitabine, abacavir, lamivudine,
zidovudine, maraviroc, stavudine, darunavir, fosamprenavir,
vicriviroc, pharmaceutically acceptable salts of any of the
foregoing, and combinations thereof to treat HIV infection in a
patient in need thereof.
[0229] In an even more specific embodiment, the second therapeutic
agent is selected from ritonavir, efavirenz, didanosine,
raltegravir, tenofovir disoproxil lamivudine, abacavir, zidovudine,
emtricitabine, efavirenz, pharmaceutically acceptable salts of any
of the foregoing, and combinations thereof. In another specific
embodiment, the method comprises co-administering a compound of any
one of Formulae A, I, Ia, Ib, or Ic, and two to three of the second
therapeutic agents set forth above in this paragraph. In an even
more specific embodiment, the method comprises co-administering a
compound of any one of Formulae A, I, Ia, Ib, or Ic, and two of the
second therapeutic agents set forth above in this paragraph.
[0230] The term "co-administered" as used herein means that the
second therapeutic agent may be administered together with a
compound of this invention as part of a single dosage form (such as
a composition of this invention comprising a compound of the
invention and an second therapeutic agent as described above) or as
separate, multiple dosage forms. Alternatively, the additional
agent may be administered prior to, consecutively with, or
following the administration of a compound of this invention. In
such combination therapy treatment, both the compounds of this
invention and the second therapeutic agent(s) are administered by
conventional methods. The administration of a composition of this
invention, comprising both a compound of the invention and a second
therapeutic agent, to a patient does not preclude the separate
administration of that same therapeutic agent, any other second
therapeutic agent or any compound of this invention to said patient
at another time during a course of treatment.
[0231] Effective amounts of these second therapeutic agents are
well known to those skilled in the art and guidance for dosing may
be found in patents and published patent applications referenced
herein, as well as in Wells et al., eds., Pharmacotherapy Handbook,
2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR
Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,
Tarascon Publishing, Loma Linda, Calif. (2000), and other medical
texts. However, it is well within the skilled artisan's purview to
determine the second therapeutic agent's optimal effective-amount
range.
[0232] In treatment-naive patients, the recommended dose of
Reyataz.RTM. (atazanavir sulfate) for the treatment of HIV-1
infection is 400 mg once daily with food. When co-administered with
tenofovir, the recommended dose is Reyataz 300 mg and ritonavir 100
mg. In treatment-experienced patients, the recommended dose of
Reyataz for the treatment of HIV-1 infection is 300 mg with
ritonavir 100 mg once daily with food. Based on the animal data
disclosed herein, certain compounds of this invention, following a
once daily dose in the range of 325 mg to 450 mg, are expected to
have the advantage in humans of achieving a C.sub.min and/or AUC
that is comparable to the C.sub.min and/or AUC achieved with a
once-daily dose of 300 mg dose of atazanavir boosted with 100 mg
ritonavir. Accordingly, one embodiment of this invention provides a
method of treating HIV infection by administering to a subject in
need thereof a composition comprising a compound of this invention
at a once daily dose in the range of 325 mg to 450 mg. In one
embodiment, such a composition is administered without
co-administration of ritonavir.
[0233] Another embodiment relates to a method of treating HIV
infection by administering a composition comprising a compound of
this invention at a once daily dose in the range of 250 mg to 400
mg.
[0234] In one embodiment of the invention, where a second
therapeutic agent is administered to a subject, the effective
amount of the compound of this invention is less than its effective
amount would be where the second therapeutic agent is not
administered. In another embodiment, the effective amount of the
second therapeutic agent is less than its effective amount would be
where the compound of this invention is not administered. In this
way, undesired side effects associated with high doses of either
agent may be minimized. Other potential advantages (including
without limitation improved dosing regimens and/or reduced drug
cost) will be apparent to those of skill in the art.
[0235] In yet another aspect, the invention provides the use of a
compound of Formula I alone or together with one or more of the
above-described second therapeutic agents in the manufacture of a
medicament, either as a single composition or as separate dosage
forms, for treatment or prevention in a patient of a disease,
disorder or symptom set forth above. Another aspect of the
invention is a compound of any one of Formulae A, I, Ia, Ib or Ic
for use in the treatment or prevention in a patient of a disease,
disorder or symptom thereof delineated herein. In a further aspect,
the compounds of the invention may be used in medicine, such as in
therapy. In any of these uses, the compound is preferably
administered without co-administration of ritonavir.
Diagnostic Methods and Kits
[0236] The compounds and compositions of this invention are also
useful as reagents in methods for determining the concentration of
atazanavir in solution or biological sample such as plasma,
examining the metabolism of atazanavir and other analytical
studies.
[0237] According to one embodiment, the invention provides a method
of determining the concentration, in a solution or a biological
sample, of atazanavir, comprising the steps of: [0238] a) adding a
known concentration of a compound of Formula A to the solution of
biological sample; [0239] b) subjecting the solution or biological
sample to a measuring device that distinguishes atazanavir from a
compound of Formula A; [0240] c) calibrating the measuring device
to correlate the detected quantity of the compound of Formula A
with the known concentration of the compound of Formula A added to
the biological sample or solution; and [0241] d) measuring the
quantity of atazanavir in the biological sample with said
calibrated measuring device; and [0242] e) determining the
concentration of atazanavir in the solution of sample using the
correlation between detected quantity and concentration obtained
for a compound of Formula A.
[0243] Measuring devices that can distinguish atazanavir from the
corresponding compound of Formula A include any measuring device
that can distinguish between two compounds that differ from one
another only in isotopic abundance. Exemplary measuring devices
include a mass spectrometer, NMR spectrometer, or IR
spectrometer.
[0244] In another embodiment, the invention provides a method of
evaluating the metabolic stability of a compound of Formula A
comprising the steps of contacting the compound of Formula A with a
metabolizing enzyme source for a period of time and comparing the
amount of the compound of Formula A with the metabolic products of
the compound of Formula I after the period of time.
[0245] In a related embodiment, the invention provides a method of
evaluating the metabolic stability of a compound of Formula A in a
patient following administration of the compound of Formula A. This
method comprises the steps of obtaining a serum, urine or feces
sample from the patient at a period of time following the
administration of the compound of Formula A to the subject; and
comparing the amount of the compound of Formula A with the
metabolic products of the compound of Formula A in the serum, urine
or feces sample.
[0246] The present invention also provides kits for use to treat
HIV infection. These kits comprise (a) a pharmaceutical composition
comprising a compound of any one of Formulae A, I, Ia, Ib or Ic or
a salt thereof, wherein said pharmaceutical composition is in a
container; and (b) instructions describing a method of using the
pharmaceutical composition to treat HIV infection.
[0247] The container may be any vessel or other sealed or sealable
apparatus that can hold said pharmaceutical composition. Examples
include bottles, ampules, divided or multi-chambered holders
bottles, wherein each division or chamber comprises a single dose
of said composition, a divided foil packet wherein each division
comprises a single dose of said composition, or a dispenser that
dispenses single doses of said composition. The container can be in
any conventional shape or form as known in the art which is made of
a pharmaceutically acceptable material, for example a paper or
cardboard box, a glass or plastic bottle or jar, a re-sealable bag
(for example, to hold a "refill" of tablets for placement into a
different container), or a blister pack with individual doses for
pressing out of the pack according to a therapeutic schedule. The
container employed can depend on the exact dosage form involved,
for example a conventional cardboard box would not generally be
used to hold a liquid suspension. It is feasible that more than one
container can be used together in a single package to market a
single dosage form. For example, tablets may be contained in a
bottle, which is in turn contained within a box. In one embodiment,
the container is a blister pack.
[0248] The kits of this invention may also comprise a device to
administer or to measure out a unit dose of the pharmaceutical
composition. Such device may include an inhaler if said composition
is an inhalable composition; a syringe and needle if said
composition is an injectable composition; a syringe, spoon, pump,
or a vessel with or without volume markings if said composition is
an oral liquid composition; or any other measuring or delivery
device appropriate to the dosage formulation of the composition
present in the kit.
[0249] In certain embodiment, the kits of this invention may
comprise in a separate vessel of container a pharmaceutical
composition comprising a second therapeutic agent, such as one of
those listed above for use for co-administration with a compound of
this invention.
[0250] The invention now being generally described, it will be more
readily understood by reference to the following examples which are
included merely for purposes of illustration of certain aspects and
embodiments of the present invention, and are not intended to limit
the invention in any way.
EXAMPLES
Example 1
Synthesis of 1,14-Di(methyl-d.sub.3)
(3S,8S,9S,12S)-3,12-bis[(1,1-dimethylethyl)-d.sub.9]-8-hydroxy-4,11-dioxo-
-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazate-
tradecanedioate (Compound 122)
##STR00033##
[0252] Compound 122 was prepared according to Scheme 1, above. The
details of each step in the synthesis are set forth below and
referred to as General Method A.
[0253] Synthesis of tert-butyl
2-(4-(pyridin-2-yl)benzylidene)hydrazinecarboxylate (XII,
Y.sup.1a.dbd.H). A mixture of 4-(pyridin-2-yl)benzaldehyde X (17.7
g, 96.6 mmol) and tert-butyl carbazate (12.2 g, 92.3 mmol) in
ethanol (125 mL) was kept at reflux under nitrogen for 4 hours
(hrs). The reaction mixture was cooled to 40.degree. C. and ice (60
g) was added. The resulting mixture was stirred for 20 minutes
(min). The precipitate was collected by filtration, washed with
water and dried in a vacuum oven (60.degree. C.) to give the
product XII, wherein Y.sup.1a.dbd.H (25.0 g, 91.1%).
[0254] Synthesis of tert-butyl
2-(4-(pyridin-2-yl)benzyl)hydrazinecarboxylate (XIII,
Y.sup.1a=Y.sup.1b.dbd.H). A solution of XII, Y.sup.1a H (23.15 g,
77.85 mmol) in methanol (350 mL) was treated with 20% palladium on
activated carbon (2.3 g, 50% wet) and hydrogenated at 10 psi for 4
hrs. The reaction mixture was filtered through Celite, the filter
cake was washed with methanol and the solvent was removed in a
rotary evaporator. The residue was recrystallized from heptane and
dried in a vacuum oven (40.degree. C.) to give XIII, wherein
Y.sup.1a.dbd.Y.sup.1b .dbd.H (22.48 g, 96.5%).
[0255] Synthesis of tert-butyl
2-((2S,3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutyl)-2-(4-(py-
ridin-2-yl)benzyl)hydrazinecarboxylate (XV,
Y.sup.1a.dbd.Y.sup.1b.dbd.H). A mixture of tert-butyl
(S)-1-((R)-oxiran-2-yl)-2-phenylethylcarbamate XIV (1.18 g, 4.48
mmol), XIII, Y.sup.1a.dbd.Y.sup.1b.dbd.H (1.23 g, 4.11 mmol) and
isopropanol (15 mL) was kept at reflux under nitrogen overnight.
The solvent was removed in a rotary evaporator and the residue was
purified by chromatography on silica (100 g) with 8:2
dichloromethane/ethyl acetate to give product XV, wherein
Y.sup.1a.dbd.Y.sup.1b.dbd.H (1.74 g, 75%).
[0256] Synthesis of
(2S,3S)-3-amino-4-phenyl-1-(1-(4-(pyridin-2-yl)benzyl)
hydrazinyl)butan-2-ol (XVI, Y.sup.1a.dbd.Y.sup.1b.dbd.H). A
solution of XV, Y.sup.1a .dbd.Y.sup.1b .dbd.H (2.84 g, 5.05 mmol)
in dichloromethane (30 mL) was stirred under nitrogen at room
temperature and treated with 4N HCl in dioxane (60 mL). Stirring
was continued at room temperature for 20 minutes. Sufficient
methanol was added to dissolve the formed precipitate and stirring
was continued at room temperature for 2 hrs. The solvents were
removed in a rotary evaporator and the residue was dried in a
vacuum oven (60.degree. C.) to give XVI, wherein Y.sup.1a
.dbd.Y.sup.1b .dbd.H (3.27 g, 5.05 mmol assuming complete
conversion) as a multiple hydrochloride salt.
[0257] Synthesis of 1,14-Di(methyl-d.sub.3)
(3S,8S,9S,12S)-3,12-bis[(1,1-dimethylethyl)-d.sub.9]-8-hydroxy-4,11-dioxo-
-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazate-
tradecanedioate (122). A mixture of
(S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid
XVII-d.sub.12 (R.sup.1a.dbd.R.sup.1b.dbd.CD.sub.3,
R.sup.2.dbd.R.sup.3--C(CD.sub.3).sub.3; 0.90 g, 4.44 mmol; prepared
according to Scheme 5 and Example 13) and
O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TPTU) (1.32 g, 4.44 mmol) in dichloromethane (40
mL) was treated with diisopropylethylamine (1.16 g, 8.88 mmol) and
stirred under nitrogen at room temperature for 30 min. This
solution was added to an ice-cold suspension of XVI,
Y.sup.1a.dbd.Y.sup.1b.dbd.H, hydrochloride (1.15 g, 1.78 mmol) and
the resulting solution was stirred at room temperature overnight.
The reaction mixture was diluted with dichloromethane (140 mL),
washed with water (2.times.100 mL) and saturated sodium bicarbonate
solution (150 mL), dried over sodium sulfate and filtered. The
solvent was removed in a rotary evaporator and the crude product
was purified by chromatography on silica (120 g) with 2% ethanol in
1:1 heptane/ethyl acetate (4.5 L). The solvent was removed from the
pure fractions and the residue (0.57 g) was taken in ethyl acetate
(10 mL), stirred at 60.degree. C. for 20 min and diluted with MTBE
(60 mL). After cooling, the precipitate was collected by
filtration, washed with MTBE and dried in a vacuum oven (55.degree.
C.) to give Compound 122 (0.40 g). Less pure fractions resulting
from chromatography gave an additional 0.57 g impure material.
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 2.54 (d, 1H), 2.87-2.95
(m, 3H), 3.57 (d, 2H), 3.75 (d, 1H), 3.91-4.08 (m, 3H), 4.81 (bs,
1H), 5.15-5.30 (m, 2H), 6.38-6.43 (m, 2H), 7.14-7.23 (m, 6H,
partially obscured by CDCl.sub.3), 7.41 (d, 2H), 7.68-7.76 (m, 2H),
7.94 (d, 2H), 8.68 (d, 1H). HPLC (method: 20 mm C18-RP
column--gradient method 2-95% Acetonitrile+0.1% formic acid in 3.3
min with 1.7 min hold at 95% Acetonitrile; Wavelength: 254 nm):
retention time: 3.22 min. MS (M+H.sup.+): 729.6.
Example 2
Synthesis of 1,14-Dimethyl
(3S,8S,9S,12S)-3,12-bis[(1,1-dimethylethyl)-d.sub.9]-8-hydroxy-4,11-dioxo-
-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazate-
tradecanedioate (Compound 106)
##STR00034##
[0259] Compound 106 was prepared according to Scheme 1, above,
following the General Method A described above.
[0260] Synthesis of 1,14-Dimethyl
(3S,8S,9S,12S)-3,12-bis[(1,1-dimethylethyl)-d.sub.9]-8-hydroxy-4,11-dioxo-
-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazate-
tradecanedioate (106). Compound 106 was prepared via General Method
A above from
(2S,3S)-3-amino-4-phenyl-1-(1-(4-(pyridin-2-yl)benzyl)hydrazinyl)butan-2--
ol (XVI, Y.sup.1a.dbd.Y.sup.1b.alpha.H, hydrochloride) and
(S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid-dg
(XVII-d.sub.9, R.sup.1a.dbd.R.sup.1b .dbd.CH.sub.3,
R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3; prepared according to
Scheme 5). .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 2.54 (d, 1H),
2.84-2.89 (m, 1H), 2.93 (d, 2H), 3.57 (d, 2H), 3.63 (s, 3H), 3.66
(s, 3H), 3.75 (d, 1H), 3.91-4.08 (m, 3H), 4.81 (bs, 1H), 5.15-5.32
(m, 2H), 6.36-6.45 (m, 2H), 7.18-7.24 (m, 6H, partially obscured by
CDCl.sub.3), 7.41 (d, 2H), 7.68-7.76 (m, 2H), 7.94 (d, 2H), 8.68
(d, 1H). HPLC (method: 20 mm C18-RP column--gradient method 2-95%
ACN+0.1% formic acid in 3.3 min with 1.7 min hold at 95% ACN;
Wavelength: 254 nm): retention time: 3.23 min. MS (M+H.sup.+):
723.6.
Example 3
Synthesis of 1,14-Di(methyl-d.sub.3)
(3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenyl-
methyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecaned-
ioate (Compound 103)
##STR00035##
[0262] Compound 103 was prepared according to Scheme 1, above,
following the General Method A described above.
[0263] Synthesis of 1,14-Di(methyl-d.sub.3)
(3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenyl-
methyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecaned-
ioate (103). Compound 103 was prepared via General Method A, from
(2S,3S)-3-amino-4-phenyl-1-(1-(4-(pyridin-2-yl)benzyl)hydrazinyl)butan-2--
ol (XVI, Y.sup.1a.dbd.Y.sup.1b.dbd.H, hydrochloride) and known
compound (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic
acid-d.sub.3 (XVII-d.sub.3, R.sup.1a.dbd.R.sup.1b.dbd.CH.sub.3,
R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3) (Zhang, Huiping et al.,
Journal of Labelled Compounds & Radiopharmaceuticals, 2005,
48(14), 1041-1047). .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.79
(s, 9H), 0.87 (s, 9H), 2.52 (d, 1H), 2.82-2.95 (m, 3H), 3.58 (d,
2H), 3.77 (d, 1H), 3.91-4.08 (m, 3H), 4.81 (s, 1H), 5.15-5.32 (m,
2H), 6.35-6.45 (m, 2H), 7.16-7.24 (m, 6H, partially obscured by
CDCl.sub.3), 7.41 (d, 2H), 7.68-7.76 (m, 2H), 7.94 (d, 2H), 8.68
(d, 1H). HPLC (method: 20 mm C18-RP column--gradient method 2-95%
ACN+0.1% formic acid in 3.3 min with 1.7 min hold at 95% ACN;
Wavelength: 254 nm): retention time: 3.24 min. MS (M+H.sup.+):
7.11.3.
Example 4
Synthesis of 1,14-Di(methyl-d.sub.3)
(3S,8S,9S,12S)-3,12-bis[(1,1-dimethylethyl)-d.sub.9]-8-hydroxy-4,11-dioxo-
-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl-d.sub.2]-2,5,6,10,13-pe-
ntaazatetradecanedioate (Compound 131)
##STR00036##
[0265] Compound 131 was prepared according to Scheme 1, above,
following the General Method A described above. Deuterium gas
(Cambridge Isotopes, 99.8 atom % D), MeOD (Aldrich, 99.5 atom % D),
iPrOD (Aldrich, 98 atom % D) and deuterium chloride (Aldrich, 99
atom % D) were used in this synthesis. Deuterated aldehyde X was
prepared according to Scheme 2b using LiAlD.sub.4 (Cambridge
Isotopes, 98 atom % D). .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.
2.71 (dd, 2H), 2.94 (d, 2H), 3.56 (d, 2H), 3.77 (d, 1H), 4.02-4.05
(m, 1H), 4.83 (s, 1H), 5.19-5.29 (m, 2H), 6.40-6.47 (m, 2H),
7.20-7.23 (m, 6H, partially obscured by CDCl.sub.3), 7.41 (d, 2H),
7.69-7.76 (m, 2H), 7.95 (d, 2H), 8.69 (d, 1H). HPLC (method: 20 mm
C18-RP column--gradient method 2-95% ACN+0.1% formic acid in 3.3
min with 1.7 min hold at 95% ACN; Wavelength: 254 nm): retention
time: 3.22 min; purity: 99.2%. MS (M+H.sup.+): 731.7.
Example 5
Synthesis of 1,14-Di(methyl-d.sub.3)
(3S,8S,9S,12S)-3-(1,1-dimethylethyl)-12-[(1,1-dimethylethyl)-d.sub.9]-8-h-
ydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6-
,10,13-pentaazatetradecanedioate (Compound 120).
##STR00037##
[0267] Compound 120 was prepared according to Scheme 1b, above.
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.78 (s, 9H), 2.72 (dd,
2H), 2.94 (d, 2H), 3.58-3.63 (m, 2H), 3.78 (d, 1H), 3.92-4.09 (m,
3H), 4.88 (s, 1H), 5.28 (dd, 2H), 6.46 (d, 1H), 6.73 (s, 1H),
7.14-7.25 (m, 6H, partially obscured by CDCl.sub.3), 7.42 (d, 2H),
7.68-7.78 (m, 2H), 7.94 (d, 2H), 8.68 (d, 1H). HPLC (method: 20 mm
C18-RP column--gradient method 2-95% ACN+0.1% formic acid in 3.3
min with 1.7 min hold at 95% ACN; Wavelength: 254 nm): retention
time: 3.23 min; purity: 99.6%. MS (M+H.sup.+): 720.6.
Example 6
Synthesis of 1,14-Di(methyl-d.sub.3)
(3S,8S,9S,12S)-3-[(1,1-dimethylethyl)-d.sub.9]12-(1,1-dimethylethyl)-8-hy-
droxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,-
10,13-pentaazatetradecanedioate (Compound 121).
##STR00038##
[0269] Compound 121 was prepared according to Scheme 1c, above.
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.86 (s, 9H), 2.72 (dd,
2H), 2.94 (d, 2H), 3.60-3.63 (m, 2H), 3.80 (d, 1H), 3.92-4.09 (m,
3H), 4.89 (s, 1H), 5.30 (dd, 2H), 6.43 (d, 1H), 6.74 (s, 1H),
7.14-7.26 (m, 6H, partially obscured by CDCl.sub.3), 7.42 (d, 2H),
7.68-7.79 (m, 2H), 7.93 (d, 2H), 8.68 (d, 1H). HPLC (method: 20 mm
C18-RP column--gradient method 2-95% ACN+0.1% formic acid in 3.3
min with 1.7 min hold at 95% ACN; Wavelength: 254 nm): retention
time: 3.22 min; purity: 99.4%. MS (M+H.sup.+): 720.6.
Example 7
Synthesis of 1,14-Dimethyl
(3S,8S,9S,12S)-3-(1,1-dimethylethyl)-12-[(1,1-dimethylethyl)-d.sub.9]-8-h-
ydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6-
,10,13-pentaazatetradecanedioate (Compound 104).
##STR00039##
[0271] Compound 104 was prepared according to Scheme 1c, above.
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.78 (s, 9H), 2.70 (dd,
2H), 2.94 (d, 2H), 3.59-3.66 (m, 8H), 3.78 (d, 1H), 3.92-4.09 (m,
3H), 4.86 (s, 1H), 5.27 (dd, 2H), 6.44 (d, 1H), 6.63 (s, 1H),
7.14-7.26 (m, 6H, partially obscured by CDCl.sub.3), 7.42 (d, 2H),
7.68-7.79 (m, 2H), 7.94 (d, 2H), 8.69 (d, 1H). HPLC (method: 20 mm
C18-RP column--gradient method 2-95% ACN+0.1% formic acid in 3.3
min with 1.7 min hold at 95% ACN; Wavelength: 254 nm): retention
time: 3.23 min; purity: 99.8%. MS (M+H.sup.+): 714.6.
Example 8
Synthesis of 1,14-Dimethyl
(3S,8S,9S,12S)-3,12-bis[(1,1-dimethylethyl)-d.sub.9]-8-hydroxy-4,11-dioxo-
-9-(phenylmethyl)-6-[[-4-(2-pyridinyl)phenyl]methyl-d.sub.2]-2,5,6,10,13-p-
entaazatetradecanedioate (Compound 113)
##STR00040##
[0273] Compound 113 was prepared according to Scheme 1, above,
following the General Method A described above. Deuterium gas
(Cambridge Isotopes, 99.8 atom % D), MeOD (Aldrich, 99.5 atom % D),
iPrOD (Aldrich, 98 atom % D) and deuterium chloride (Aldrich, 99
atom % D) were used in this synthesis. Deuterated aldehyde X was
prepared according to Scheme 2b using LiAlD.sub.4 (Cambridge
Isotopes, 98 atom % D). .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.
2.69 (dd, 2H), 2.94 (d, 2H), 3.56-3.59 (m, 2H), 3.64 (s, 3H), 3.67
(s, 3H), 3.77 (d, 1H), 4.02-4.05 (m, 1H), 4.84 (s, 1H), 5.18-5.32
(m, 2H), 6.40-6.45 (m, 2H), 7.14-7.26 (m, 6H, partially obscured by
CDCl.sub.3), 7.41 (d, 2H), 7.61-7.80 (m, 2H), 7.95 (d, 2H), 8.69
(d, 1H). HPLC (method: 20 mm C18-RP column--gradient method 2-95%
ACN+0.1% formic acid in 3.3 min with 1.7 min hold at 95% ACN;
Wavelength: 254 nm): retention time: 3.25 min; purity: 99.4%. MS
(M+H.sup.+): 725.4.
Example 9
Synthesis of 1-Methyl-14-(methyl-d.sub.3)
(3S,8S,9S,12S)-3-(1,1-dimethylethyl)-12-[(1,1-dimethylethyl)-d.sub.9]-8-h-
ydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6-
,10,13-pentaazatetradecanedioate (Compound 114).
##STR00041##
[0275] Compound 114 was prepared according to Scheme Ic above.
Pd(OH).sub.2 was used in place of Pd/C for the conversion of XXXII
to XXXIII. .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.78 (s, 9H),
2.70 (dd, 2H), 2.93 (d, 2H), 3.59-3.63 (m, 5H), 3.78 (d, 1H),
3.92-4.04 (m, 3H), 4.84 (s, 1H), 5.30 (dd, 2H), 6.44 (d, 1H), 6.60
(s, 1H), 7.20-7.26 (m, 6H, partially obscured by CDCl.sub.3), 7.41
(d, 2H), 7.70-7.79 (m, 2H), 7.94 (d, 2H), 8.68 (d, 1H). MS
(M+H.sup.+): 717.4.
Example 10
Synthesis of 1-Methyl-14-(methyl-d.sub.3)
(3S,8S,9S,12S)-3-(1,1-dimethylethyl)-12-[(1,1-dimethylethyl)-d.sub.9]-8-h-
ydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl-d.sub.-
2]-2,5,6,10,13-pentaazatetradecanedioate (Compound 123).
##STR00042##
[0277] Compound 123 was prepared according to Scheme 1c above.
Deuterium gas (Med-Tech, 98 atom % D), EtOD (Aldrich, 99.5 atom %
D), MeOD (Aldrich, 99.5 atom % D), iPrOD (CDN, 99.1 atom % D) and
deuterium chloride (Aldrich, 99 atom % D) were used in this
synthesis. Pd(OH).sub.2 was used in place of Pd/C for the
conversion of XXXII to XXXIII. .sup.1H-NMR (300 MHz, CDCl.sub.3):
.delta. 0.79 (s, 9H), 2.72 (dd, 2H), 2.93 (d, 2H), 3.56-3.63 (m,
5H), 3.77 (d, 1H), 4.04 (d, 1H), 4.81 (s, 1H), 5.30 (dd, 2H), 6.41
(d, 1H), 6.51 (s, 1H), 7.14-7.26 (m, 6H, partially obscured by
CDCl.sub.3), 7.41 (d, 2H), 7.69-7.76 (m, 2H), 7.94 (d, 2H), 8.68
(d, 1H). MS (M+H.sup.+): 719.5.
Example 11
Synthesis of 1,14-Dimethyl (3S,8S,9S,
12S)-3-(1,1-dimethylethyl)-12-[(1,1-dimethylethyl)-d.sub.9]-8-hydroxy-4,1-
1-dioxo-9-(phenylmethyl)-6-[[-4-(2-pyridinyl)phenyl]methyl-d.sub.2]-2,5,6,-
10,13-pentaazatetradecanedioate (Compound 111).
##STR00043##
[0279] Compound 111 was prepared according to Scheme 1c above.
Deuterium gas (Med-Tech, 98 atom % D), EtOD (Aldrich, 99.5 atom %
D), MeOD (Aldrich, 99.5 atom % D), iPrOD (CDN, 99.1 atom % D) and
deuterium chloride (Aldrich, 99 atom % D) were used in this
synthesis. Pd(OH).sub.2 was used in place of Pd/C for the
conversion of XXXII to XXXIII. .sup.1H-NMR (300 MHz, CDCl.sub.3):
.delta. 0.79 (s, 9H), 2.74 (dd, 2H), 2.93 (d, 2H), 3.58-3.66 (m,
8H), 3.77 (d, 1H), 4.03 (d, 1H), 4.82 (s, 1H), 5.30 (dd, 2H), 6.41
(d, 1H), 6.51 (s, 1H), 7.20-7.26 (m, 6H, partially obscured by
CDCl.sub.3), 7.41 (d, 2H), 7.70-7.76 (m, 2H), 7.94 (d, 2H), 8.68
(d, 1H). MS (M+H.sup.+): 716.5.
Example 12
Synthesis of 1,14-Di(methyl-d.sub.3)
(3S,8S,9S,12S)-3-(1,1-dimethylethyl)-12-[(1,1-dimethylethyl)-d.sub.9]-8-h-
ydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl-d.sub.-
2]-2,5,6,10,13-pentaazatetradecanedioate (Compound 129).
##STR00044##
[0281] Compound 129 was prepared according to Scheme Ic above.
Deuterium gas (Med-Tech, 98 atom % D), EtOD (Aldrich, 99.5 atom %
D), MeOD (Aldrich, 99.5 atom % D), iPrOD (CDN, 99.1 atom % D) and
deuterium chloride (Aldrich, 99 atom % D) were used in this
synthesis. Pd(OH).sub.2 was used in place of Pd/C for the
conversion of XXXII to XXXIII. .sup.1H-NMR (300 MHz, CDCl.sub.3):
.delta. 0.79 (s, 9H), 2.71 (dd, 2H), 2.93 (d, 2H), 3.52-3.61 (m,
2H), 3.76 (d, 1H), 3.99-4.05 (m, 1H), 4.82 (s, 1H), 5.19-5.21 (m,
2H), 6.40-6.47 (m, 2H), 7.20-7.26 (m, 6H, partially obscured by
CDCl.sub.3), 7.42 (d, 2H), 7.69-7.76 (m, 2H), 7.95 (d, 2H), 8.69
(d, 1H). MS (M+H.sup.+): 722.5.
Example 13
[0282] Synthesis of
(S)-2-(d.sub.3-methoxy-carbonylamino)-3,3-d.sub.9-dimethylbutanoic
acid (XVII-d.sub.12). Intermediate XVII-d.sub.12
(R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3; R.sup.1a.dbd.R.sup.1b
.dbd.CD.sub.3 was prepared according to Scheme 5, above. Details of
the synthesis are set forth below.
[0283] Synthesis of dg-pivalaldehyde (XXII,
R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3). In a 3-L 4-necked round
bottom flask fitted with mechanical stirrer, reflux condenser,
dropping funnel and thermometer were placed a few small crystals of
iodine and then magnesium turnings (24.7 g, 1.029 mol). The bottom
of the flask was heated with a heat gun until the iodine commenced
to vaporize and was then allowed to cool while a solution of
t-butyl chloride-dg (100.0 g, 1.029 mol, Cambridge Isotopes, 99
atom % D) in anhydrous ether was placed in the dropping funnel. A
solution of t-butyl chloride-d.sub.9 in ether (3-5 mL) was added
directly to the dry magnesium. More anhydrous ether (1 L) and a few
small crystals of iodine were added, and the resulting mixture was
heated for 0.5 hr to initiate the reaction. The rest of solution of
t-butyl chloride-dg in ether was added with stirring at a rate not
faster than one drop per second. The mixture was allowed to reflux
during the halide-ether addition and no external cooling was
applied. The reaction mixture was then heated at reflux for several
hours until almost all of magnesium disappeared. The mixture was
cooled to -20.degree. C., and a solution of anhydrous DMF (73.0 g,
1.0 mol) in ether (100 mL) was added over a 35 min period at such a
rate that the temperature of the reaction did not exceed
-15.degree. C. A second solution of anhydrous DMF (73.0 g, 1.0 mol)
was then added quickly at -8.degree. C. After an additional 5 min,
hydroquinone (0.5 g) was added, stirring was stopped, the cooling
bath was removed, and the mixture was left standing overnight at
ambient temperature under nitrogen. The mixture was cooled to
5.degree. C. and aqueous 4M HCl (600 mL) was added in portions to
quench the reaction. The mixture was diluted with water (400 mL),
and the layers were separated. The aqueous layer was extracted with
ether (3.times.200 mL), and the combined organic layers were dried
and filtered. The filtrate was subjected to fractional distillation
under atmosphere pressure of nitrogen to remove most of the ether.
The residue was transferred to a small flask and fractional
distillation was continued to collect the desired compound XXII
(R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3) (39.5 g, 40% yield) as
a colorless oil at 65-75.degree. C. Compound XXII
(R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3) was stored under
nitrogen in the freezer.
[0284] Synthesis of
(R)-2-((S)-1-cyano-2,2-d.sub.9-dimethylpropylamino)-2-phenylacetamide
(XIIa, R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3). To a stirred
suspension of (R)-phenylglycine amide (60.7 g, 400 mmol) in water
(400 mL) was added Compound XXII
(R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3) (39.5 g, 415 mmol) at
room temperature (rt). Simultaneously, 30% aqueous NaCN solution
(68.8 g, 420 mmol) and glacial acetic acid (25.4 g, 423 mmol) were
added in 30 min, whereby the temperature of the reaction increased
to 34.degree. C. The mixture was stirred for 2 hrs at 30.degree.
C., followed by stirring at 70.degree. C. for 20 hrs. After cooling
to 30.degree. C., the product was isolated by filtration. The solid
was washed with water (500 mL) and dried under vacuum at 50.degree.
C. to afford the desired compound XXIIa
(R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3) (90.0 g, 88% yield) as
a tan solid with [.alpha.].sub.D=-298.degree. (c=1.0,
CHCl.sub.3).
[0285] Synthesis of
(S)-2-((R)-2-amino-2-oxo-1-phenylethylamino)-3,3-d.sub.9-dimethylbutanami-
de (XXIIb, R.sup.2/3.dbd.C(CD.sub.3).sub.3). A solution of compound
XXIIa (R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3) (64.2 g, 252.4
mmol) in dichloromethane (500 mL) was added to concentrated.
sulfuric acid (96%, 350 mL) at 15-20.degree. C. through an addition
funnel under the cooling of an ice bath. The resulting mixture was
stirred at room temperature (rt) for 1 hr. The mixture was poured
onto ice and carefully neutralized by NH.sub.4OH solution to pH=9.
The mixture was extracted with dichloromethane and the combined
organic layers were washed with water, dried, filtered, and
concentrated in vacuo to afford the desired compound XXIIb
(R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3) (55.0 g, 80% yield) as
a yellow foam with [.alpha.].sub.D=-140.degree. (c=1.0,
CHCl.sub.3).
[0286] Synthesis of (S)-2-amino-3,3-dg-dimethylbutanamide (XXIIc,
R.sup.2/3.dbd.C(CD.sub.3).sub.3). A mixture of compound XXIIb
(R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3) (77.0 g, 282.7 mmol),
10% Pd/C (.about.50% water, 20 g) and acetic acid (50 mL) in
ethanol (1.2 L) was subjected to hydrogenation at 30 psi at rt for
several days until LCMS showed that the reaction was complete. The
mixture was filtered through Celite and washed with EtOAc. After
the filtrate was concentrated in vacuo, the residue was diluted
with water (1 L) and basified with 1M NaOH solution to pH=9. The
mixture was extracted with dichloromethane and the aqueous layer
was concentrated in vacuo to half volume, saturated with solid
NaCl, and extracted with THF. The combined extracts were dried,
filtered, and concentrated in vacuo. The residue was chased with
toluene to remove remaining water, followed by trituration with
dichloromethane to afford the desired compound XXIIc
(R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3) (38.0 g, 96% yield) as
a white solid.
[0287] Synthesis of (S)-2-amino-3,3-dg-dimethylbutanoic acid
hydrochloride (XXV, R.sup.2/3.dbd.C(CD.sub.3).sub.3). A mixture of
compound XXIIc (R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3) (31.0 g,
222.6 mmol) in 6M aqueous HCl solution (1.5 L) was heated at reflux
for 24 hrs. The mixture was concentrated in vacuo to give the crude
product. The solid was redissolved in water (500 mL) and washed
with EtOAc (2.times.200 mL) to remove impurities from previous
steps. The aqueous layer was then concentrated in vacuo, chased
with toluene, and dried under vacuum at 50.degree. C. to afford the
HCl salt of the desired compound (S)-2-amino-3,3-dimethylbutanoic
acid-dg hydrochloride (XXV,
R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3) (33.6 g, 85% yield) as a
white solid.
[0288] Synthesis of
(S)-2-(d.sub.3-methoxycarbonylamino)-3,3-d.sub.9-dimethylbutanoic
acid (XVII-d.sub.12). To a solution of compound XXV
(R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3) (4.42 g, 25.0 mmol) in
a mixture of dioxane (12.5 mL) and 2M NaOH solution (60 mL) was
added methyl chloroformate-d.sub.3 (5.0 g, 50.0 mmol, Cambridge
Isotopes, 99 atom % D) dropwise, keeping the internal temperature
below 50.degree. C. The resulting mixture was warmed to 60.degree.
C. and stirred overnight, and then cooled to rt. The mixture was
washed with dichloromethane and the aqueous layer was acidified
with conc. HCl to pH=2 and extracted with EtOAc. The combined
extracts were dried, filtered, and concentrated in vacuo to afford
the desired compound
(S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid-d.sub.12
(XVII-d.sub.12) (3.8 g) as a yellow oil.
Example 14
[0289] Synthesis of
(S)-2-(methoxycarbonylamino)-3,3-d.sub.9-dimethylbutanoic acid
(XVII-d.sub.9). Intermediate XVII-d.sub.9
(R.sup.2.dbd.R.sup.3.dbd.C(CD.sub.3).sub.3;
R.sup.1a.dbd.R.sup.1b.dbd.CH.sub.3) was prepared following Scheme 5
and the method described above for the synthesis of XVII-d.sub.12,
substituting methyl chloroformate for methyl chloroformate-d.sub.3
in the final step.
Example 15
[0290] (S)-2-(d.sub.3-methoxycarbonylamino)-3,3-dimethylbutanoic
acid (XVII-d.sub.3). Intermediate XVII-d.sub.3
(R.sup.2.dbd.R.sup.3.dbd.C(CH.sub.3).sub.3; R.sup.1a .dbd.R.sup.1b
.dbd.CD.sub.3) is known in the literature (Zhang, H et al, J Label
Comp Radiopharm 2005, 48(14):1041-1047) and was prepared from
methyl chloroformate-d.sub.3 (Cambridge Isotopes, 99 atom % D).
Example 16
[0291] Evaluation Of Metabolic Stability. Certain in vitro liver
metabolism studies have been described previously in the following
references, each of which is incorporated herein in their entirety:
Obach, R S, Drug Metab Disp, 1999, 27:1350; Houston, J B et al.,
Drug Metab Rev, 1997, 29:891; Houston, J B, Biochem Pharmacol,
1994, 47:1469; Iwatsubo, T et al., Pharmacol Ther, 1997, 73:147;
and Lave, T, et al., Pharm Res, 1997, 14:152.
[0292] Microsomal Assay. Human liver microsomes (20 mg/mL, pool of
50 individuals) were obtained from Xenotech LLC (Lenexa, Kans.).
The incubation mixtures are prepared as follows. Stock solutions
(10 mM) solutions of test Compounds 103, 106, 122 and of atazanavir
were prepared in DMSO. The 10 mM stock solutions were diluted to 1
mM in acetonitrile (ACN). The 20 mg/mL liver microsomes were
diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4,
containing 3 mM MgCl.sub.2. 1 mM test compound was added to the
diluted microsomes to obtain a mixture containing 1.25 .mu.M test
compound. The microsome-test compound mixtures were added to wells
of a 2 mL 96-well deep well polypropylene plate in triplicate. The
plate was warmed to 37.degree. C. before initiating the reactions
by addition of prewarmed NADPH in 0.1 M potassium phosphate buffer,
pH 7.4, containing 3 mM MgCl.sub.2. The final reaction mixture
composition contained:
TABLE-US-00002 Liver Microsomes 0.5 mg/mL NADPH 2 mM Potassium
Phosphate, pH 7.4 100 mM Magnesium Chloride 3 mM Test Compound 1.0
.mu.M.
[0293] The reaction mixtures were incubated at 37.degree. C. and 50
.mu.L aliquots were removed at 0, 3, 7, 12, 20, and 30 minutes and
added to shallow-well 96-well plates which contained 50 .mu.L of
ice-cold ACN with internal standard to stop the reactions. The
plates were stored at -20.degree. C. for 30 minutes, after which
100 .mu.L of water was added to the wells of the plate before
centrifugation to pellet precipitated proteins. Supernatants were
transferred to another 96-well plate and analyzed for amounts of
parent remaining by LC-MS/MS using an Applied Biosystems API 4000
mass spectrometer.
[0294] The in vitro t.sub.1/2s for test compounds were calculated
from the slopes of the linear regression of % parent remaining (ln)
vs incubation time relationship using the formula: in vitro
t.sub.1/2=0.693/k, where k=-[slope of linear regression of % parent
remaining(ln) vs incubation time]. Data analysis was performed
using Microsoft Excel Software.
[0295] The results are shown in FIG. 1 and in Table 2 below.
TABLE-US-00003 TABLE 2 Stability of Tested Compounds in Human Liver
Microsomes Compound T.sub.1/2 .+-. SD 103 20.19 .+-. 4.22 106 26.13
.+-. 0.99 122 35.39 .+-. 1.68 atazanavir 18.63 .+-. 2.99
[0296] Under the assay conditions tested compounds 103, 106 and 122
all demonstrated an increased half-life as compared to atazanavir.
Compounds 106 and 122 showed the greatest differentiation as
compared to atazanavir, demonstrating an approximately 40% and 67%
increase in half-life, respectively.
[0297] The above-described assay was repeated using atazanavir and
Compounds 103, 104, 106, 111, 114, 120, 121, 122, 123 and 131. The
results are shown in FIGS. 2 and 3 and in Table 3, below:
TABLE-US-00004 TABLE 3 Stability of Tested Compounds in Human Liver
Microsomes Compound t.sub.1/2 (min) Avg .+-. SD (n = 3) % change in
t.sub.1/2 atazanavir 18.8 .+-. 0.6 -- 106 25.6 .+-. 0.6 +36 103
17.2 .+-. 0.9 -9 122 28.3 .+-. 0.3 +51 120 26.9 .+-. 1.4 +43 121
18.8 .+-. 1.5 -- 131 30.9 .+-. 1.4 +64 104 23.3 .+-. 0.4 +24 114
31.5 .+-. 0.8 +68 123 23.9 .+-. 0.8 +27 111 23.9 .+-. 0.3 +27
[0298] Under the assay conditions, compounds 104, 106, 111, 114,
120, 122, 123 and 131 all demonstrated an increased half-life of
.gtoreq.24% compared to atazanavir.
Example 17
[0299] Pharmacokinetic Properties. The pharmacokinetic properties
of the compounds of the invention were tested in both rats and
chimpanzees using both oral and intravenous dosing.
[0300] Rat Pharmacokinetics. Compound 122 and atazanavir were
dissolved in a 5% glucose solution with 10% DMI, 15% EtOH and 35%
PG respectively up to 2 mg/mL. Then the combo dose was prepared by
mixing both by 1:1 to yield a final concentrations at 1 mg/mL for
each compound (pH=5-6) for intravenous and oral administration.
[0301] Male Sprague-Dawley rats (body weight: 170 g to 235 g) were
used in this study. Rats were dosed either orally or intravenously
with either Compound 122 (2 mg/kg), atazanavir (2 mg/kg) or a 1:1
combination of Compound 122 and atazanavir (1 mg/kg of each). Blood
samples (300 .mu.L) were collected via the retro-orbital vein at
pre-dose and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hours
post-dose. Blood samples were placed into heparinized eppendorf
tubes (evaporated) and then centrifuged at 8000 rpm for 6 minutes.
100 .mu.L aliquots of plasma were transferred to clean Eppendorf
tubes and stored with the dose formulation at -20.degree. C. until
bioanalysis. For bioanalysis, plasma was thawed and added to it was
20 .mu.L methanol and 500 .mu.L of a 50 ng/ml internal standard
solution (quetiapine in methanol). The sample was vortexed,
centrifuged at 15,000 rpm for 5 minutes and the supernatant
transferred to glass autosampler vials.
[0302] Analyses of plasma samples were performed using a high
performance liquid chromatography/mass spectrometry (HPLC/MS/MS)
method. The LC system comprised an Agilent (Agilent Technologies
Inc. USA) liquid chromatograph equipped with an isocratic pump
(1100 series), an autosampler (1100 series) and a degasser (1100
series). Mass spectrometric analysis was performed using an API3000
(triple-quadrupole) instrument from AB Inc (Canada) with an ESI
interface. The data acquisition and control system were created
using Analyst 1.4 software from ABI Inc. Following intravenous
co-administration of Compound 122 and atazanavir, atazanavir
disappeared more rapidly from the blood. The accelerated reduction
of atazanavir as compared to Compound 122 began between 1 and 2
hours post-IV administration.
[0303] The half-life and AUC following intravenous injection are
shown in the table 4 below. Compound 122 showed a 10.7% increase in
half-life and a 6.0% increase in AUC following intravenous
injection.
TABLE-US-00005 TABLE 4 Half-life of Compound 122 versus Atazanavir
Following Intravenous Co-Dosing in Rats. Compound T.sub.1/2 (h) AUC
(ng * h/mL) Atazanavir 0.23 .+-. 0.01 475 .+-. 15.9 122 0.25 .+-.
0.02 503 .+-. 25.1
[0304] Oral co-administration of Compound 122 and atazanavir
produced an even more pronounced difference in pharmacokinetics
between the two compounds. As shown in Table 5, Compound 122
demonstrated a significant increase in C.sub.max as compared to
atazanavir following oral co-dosing. The C.sub.max, half-life and
AUC of the two compounds following oral co-administration is shown
in the table below. Compound 122 showed a 43% increase in
half-life, a 67% increase in C.sub.max, and an 81% increase in AUC
as compared to atazanavir after oral co-dosing of the two compounds
in rats.
TABLE-US-00006 TABLE 5 Half-life, C.sub.max, C.sub.min. and AUC of
Compound 122 versus Atazanavir Following Oral Co-Dosing in Rats.
Compound T.sub.1/2 (h) C.sub.max (ng/mL) AUC (ng * h/mL) Atazanavir
0.32 .+-. 0.06 109 .+-. 67.2 86 .+-. 51.2 122 0.46 .+-. 0.16 183
.+-. 113.2 156 .+-. 70.6
[0305] Chimp Pharmacokinetics. Run A: A 4 mg/mL solution of
atazanavir and each of Compounds 114, 120 and 122 were prepared in
10% DMI (dimethyl isosorbide), 15% EtOH, 35% PG in D5W.
Specifically, for each compound, 240 mgs of compound was dissolved
in a solution composed of 6 mL of DMI, 9 mL of EtOH and 21 mL PG.
Once the compound was fully dissolved, 24 mL of D5W was added and
the solution mixed. This resulted in a 60 mL solution at 4 mg/mL
for each compound.
[0306] Fifty-five mL of each drug solution is then combined and the
mixture was sterile filtered using a 0.2 .mu.m filter. This
produced 220 mL of a 1:1:1:1 mixture atazanavir:Compound
114:Compound 120:Compound 122. The final concentration of each drug
in the solution was 1 mg/mL. Each animal received 50 mL of this
solution through either IV or PO routes.
[0307] Four chimps (two male and two female) were used in this
study and were fasted overnight prior to administration of the
compound solution. Animals were sedated with ketamine and/or
telazol prior to dosing. Intravenous dosing was achieved by IV
infusion over 30 minutes.
[0308] Approximately 4.5 mL of blood was collected into vacutainer
tubes with sodium heparin as an anticoagulant at 0 (preinfusion),
15 min., 29.5 min (immediately before the end of the infusion), and
then at 6, 15, 30, and 45 minutes, and 1, 2, 4, 6, 8, 10, 12, 24
hours after the infusion is stopped. A similar procedure was used
to collect blood after oral dosing with samples taken at 0
(predose), 15, and 30 minutes, and at 1, 1.5, 2, 4, 6, 8, 10, 12,
24 hours postdose. Following sample collection, the vacutainer
tubes were rocked by hand several times to insure adequate mixing.
Blood samples were placed immediately on wet ice and centrifuged
within 1 hour from time of collection. Following centrifugation,
the resulting plasma was stored frozen at -70.degree. C. until
analysis. The results are summarized in FIGS. 4 and 5 and tables 6
and 7.
[0309] The percentage increase in half-life of the compounds of
this invention relative to atazanavir following intravenous
co-administration is shown in Table 6 below. Compounds 120, 122,
and 114 had significantly longer half lives than atazanavir when
co-dosed in chimps.
TABLE-US-00007 TABLE 6 Percent Increase in Half-Life Relative to
Atazanavir Following Intravenous Co-Dosing in Chimps. Female Chimp
Male Chimp Compound T1/2 % Over Atazanavir T1/2 % Over Atazanavir
122 44% 60% 120 42% 58% 114 32% 46%
[0310] Concentrations in ng/mL of compounds 120, 122, and 114
detected intact in urine 24 hours after intravenous or oral
administration are summarized in Table 7. Table 7 also shows the
ratio of each tested compound of this invention as compared to
atazanavir. There were higher concentrations of the unmetabolized
tested compounds in the urine as compared to atazanavir, indicating
a slower rate of metabolism for the tested compounds as compared to
atazanavir.
TABLE-US-00008 TABLE 7 Higher Urine Concentrations of Tested
Compounds Compared to Atazanavir in Co-Dosed Chimps. Admin Compound
Tested Ratios CHIMP Atazanavir 122 120 114 122:Atazanavir
120:Atazanavir 114:Atazanavir 90A005 PO 516 1180 1110 963 2.29 2.15
1.87 A242E 569 1280 1230 1070 2.25 2.16 1.88 A207B IV 2000 3130
3030 2750 1.57 1.52 1.38 A336C 1790 3250 3110 2820 1.82 1.74
1.58
[0311] Run B: Same as Run A, except the dose was 150 mg orally of
each of atazanavir and compounds 114 and 120, and the vehicle was
10 percent ethanol, 40 percent polypropylglycol in 2.5 percent
citric acid. The C.sub.max, C.sub.min, half-life, AUC, and
clearance (CL, mL/minute/kg) of the compounds following oral
co-administration are shown in table 8 and 9 below and FIGS. 4 and
5. Compounds 114 and 120 had significantly longer half lives
C.sub.max, C.sub.min, and AUC, and had slower clearance rates than
atazanavir when co-dosed in chimps.
TABLE-US-00009 TABLE 8 Run B: T1/2, C.sub.max, C.sub.min. AUC, and
Clearance Differences of Tested Compounds Following Oral Co-Dosing
in Chimps. Compound T.sub.1/2 C.sub.max C.sub.min AUC.sub.0-12 CL
Atazanavir 4.1 2800 32 19560 96 120 6.5 3590 69 26930 65 114 6.2
3180 48 23890 73
[0312] Concentrations in ng/mL of the administered compounds
detected intact in urine 24 hours after oral administration are
summarized in Table 9. There were higher concentrations of the
unmetabolized compound 120 and 114 in the urine as compared to
atazanavir, indicating a slower rate of metabolism for the tested
compounds.
TABLE-US-00010 TABLE 9 Run B: Higher Urine Concentrations of Tested
Compounds Compared to Atazanavir in Co-Dosed Chimps. Compound
Tested Ratios CHIMP Admin Atazanavir 120 114 120:Atazanavir
114:Atazanavir 91A005 PO 1640 2930 2530 1.79 1.54 96A021 3260 5030
4580 1.54 1.40
Example 18
[0313] HIV Anti-viral Activity. The HIV antiviral activity of
compound of the present invention was tested in CEM-SS cells
infected with HIV-1. CEM-SS cells were passaged in T-75 flasks in
RPMI 1640 medium supplemented with 10% heat inactivated fetal
bovine serum, 2 mmol/L L-glutamine, 100 U/mL penicillin and 100
flg/mL streptomycin prior to use in the antiviral assay. On the day
preceding the assay, the cells were split 1:2 to assure they were
in an exponential growth phase at the time of infection. Total cell
and viability quantification was performed using a hemocytometer
and Trypan Blue dye exclusion. Cell viability was greater than 95%
for the cells to be utilized in the assay. The cells were
resuspended at 5.times.10.sup.4 cells per mL in tissue culture
medium and added to the drug-containing microtiter plates in a
volume of 50 .mu.L.
[0314] The virus used for the assay was the lymphocyte-tropic virus
strain HIV-I.sub.RF. The virus was obtained from the NIH AIDS
Research and Reference Reagent Program and stock virus pools were
produced in CEM-SS cells. A pre-titered aliquot of virus was
removed from the freezer (-80.degree. C.) and allowed to thaw
slowly to room temperature in a biological safety cabinet. Virus
was resuspended and diluted into tissue culture medium such that
the amount of virus added to each well in a volume of 50 .mu.L was
the amount determined to yield 85 to 95% cell killing at 6 days
post-infection.
[0315] Each plate contains cell control wells (cells only), virus
control wells (cells plus virus), compound toxicity wells (cells
plus compound only), compound colorimetric control wells (compound
only) as well as experimental wells (compound plus cells plus
virus). Samples were tested in triplicate with eleven half-log
dilutions per compound starting at 0.1 .mu.M of compound. Compounds
104, 120 and 122 were tested, as was atazanavir and AZT. All
compounds were also tested in the presence of 2 mg/mL .alpha..sub.1
acid glycoprotein (AAGP), 10 mg/mL human serum albumin (HSA) or a
combination of AAGP plus HAS.
[0316] Following incubation at 37.degree. C. in a 5% CO.sub.2
incubator, the test plates were stained with the tetrazolium dye
XTT
(2,3-bis(2-methoxy-4-nitro-5sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tet-
razolium hydroxide). XTT-tetrazolium was metabolized by the
mitochondrial enzymes of metabolically active cells to a soluble
formazan product, allowing rapid quantitative analysis of the
inhibition of HIV induced cell killing by anti-HIV test substances.
XTT solution was prepared daily as a stock of 1 mg/mL in RPMI 1640.
Phenazine methosulfate (PMS) solution was prepared at 0.15 mg/mL in
PBS and stored in the dark at -20.degree. C. XTT/PMS stock was
prepared immediately before use by adding 40 .mu.L of PMS per mL of
XTT solution. Fifty microliters of XTT/PMS was added to each well
of the plate and the plate was reincubated for 4 hours at
37.degree. C. Plates were sealed with adhesive plate sealers and
shaken gently or inverted several times to mix the soluble formazan
product and the plate was read spectrophotometrically at 450/650 nm
with a Molecular Devices Vmax plate reader.
[0317] Raw data was collected from the Softmax Pro 4.6 software and
imported into a Microsoft Excel 2003 spreadsheet for analysis by
linear curve fit calculations. The results of the assay are shown
in the table 10 below.
TABLE-US-00011 TABLE 10 HIV Anti-viral Activity in CEM-SS cells
infected with HIV-1 CEM-SS/HIV-1.sub.RF EC.sub.50 (nM) No Serum
+0.5 mg/mL +10 mg/mL + AAGP + Compound Protein Added AAGP HAS HSA
AZT 2 1 2 2 Atazanavir 1 4 4 8 104 <0.3 2 0.9 4 120 0.5 3 1 4
122 0.4 2 0.8 6
[0318] Compounds 122 and 120 yielded EC.sub.50 values of less than
0.4 and 0.5 nM, respectively, in cell culture medium and a 5 to
6-fold increase to 2 and 3 nM, respectively, in the presence of 0.5
mg/mL AAGP. Compound 104 yielded an EC.sub.50 value of less than
0.3 nM in cell culture medium and a greater than 7-fold increase to
2 nM in the presence of AAGP. In the presence of 10 mg/mL HSA,
Compounds 104, 120 and 122 yielded EC.sub.50 values of 0.8, 1 and
0.9 nM, respectively, which was two- to greater than three-fold
less potent than in cell culture medium alone. Antiviral activity
decreased 8 to 15-fold for compound 122 and 120 in the presence of
AAGP plus HSA with EC.sub.50 values of 6 and 4 nM, respectively.
Compound 104 yielded an EC.sub.50 value of 4 nM in the presence of
AAGP plus HSA, which was greater than 13-fold less potent than in
cell culture medium alone. The presence of AAGP, alone or in
combination with HSA, resulted in the most significant protein
binding and loss of antiviral activity for Compounds 104, 120 and
122. Each of these serum protein affects is similar to that
observed for atazanavir. Each of the compounds of this invention
tested in this assay were at least as potent as atazanavir.
[0319] Without further description, it is believed that one of
ordinary skill in the art can, using the preceding description and
the illustrative examples, make and utilize the compounds of the
present invention and practice the claimed methods. It should be
understood that the foregoing discussion and examples merely
present a detailed description of certain preferred embodiments. It
will be apparent to those of ordinary skill in the art that various
modifications and equivalents can be made without departing from
the spirit and scope of the invention. All the patents, journal
articles and other documents discussed or cited above are herein
incorporated by reference.
* * * * *