Note: Descriptions are shown in the official language in which they were submitted.
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HIV-1 Protease Ihzhibitors
RELATED APPLICATIONS
The present application claims priority from U.S. provisional patent
application
serial No. 60/693,134, filed on June 22, 2005, which is hereby expressly
incorporated by
reference.
GOVERNMENT SUPPORT
This invention was made with support provided by the NIH/NIAID (Grant No. P01
GM 066524); therefore, the government may have certain riglits in the
invention.
BACKGROUND OF THE INVENTION
Protease inhibitors (PIs) are potent antiretroviral drugs for the treatment of
patients
infected with Human Immunodeficiency Virus (HIV). Several known PIs are
recommended as part of the "preferred regimen" for patients in the guidelines
of
International AIDS Society-USA (IAS-USA) and the U.S. Department of Health and
Human Services (DHHS). However, use of these drugs has sometimes been
associated
with the development of irreversible HIV resistance, due to mutation of the
virus.
The development of HIV 1 protease inhibitors is regarded as a major success of
structure-based drug design; in fact, known protease inhibitors are generally
considered to
be the most potent drugs currently available for the treatment of AIDS. These
agents are
often combined with other agents to establish highly active antiretroviral
therapy (HAART),
which is credited with an approximately three-fold drop in the death rate from
AIDS since
about 1995. Despite this remarkable success, there is still much concern
regarding the
treatment of AIDS, largely because of the emergence of HIV mutants that resist
current
therapy. Drug resistance occurs when mutations in the target protein allow the
protein to
retain function while no longer being inhibited efficiently by the drug. In
the case of HIV-1
protease, drug resistance occurs when, even in the presence of protease
inhibitors, the
enzyme is able to cleave the Gag and Pol polyproteins in at least nine
different locations,
allowing viral maturation. Viral resistance is regarded as a critical factor
in clinical failure
of antiviral therapy. The relatively rapid appearance of resistant viral
mutants among
treated HIV patients is attributable to the virus's high rate of replication,
coupled with a
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WO 2007/002172 PCT/US2006/024108
high intrinsic rate of mutation due to the infidelity of the HIV reverse
transcriptase. In
addition, the current HIV 1 protease inhibitors were designed specifically to
inhibit
primarily a single variant of HIV-1 protease.
Developing different classes of therapeutic agents is not likely to be an
adequate
solution to the problem of resistance to protease inhibitors, primarily
because the same
basic mechanisms readily generate viral strains resistant to other agents.
Thus, resistance is
a major clinical problem for the other major class of HIV drugs, the reverse
transcriptase
inhibitors, and resistance to newer, preclinical agents, such as the fusion
inhibitors is readily
elicited iri culture.
The challenge for the research community is therefore to develop drugs, e.g.,
HIV 1
protease inhibitors, that are less vulnerable to drug resistance and/or more
active against
current protease resistant HIV-1 isolates. The present inventions address this
challenge by
integrating clinical data, in vitro virology, protein crystallography,
computational modeling
and chemical design, and high-throughput chemistry and compound screening. HIV
protease is a particularly appealing target, as inhibition of its activity is
clinical effective;
however, it can evolve to tolerate extensive mutation that confers drug
resistance while
retaining enzymatic function. As the design of the initial protease inhibitors
was structure
based, a huge knowledge reservoir exists for this protein.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery of new
small
molecule protease inhibitors (Pls). These inhibitors, and methods of making
and using
them, are described herein. Because these inhibitors do not protrude beyond
the substrate
binding envelope on the protease, it is expected that these inhibitors will be
less likely to
induce the development of resistant strains.
In one aspect, the invention features PIs described herein, or an enantiomer,
diastereomer or a pharmaceutically acceptable salt thereof, and pharmaceutical
compositions for inhibiting HIV protease that include a pharmaceutical carrier
and a
therapeutically effective amount of a PI described herein.
In another aspect, the invention features methods for treating HIV in a
subject, by
administering a therapeutically effective amount of a compound or
phamiaceutical
composition described herein. In some embodiments, the methods further include
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administering a second therapeutic agent, e.g., a non-nucleoside reverse
transcriptase inhibitor
(NNRTI) such as efavirenz (SustivaTM), nevirapine (ViramuneTM) and delavirdine
(RescriptorTM); an nucleoside reverse transcriptase inhibitor (NRTI) such as
AZT (zidovudine,
RetrovirTM)/3TC (lamivudine, EpivirTM) and d4T (stavudine, ZeritTM)/3TC, and d-
drugs (ddl
[didanosine, VidexTM/VidexECTM], ddC [zalcitabine, HividTM], d4T); a
nucleotide reverse
transcriptase inhibitor, sucli as tenofovir (VireadTM); and a fusion
inhibitor, such as enfuvirtide
(FuzeonTM). In some einbodiments, the compound or pharmaceutical composition
is
administered as part of a highly active antiretroviral therapy (HAART)
regimen.
Unless otherwise defined, all technical and scientific terms used herein have
the same
meaning as commonly understood by one of ordinary skill in the art to which
this invention
belongs. Methods and materials are described herein for use in the present
invention; other,
suitable methods and materials known in the art can also be used. The
materials, methods, and
examples are illustrative only and not intended to be limiting. All
publications, patent
applications, patents, and other references mentioned herein are incorporated
by reference in
their entirety. In case of conflict, the present specification, including
definitions, will control.
Other features and advantages of the invention will be apparent from the
following
detailed description and figures, and from the claims.
BRIEF DESCRIPTION OF DRAWINGS
Figures la-b depict possible synthetic routes to selected inventive compounds.
Figures 2a-f depict selected compounds of formula I and associated K; values.
Figures 3a-d depict selected compounds of formula III.
Figures 4a-c depicts additional selected compounds of formula I.
Figure 5 depicts additional selected compounds of formula I.
Figures 6a-k depict anti-HIV drugs by class.
Figure 7 depicts the synthesis of protease inhibitors containing [A] a
hydroyethylamine
(HEA) core or [B] a hydroxyethylene (HE) core. Key: (a) EtOH, 70 C; (b) aq.
Na2CO3,
CH2C12, r. t; (c) TFA, CHzCIZ; (d) Et3N, THF; (e) R4X2CO2H, EDCI,
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HOBt, DIPEA, 0 C to r. t.; (f) H2, Pd/C, MeOH, r. t; and (g) aq. NaHCO3,
EtOAc, 0 C to
r. t..
Figure 8 depicts the synthesis of protease inhibitors containing an aza-
hydroxyethylamine (Aza-HEA) core. Key: (a) (CH3)2CHOH, 80 C (b) H2, Pd/C,
MeOH,
r. t; (c) R4X2CO2H, EDCI, HOBt, DIPEA, 0 C to r. t.; (d) TFA, CH2C12i and (e)
R3X1COZH, EDCI, HOBt, DIPEA, 0 C to r. t.; aq. NaHCO3, EtOAc.
DETAILED DESCRIPTION
The protease inhibitors described herein were designed rationally using an
ensemble
of HIV-1 protease variant sequences (available online at hivdb.stanford.edu)
and three-
dimensional structures that the homodimeric HIV protease can tolerate, to
maximize the
likelihood that these HIV-1 protease inhibitors that will evade mutational
resistance.
Recently, a structure-based strategy was proposed to reduce the probability of
drug
resistance by designing inhibitors that interact only with the same residues
that are
necessary to recognize substrate. (King, N. M. et al. Chena. Biol. 2004, 11,
1333-1338; and
Prabu-Jeyabalan, M. et al. J. Virol. 2003, 77, 1306-1315.) Analysis of the
crystal
structures of HIV-1 protease in complex with substrate peptides suggested that
substrate
specificity for HIV-1 protease is based not on a particular amino acid
sequence, but on a
conserved shape ("substrate envelope"). (Prabu-Jeyabalan, M. et al. Structure
2002, 10,
369-381.) Comparison of the substrate structures with protease inhibitor
structures reveal
critical differences between inhibitor and substrate binding to the enzyme. In
case of
substrates, most of the conserved hydrogen bonds occur primarily between the
backbone of
the protease and the backbone of the substrate. Thus, it was determined that
it is important
that the inhibitors are designed to form hydrogen bonds with relatively
conserved residues
and preferably with the backbone atoms of the protease rather than the side
chain atoms.
Remarkably, the new compounds are competitive inhibitors that bind in the
center of
the substrate envelope, which is the active site of the protease molecule.
However, the new
compounds are designed such that they do not significantly protrude beyond the
substrate
envelope, and therefore are less likely to induce escape mutations. The new
protease
inliibitors are useful in the treatment of HIV in susceptible mammals, e.g.,
humans and
certain other primates, and can be administered as a monotherapy, or in
combination with
other tlierapeutic agents, e.g., as part of a highly active antiretroviral
therapy (HAART)
regimen.
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Selected Protease Inhibitors of the Invention. One aspect of the present
invention
relates to a compound, or a pharmaceutically acceptable salt thereof, of
fonnula I:
0 R2
Rs, X~N N S X R4~
H~ 2
Rl R5
I
wherein, independently for each occurrence,
Xl is absent, -0-, -S- or -NR-;
X2 is absent, -0-, -S- or -NR-;
Rl is -OH, -SH or -NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,
(heterocyclyl)alkyl,
aralkyl or heteroaralkyl;
R3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl,
cycloallcyl,
cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl,
aralkyl or
heteroaralkyl;
R5 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl,
(keto)alkyl,
cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl; and
the stereochemical configuration at any stereocenter is R, S, or a mixture of
these
configurations;
s' 0O O
N
provided that when Xl is absent; R3 is not R3A or N-R3A; wherein
R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl,
cycloalkyl,
cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein X, is absent.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein X2 is absent.
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In certain embodiinents, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein XI is absent; and X2 is
absent.
In certain enlbodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Rl is OH.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R2 is aralkyl or
heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R2 is aralkyl.
In certain embodiments, the present invention relates to the aforementioned
A1 A2
A3
compound and any of the attendant definitions, wherein R2 is A5 A4 ; and Al,
A2,
A3, A4 and A5 are independently selected from the group consisting of
hydrogen, halogen,
azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino,
nitro,
sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl,
ether,
alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl,
heteroaryl,
trifluoromethyl and cyano.
In certain embodiments, the present invention relates to the aforementioned
A1 A2
A3
compound and any of the attendant definitions, wherein R2 is A5 A4 ; Al, A2,
A4
and A5 are hydrogen; and A3 is halogen, azide, alkyl, aralkyl, alkenyl,
alkynyl, cycloalkyl,
hydroxyl, alkoxyl, amino, nitro, sulfliydryl, imino, amido, phosphonate,
phosphinate,
carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone,
aldehyde, ester,
heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
In certain embodiments, the present invention relates to the aforementioned
Al A2
A3
compound and any of the attendant definitions, wherein R2 is A5 A4 ; Al, A2,
A3
and A5 are hydrogen; and A4 is halogen, azide, alkyl, aralkyl, alkenyl,
alkynyl, cycloalkyl,
hydroxyl, alkoxyl, amino, nitro, sulfliydryl, imino, amido, phosphonate,
phosphinate,
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carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone,
aldehyde, ester,
heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is alkenyl,
(amino)alkyl,
(amido)alkyl, (keto)alkyl, cycloallcyl, cycloalkenyl, heterocyclyl, aryl,
heteroaryl,
(heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is aryl or
heteroaryl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wlierein R4 is alkyl, aryl or
heteroaryl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein RS is alkyl,
(cycloalkyl)alkyl,
(amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
conipound and any of the attendant definitions, wherein RS is alkyl,
(cycloalkyl)alkyl or
(heterocyclyl)alkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent; X2 is
absent; Rl is
OH; R2 is aralkyl; R3 is aryl or heteroaryl; R4 is alkyl, aryl or heteroaryl;
and R5 is alkyl,
(cycloalkyl)alkyl or (heterocyclyl)alkyl.
Another aspect of the present invention relates to a compound, or a
pharmaceutically acceptable salt thereof, of formula II:
Ph
0 0 0
R3,X'~'H N.S.R4 N-( OH R
s
II
wherein, independently for each occurrence,
Xi is absent or -0-;
R3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl,
aryl,
heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
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R4 is aryl, heteroaryl, aralkyl or heteroaralkyl; and
R6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or
heteroaralkyl;
p
provided that when Xl is absent; R3 is not R3A or N-R3A; wherein
R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl,
cycloalkyl,
cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is alkenyl,
(amino)alkyl,
(amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,
heteroaryl,
(heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is aryl or
heteroaryl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R4 is alkyl, aryl or
heteroaryl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R6 is alkyl,
(cycloalkyl)alkyl,
(amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R6 is alkyl,
(cycloalkyl)alkyl or
(heterocyclyl)alkyl.
In certain embodiments, the present invention relates to the aforementioned
0H3CN
compound and any of the attendant definitions, wherein R3 is CH3
H3C~N~~ H3CH3CH3C
O O O CH3
O p
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O
H3CO H3C N~ N HO VN N/ N OH ~ e > > s ~
O CH3 CF3
FsC~~ , HsC "-
F
N CHs
S 11 CH3 HO~ F ~..
/
I \
F
F
OH
HO HO
H
HO HO ~ ~`~ CH3
I ~ I ~ ~ H3C"j/`~
CI Br
H3C NI~ CH CI ~`~. HO HO ~~r..
~ 3
I I~
0 3
CH >
> > > > H F
CH3 ~ H3C N H3C N N H
\
H3C~ ~ ^ o ~ 0
OH , CH3 CH3, s or F
In certain embodiments, the present invention relates to the aforementioned
OCH3
compound and any of the attendant definitions, wherein R4 is F
p N H3 NI~ NO H3C N
:~O ~N ~ }-CH3 ~ ~ N CH s , CHs , S
OCH3 ,
F
F
N OCH3
-CH3 S~
,---,/
F o ,
NH2 H3C I H C
/\
~,. , ~.. F or 4`'- CH3 .
In certain embodiments, the present invention relates to the aforementioned
/~p c compound and any of the attendant definitions, wherein R6 is ~
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(:H3
H3C HO HO
`'~-CH3 S `~õ~CH3 `V-CH3 CH3
> > > > > > >
H3C CH3 H3C C CH3
H3C CH3 )1,OH 1,,OH
~ H H O CH3or
0
JII-N'CH3
6OH
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent; and R3 is
0
H3C N N 0
H3C.N\ H3CCH3 H3C\
CH3 0 , 0 O
~+ 0
0
H3C\ H3CO I H3C N~ ~ NHO V ON ~ N
11
>
N ~
cr O
OH O 0\/~ ~`/~/~`'
> > > >
N
CH3 CF3 / S S CHCC\ F3C~ H3C~~ >
> > > , ,
F
HO I~~ F CH3 ~ HO HO OH `~r CH3 ~
F )~ ~~
F HO / HO ~
>
CI
OH S H3CUN CH3
I~
H3C,"\ 0 CH3 ~/~ I / - 10-
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H
Br ~ ~ HO CH3 `~ H3C N
HO ~4..
H3C N
~ H3C p ^ y ~
I/ OH CH3 CH3, 0 CH3 or
F
N
F I O
In certain embodiments, the present invention relates to the aforementioned
~ \
H3C N~N
Y\
compound and any of the attendant definitions, wherein Xl is absent; R3 is CH3
O
H3C- NFi3CH3C '~ H3C~~
0 , 0 O CH3
\ O~v O O N~ ~.
H
3CO y H3C N\ N HO N~
N/ N~ I/ OH
> > > ,
O CH3 CF3
O-\ , F3C " \ H3C \ F
N CH3
S 11 CH3 HO F ~
/ I
S F
~ , Br F OH CH3
OH
HO I ~ ~.. HO ~ ~ ~+ - ~ S HO ~ HO ~ > ~ H3C~<31 > > > >
CI Br
H3C N CH CI ~.. HO ~~.. HO ~~..
3
y
0 CH3 I ~ C F
H3
za~ H3CyN HgCu N N
H3C O /~ II I/ IOI
OH , CH3 CH3 ~ 0 CH3 or F ; and R4 is
3
OCH ~ N H3 N N H3C N
/ N ~CH
3
~ N S
OO CH 3 3
CH
F > > > > > 3
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F
F
N
~/ ~ ~~CH3 I/ S
`~ OCH3 , F , , ~ , ~ OCH NH2 H3C
3 H3C
~ ~CH3
,~, ~ F or~
In certain embodiments, the present invention relates to the aforementioned
il--\
H3C N,N
Y'll
compound and any of the attendant definitions, wherein Xl is absent; R3 is CH3
O
H3C,N\ H3C\ O CH3 H3CH3C\ ^/~,.
~O 0 O j0~ _ O N~ ~-
H3C0 H3C N
N HO VIN-
N `+
/ N~ OH
> > > > > >
O CH3 CF3
F3C"I~~~ H3C"J':~~~
F
N HO CH3
s S 11 CHci:~~ ~ F ~..
Br/ F F I/
> > > >
OH CH3
H O/v / I~~z HO
HO HOI~~c > = `~ S I
H3C,"I'/"ZI
> >
CI Br
H
H3C N CH CI ~~.. HO ~.. HO
3
O CH3 ~`~ I / , I / CH3 H F
H C ~ H3C II N H3C N N
~ y~
3 0
OH CH3 CH3 ~ 0 CH3 or F ; and R6 is
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CH3
H3C I) I HO HO
0 ,"~CH3 ~ S ~KCH3 CH3
a a a a a a a a
H3C H3C CH3 H3C CH3 ~
CH3 CH3 ~OH OH ' N
, H H
0
0 ~N,CH3
CH3 or ~ OH
In certain einbodiments, the present invention relates to the aforementioned
OCH3
compound and any of the attendant definitions, wherein R4 is F
o CH3 N NO H3C
N N ~
~ j ~ }-CH3 ~ ~
N \ ~g ~
~O , , CH3, CH3, ~4.. OCH3
F
F
~ N OCH3
~'\CH3 ( / S
F , O
, ~ ,~.
NH2 H3C H3C ~ H C
/\CH3 ,, 'O 'IO /'CH3
F or ~ and R6 is ~r, ~
CH3
HO HO H3C
yz~, S yt, I `+~~~ `~,.~KCH3 '~~CH3 -CH3 cH3
" a " a a a a a a
H3C CH 3 H3C CH3 0 ~CH3
~OH ~OH JN~ \~ ~CH ~ N
~ ~, ~- H , ~ 3 or OH
In certain embodiments, the present invention relates to the aforementioned
/ ~
H3C N N
Y'll
compound and any of the attendant definitions, wherein Xl is absent; R3 is CH3
H O
H3C.N~A.. H3C~~.. CH3 H3C\ ^/~.. H3C
0 , 0 O 0 a 0 - 13-
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O N H3CO H3C N N HO
11
N N
OH
, a a a a
O CH3 CF3
0~~ F3C~~ a H3C'~~ ,
F
S NCH HO I~~+ CH3 ~ 11 CU\ (:~~ F Br , F F , I / OH CH3
HO I~, HO I~~ = ~.L S
OH
HO / HO ~ H3C,,-,~~
a a a a a
CI Br
H3C NCH CI ~~r.. HO ~~`4,. HO
3
0 CH3 I/
C H F
H3
`~ H3C~N H3C N N
H3C y Jc
OH OCH3 CH3 0 CH3 or F 0
; R4 1s
~ OCH3 N N
H3 N' `~N O ~
> N H3C N CH
~~ }- 3
CH3 CH3
F a ~ a a a a
F
F
~/ O CH3 S
`~ OCH3 , F , ,
I~ OCH3 NH2 H3C H C
~ / `CH3 .
~ F or ~ - and R61s
CH3
~ H3C I~ I ~ HO HO
O O /~CH3 S ~,. ~..~`CH3 ~CH
~ a a a a a 3
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H3C H3 C CH3 H3C CHs
CH3 H ~OH
CH3
H H
0
O ~N,CH3
'~~CH3 or ~ OH
Another aspect of the present invention relates to a compound, or a
pharmaceutically acceptable salt thereof, selected from the group consisting
of
CH3 I CH3
H 0 Q. ~/ 0 Q~ /~
N NSD N
H3C'N~N NS~ N H3C N'
O H OH I/ H OH
$ ~ 'GJ
NC
H, CH,
O 0 ~
pq
H3C0 I N N S\O N HaC N~ N NS` N
N H OH I H OH 0
O~/ , ~
CH3
\~ N \~ /
O O r~> O ON NN H3C N~ N N'S~ \ OCH3
H OH O ~/ H OH O
00
00
/ CH3 p OCH3
b
HO\ 0~~~> 0 O H3C N~ H N SO N H3C0 H N-SO
jOj OH N OH
0_/ 0~/
F OCH3 F
F F
O \lo /~ F 0 o O o
H ` \ o \ v \
H3C~N,LH N'S F HO S0 O NS~
0 CH3 OH OH H OH
51/ , F SJ
OCH3 F / OCH3
0` \ ~ o O\ 0 0 \ ~
CH3 O
11
I F \ I ~
F N N'SO H3C\ ^\J~N NSO HO e
N N
'SO
H OH 0~ H OH F HO H OH
, ~ , ~
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F OCH3 F
F I F
CH3 0 o p` \ OH 0 P p\ \ ~ I O O\
F3C" v N N'S~ HO e N N'S N N'S`
O
H H OH F
~
H OH
I-S o F HO OH
I'~
pCH3
/ NCI 0 IO
CH3 0
H N\SO \ ~ CH3 O p C l
/~ S CH3
p
H N~SO CH ~/ H OH N'
OH OH 3 \
~ i ~
SJ
,
N Br 0 p \ N
CF3 0 Q~ O H C O
H3C" v N N'S 3 N N' p a H3C N N/\
H OH O CH3 H OH \ CI ~H O CH3
0 OH r
SI / J~'
OCH3 OCH3
/
/
H O \ I H O o~ \ I
H C,N~N N.S\ \ H3C'N~H N-S~
3 O H OH 0 O OH YOH
CH3
OCH3 OCH3
3
/ O 0
H \ I O p /
` \
H3C'N~N N'S H3C N\ N'
0 H OH ~,,OH ~/ H OH O
CH3 ~
OCH3 OCH3 OCH3
3
b / / o
O oO ~ \ I ~ O~~ \ ~
H C I N~ H N~SO H C I N~ H ~S (~ 1 ll N N S`
3 // OH OH 3 OH õOH v`/ `H O
~ OH ~
CH3 ~ C`iH3
OCH3 CH3
OCH3 po,
O O \ I H O I O\ ~ N
~H N O ~H 0 H H3C-N~N N-SH3
OH yOH OH , p OH 0
CH3 ~ CH3
CH3 / CH3
H 0 0 I_ N 0 I S\
H3C;N~H N.SO~,{CH3 H3C N~ N N\S~N
0 OH ~,OH ~/ H OH O CH3
CH3 ~
- 16-
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I CH3 CH3 CH,
0 O ~N S~ O~ S4
H3C N N NS~ ~l~ O~ ~N H
I H OH OOH CH3 H OH N~SO CH3 OH N OOH CH3
CH, ~ CH3
/
0 p H p o \\ p \
H C'N~~N N'S` \ H3C.N~N N'S~ H3C N S`
o H OH O \
3 0 H N
OH `~,,OH ~/ H OH ' 0
~ 1CH3 ~ / I ~
0 O~ 0~ \ I O O p ~\)
H3C I N~ H N.S` ~ N Q \\ ~ ~o/\~f
S H N~
/ OH ~111OH H OH , O OH ~1110H
CH3 9 CH3
OCH3 N
CH3 O p\ CH3 O 0 I_S>
H N.O ~H N~O
0 OH ~ /CH3 0 OH ~ /CH3
CH, H3 I CT H3
N
al OCH3 ocs\
O O~ O p HO \ N N,S` HO \ N N'S`
I/ H' OH OCH3 H OH ~ H3
Y 3 3
/ F H3C O 0H~~\ OCH3
CF3 O õ pS \ ~ OS \ ~
H3C~~N N' ~p N N' 0
H OH ~/CH3
H OH ~F H3C~CH3 T
J
S ~ CH3
H3 O \ / N OCH3
C
~ p ~
HN N NO H3CCH3 p ~N N'S0
H3C^CHH OH ~/CH3 OH H OH ~/CH3
CH3 ' CT H3
P / N \ ~ OCH3 c N
ps \ ~ SOH O pOH O p S
H3CN N' ~0 ~N N' ~O N N'S\
OH H OH y CH3 CH3 H OH YCH3 CH3 H OH ~,/OCH3
CH3 C H3 , iCH3
- 1 7-
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OCH3 N
CH3 O pS CH3 O ~S~
I S
N N' ``
~`N N'
O H OH Q/-ICH3 0 H O H OH Q,~-ICH3
O O ~
P1- OCH, pocr-
HOr N
/ O\ ~ N N'S HO \ N N S
H OH ~~CH3 I/ H OH Q,~-ICH3
, ,
H3pYp p \ 1 p\ / I OCH3 H3C~p p \ p / N
~ \ ~` \ s
HN N N~SN HN N N-S`
H3C~CHH OH ~^CH3 H3C~CHH OH ~/~CH3
/ OCH, N
CH3 O \ pS a CH3 O pS / \
H3C N N' H3 C~N N'
OH H OH Q~-ICH3 OH H OH Q/-ICH3
I OCH3 N
OH O pS OH 0
pS / ~ s~>
\
H N' ~H N' ~O
CH, OH Q O/~CH3 CH, OH `/-ICH3
OCH3 N
CH3 O \ pS / ~ CH3 O \ pS / S~~
J \ \ ~ \
H N ~O ~H N- ~
O
~ O
O OH ~CH3 O OH CH3
CH3 ~ CH3
OCH3 N
O \ `` p ~ ~
\ ~ O ` \ S
HO \ N NS~ HO N N'S~
I/ H OH CH3 I\ / H OH CH3
CH, CH, H3C O \ ~ OCH3 H3C O ~N
0 \ ~ ~~ q \ S)
HN H N - sO HN H N,sO
H3CIICH3 OH ~CH3 H3CI ~CH3 OH CH3
CH, ~ CH3
OCH3 N
CH3 O \ p` \ S / ~ CH3 O \ pS /
~ \ S
H3C H N \O H3C~H N~ ~O
OH OH `'CH3 OH OH ~CH,
CH3 , CH, - 18-
CA 02667445 2008-12-19
WO 2007/002172 PCT/US2006/024108
OCH3 N
OH 0 \ pS \ ~ OH 0 pS \ I \~
S
~H N~O H N-~O
CH3 OH ~CH3 CH3 OH ~CH3
CH3 a CH3
I OCH3 I OCH3
0 p\ CF, 3 O O` \ ~
H3C~H N.SO H3C/j\H N.SO
IOI OH ~/CH3 OH ~/CH3
CT H3 ~C"H3
OCH3 / ~ OCH3
H 0 Q, \ CH3 0 \ 0 I
H Cu N~N NS` F \ N N'S\3 O CH3 H OH OCH3 I/ H OH OCH3
TCHa , and TCHa
Another aspect of the present invention relates to a compound, or a
pharmaceutically acceptable salt thereof, selected from the group consisting
of
F
CH3 \ I / \ I CH3
0
H NSCH3 O H N \ CHI HO p N,
S CH3
0 O
_N OH O iN OH O 3 N H OH 140
HO O H3C'N'OH , HOI O H3C'N'OH H3C'N'OH
F F
O IO p \ IO CH3 O IO
'J'
HO N N'SO N N.S~ CH3 N N~S
I i N H OH YO CH3 N/ H OH ~ OO N/ H OH YO CH3
H3C'N, OH H3C~N', OH H3C'N, OH
I CH3 \ I / \ I CH3
H3CO p p$'j,CH3 H3CO 0 O$ 0 O$''CH3
11\ N N' ~0 ~\ N N' ~O N'
N/ H OH ~0 N/ H OH ~O CH3 I iN H OH "40
H3C'N, OH H3C'N'OH a CH3 H3C'N'OH
F F
/
O
O~ O 3
\ p~ 1 p \ I Q~
N NISO N.S`CH3 N NJS\
/N OH ~O 3 3
H CH 'N OH YO I i N H OH ` OO CH
CH3 H3C'N, OH a HO p CH3 HO O C~H3
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F
P%li 0 CH3 0/ 0 CH3
~~ ~ ~\ I CH
HO \ N N'S\ CH3 HO \ N N'S~ N N~O s
O I i N H OH O CH3 N H OH O
I N H OH Y~
CH3 3 CH3
F
I F
O \~o 1 O CH3 0 O
N NS` H3C0 \ N N SCH3 H3C0 \ N N'Sl
N H OH I` 00 CH3 N/ H OH ' vO N/ H OH O CH3
^~", ~
~,H3 ' l~t'~3 ~ CH3
F
O 3 O~ ~ O O` 1 H 0 0 ~ ~N-CH3
N N'S` CH3 N N.S~ H3C' N~N N'S`
i N H OH YO I i N H OH (O CH3 0 H OH ^/CH3
CH3 CH3 CH3 CH3 OH ,CH3
H3C /N\N O N=~
0~ ~N-CH3
~A
N N'SO
CH3 H OH ~O`
Iv)
O N=~ O~ N-CH3 F OI O~ ~N-CH3
H3CO\~N N'S` N\^~`N N.SO
IN J/'I H OH ONH F O H OH j\ ~CH3
O(H TCH3
~,~ O`` ~N-CH3 F H _ O~J R, ~N-CH3
H
NSO ~rN ~ /~/\N OH 0 FIOI H OH
v
N--\ N=::\
F H O O` ~N-CH3 O ~~ ~N-CH3
\ N\^`~N NSO H3C N,N N'S~
F I/ ~0 H OH 0 I H OH
v , ~ ,
0 IO N=\N-
CH
H3C N, N N'S` ~ 3
O
H OHj~CH3
OH ~CH3
-20-
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WO 2007/002172 PCT/US2006/024108
O \ I N=~N N%~
H C N ~S~-CH3 HO 0 N-CH3
3N N' O I\ N NI' ~Q
I/ H OH ,,, ~NH N H OH
(~~//,
/
N
O \ I N~
O`/v 1` -N-CH3 H O R\ ~N-CH3
H N,SO H3C'N~IN N'So
OH CHa 0 H OH 1-p`
OH CH3 Iv)
7 !
/~ \l
HaC-N,N O \ I N=~ N N=\ ~~ -CH3 0 N-CH3
~H N.O H3COI\ N N.SO
CH3 OH /T CH3 N/ H OH 1 /,
OH CH3 (~/,
e e
\ I
H OII ~N-CHa OII 0~ ~N-CH3
H3C'N~N N-S`O N'SO
O I H OH NH H OH ~
V ~ lv) e
O O~ ~N-CH3 F H 0 0 ' N-CH3
p
HO` ^ ~LN I' SD N~N ~ S~
IiNT H OH ~p F I/ 0 H OH /N~{
(~/) 0 F
F
H 0 L,N-CH3 H O O`
H3C'N~N N'S~ OYN~N N'Sb
O H OH 1",, ~0_ CHa CHa H OH , F
(~/,
F
N N
H 0 O\~ H3C 0 O \ O`~ rV,0
O\/N,, H N.SI / 0 O F OH N O CH3 ~\
3 H N.S/O CH3
C(H3 CH OH S OH S N.No OH S
/ I /
f ) D
N N N
CH3 0 0
S r,O H3C 0 \ OS I_ O \ CHa Q ~S I_ O
FaC~~~H N\O/ CHa 1 ~I H NOCHa H N0~CHa
OH S ~ OH OH
~ e e
- ~l-
CA 02667445 2008-12-19
WO 2007/002172 PCT/US2006/024108
N / ~ rN
F CH3 O \ Q3 \ I OCH S0~ OS~O Br O \ OS I_ O
H N- O H N~ O CH3 H ~O~IfCH3
OH OH S OH
I/ ~/ , ~/ and
F
F
#1F
O OS ~H N/ ~OH Another aspect of the present invention relates to a compound,
or a
pharmaceutically acceptable salt thereof, selected from the group consisting
of
OCH3 OCH3
o H,CS_ -/~
o ,~ ~
H N~ ~/ NH N~~O
F3C-S \ / ;T"~'
p O
Oy O OH
,and
/ ~
O, OCH3
OH O ~
NH NS\O
H3C )-O OH
Z (',H3 O
CH3
Another aspect of the present invention relates to a compound, or a
pharmaceutically acceptable salt thereof, of formula III:
0 R2 R5 R4
R3.X~N~NYX2
R1 R7 0
III
wherein, independently for each occurrence,
Xi is absent, -0-, -S- or -NR-;
X2 is absent, -0-, -S- or -NR-;
Rl is -OH, -SH or -NHR;
R is hydrogen, alkyl, aralkyl, heteroarallcyl or acyl;
R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,
(heterocyclyl)alkyl,
aralkyl or heteroaralkyl;
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R3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (lceto)alkyl,
cycloallcyl,
cycloalkenyl, heterocyclyl,- aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl,
arallcyl or
heteroaralkyl;
R5 is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R7 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl,
(keto)alkyl,
cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl; and
the stereochemical configuration at any stereocenter is R, S, or a mixture of
these
configurations;
YO~IrO O-~fO
provided that when Xl is absent; R3 is not R3A or N-R3A; wherein
R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl,
cycloallcyl,
cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl;
O~o O-'~O
N
and provided that when X2 is absent; R4 is not R4A or N-R4A;
wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl,
(lceto)alkyl,
cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl,
aralkyl or
heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein X2 is absent.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent; and X2 is
absent.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Rl is OH.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R2 is aralkyl or
heteroaralkyl.
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WO 2007/002172 PCT/US2006/024108
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R2 is aralkyl.
In certain embodiments, the present invention relates to the aforementioned
A1 A2
A3
compound and any of the attendant definitions, wherein R2 is A5 A4 ; and Al,
A2,
A3, A4 and A5 are independently selected from the group consisting of
hydrogen, halogen,
azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl,
ainino, nitro,
sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl,
ether,
alkylthio, sulfonyl, sulfonainido, ketone, aldehyde, ester, heterocyclyl,
aryl, heteroaryl,
trifluoromethyl and cyano.
In certain embodiments, the present invention relates to the aforementioned
Al A2
A3
compound and any of the attendant definitions, wherein R2 is A5 A4 ; Al, A2,
A4
and A5 are hydrogen; and A3 is halogen, azide, alkyl, aralkyl, alkenyl,
alkynyl, cycloalkyl,
hydroxyl, alkoxyl, amino, nitro, sulflrydryl, imino, amido, phosphonate,
phosphinate,
carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone,
aldehyde, ester,
heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
In certain embodiments, the present invention relates to the aforementioned
A1 A2
A3
compound and any of the attendant definitions, wherein R2 is A5 A4 ; Al, A2,
A3
and A5 are hydrogen; and A4 is halogen, azide, alkyl, aralkyl, alkenyl,
alkynyl, cycloalkyl,
hydroxyl, alkoxyl, amino, nitro, sulflrydryl, imino, amido, phosphonate,
phosphinate,
carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone,
aldehyde, ester,
heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is alkenyl,
(amino)alkyl,
(amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,
heteroaryl,
(heterocyclyl)alkyl, aralkyl or heteroaralkyl.
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In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is aryl or
heteroaryl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R4 is alkyl, aryl or
heteroaryl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein RS is hydrogen.
In certain embodiments, the present invention relates to the aforementioned
Bi B2
B3
compound and any of the attendant definitions, wherein R7 is B5 B4 ; and B1,
B2,
B3, B4 and B5 are independently selected from the group consisting of
hydrogen, halogen,
azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino,
nitro,
sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl,
ether,
alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl,
heteroaryl,
trifluoromethyl and cyano.
In certain embodiments, the present invention relates to the aforementioned
B1 B2
g3
compound and any of the attendant definitions, wherein R7 is B5 B4 ; B1, B2,
B4
and B5 are hydrogen; and B3 is halogen, azide, alkyl, aralkyl, alkenyl,
alkynyl, cycloalkyl,
hydroxyl, alkoxyl, amino, nitro, sulfliydryl, imino, amido, phosphonate,
phosphinate,
carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone,
aldehyde, ester,
heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
In certain embodiments, the present invention relates to the aforementioned
Bi B2
B3
compound and any of the attendant definitions, wherein R7 is B5 B4 ; B1, B2,
B3
and B5 are hydrogen; and B4 is halogen, azide, alkyl, aralkyl, alkenyl,
alkynyl, cycloalkyl,
hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,
phosphinate,
carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone,
aldehyde, ester,
heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
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In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R7 is alkyl,
(cycloalkyl)alkyl,
(amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R7 is alkyl,
(cycloalkyl)alkyl or
aralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent; X2 is
absent; Rl is
OH; R2 is aralkyl; R3 is aryl or heteroaryl; R4 is alkyl, aryl or heteroaryl;
R5 is hydrogen;
and R7 is alkyl, (cycloalkyl)alkyl or aralkyl.
Another aspect of the present invention relates to a compound, or a
pharmaceutically acceptable salt thereof, of formula IV:
O Ph
R3.XJ~N NuRq.
~ H II
OH R7 0
IV
wherein, independently for each occurrence,
XI is absent or -0-;
R3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl,
aryl,
heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is aryl, (amino)alkyl, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl,
heteroaryl,
aralkyl or heteroaralkyl; and
R7 is alkyl, cycloalkyl, (cycloalkyl)alkyl or aralkyl;
O~ ~s O--fO
N s'
provided that when XI is absent; R3 is not R3A or N-R3A; wherein
R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl,
cycloalkyl,
cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl;
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.~~N O ~ OO
and provided that when X2 is absent; R4 is not R4A or N- R4A;
wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl,
(keto)alkyl,
cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl,
aralkyl or
heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is (amino)alkyl,
(amido)alkyl,
(keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl,
aralkyl or
heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R4 is aryl,
(amino)alkyl,
(amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R7 is alkyl, cycloalkyl
or
(cycloalkyl)alkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent; and R3 is
(amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl,
heteroaryl,
(heterocyclyl)alkyl, arallcyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent; R3 is
(amino)alkyl,
(amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,
(heterocyclyl)alkyl,
aralkyl or heteroaralkyl; R4 is aryl, (amino)alkyl, (amido)alkyl, (keto)alkyl
(heterocyclyl)alkyl or heterocyclyl; and R7 is alkyl, cycloalkyl or
(cycloalkyl)alkyl.
In certain einbodiments, the present invention relates to the aforementioned
CH3
compound and any of the attendant definitions, wherein R3 is 'CO
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F
~_
\ / H3C OyCH3
OCH3 O\ / -
~ O H3C~ ,,NH
HO , ~ O ~
H C O~CH3 H3C , I
H3C3 NH <~O o 0l
CH3, or _O .
In certain embodiments, the present invention relates to the aforementioned
OCH3
com ound and any
p of the attendant definitions, wherein R4 is F
H3C Oy CH3 H3C O y CH3
- NH OCH3
H3
O \ / C~ H3C~H ry-
5,
H3C Oy CH3 H3C OyCH3 H3C Oy CH3
H3C NH H3C\ NH H3C\ ~ NH
O,
H3CCH3CH3 H3CTCH3 H3C CH3 H3C,---ICH3
O~CH3
H3C N
H3C NH NH `~, NH ~ ~~ ~
O~O O N O N
CH3, O OCH3, H or H
In certain embodiments, the present invention relates to the aforementioned
CH3
compound and any of the attendant definitions, wherein R7 is ~CH3,
w P -\0 10 orI
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein X, is absent; and R3 is
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F
CH3 -
OCH3
O HO 0 -
, O
O \ / ,
H3C O~CH3 H3C OCH3 H3C
H3C ~,,NH H3C
o
clq
0,CHsor 0, In certain embodiments, the present invention relates to the
aforementioned
compound and any of the attendant definitions, wherein X, is absent; R3 is
CH3 F -
~ ~ j/' O OCH3 \ / - ,
rl~ 5 O O \ / F~O
, ,
H3C Oy CH3 H3C O~CH3 H3C
O\
H3C ~,,NH H3C
CH3, or 0; and
O CH3
OCH - H3C NH
~ ~ 3 O) O \ / H3 ,,,,,,,,
C~``
is F o ~ > > >
H3C O`\/CH3 H3C O\/CH3 H3C Oy CH3
H3C~NH ^ /OCH3 H3C NH H3CNH
O cO H3CCH3CH3 H3CTCH3 H3C CH3
H3C O~CH3 H3C O~CH3 = XN
H3C NH H3C NH NH "NH
O--OCH OOCH O~ N
3, 3, H
H3C,---,CH3
D
O N
or H .
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent; R3 is
CH3 F
OCH3 -
O ry O \ / ~-CO
HO 0 , , ,
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H3C O~CH3 H3C O~CH3 H3C
H3C~ NH H3C j
CH3~ or O >=R
7
CH3
is CH3,
In certain embodiments, the present invention relates to the aforementioned
I ~ OCH3
compound and any of the attendant v\
definitions, wherein R4 is F
~ ~ / H3C Oy CH3 H3C Oy CH3
O\ O - H3C~ ,,NH H3C~NH ryOCH3
~ O/ ~ / , O
H3C Oy CH3 H3_ C Oy CH3 H3C Oy CH3
H3C NH H3C\ NH H3C\ NH
0,
HCCH33 H3CTCH3 H3C CH3 H3C~CH3
O\/CH3 JCH3
H3C
'( - ~ ,
H3C NH NH `~õNH ~ ~~ O ~~ N
O N
O~ OCH3, O OCH3, H or H and
CH3
R7 is CH3, or
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent; R3 is
CH3 F
a ~ \ / OCH3 O~ / -
O
, ~ ~~0
, HO , - 0
O~CH3 H3C OCH3 H3C
H3C
H3C~,,NH H3C O ~i0 ,
~H3, / V O! OT `O .
R4
O~ CH3
OCH3 ~ ~ O - H3C ~ NH
I ~ > O / H3C~
is F O
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H3C O\/CH3 H3C O`\/CH3 H3C O\'CH3
NH OCH3 ~__C H3C NH H3C NH
H3C ry- O ~,
H3CCH3CH3 H3C~CH3
CH3 OICH3
H3C O ~ H3C
H3C\ NH H3C\ NH NH "NH
O~OCH3~ OOCH3,
H3C CH3 H3C"---.CH3
``~,.
~ N CH3
I ~~ )N O H or O H ; and R7 is ~CH3, or
Another aspect of the present invention relates to a compound, or a
pharrnaceutically acceptable salt thereof, selected from the group consisting
of
H3C / \ I H3C I H3C CH3
O O N NH
O N \ ~
N \ ~ N
H OH O H OH O O--J--CH
3
H3C CH3 H3C CH,
H3C / O H3C CH3
H3C / 0 H3C CH3 \ I O~H NNH
H
\ OH N NH OH O O--CH3
OH rOl O-~-CH3
\ I / ~
OH O H ~ I OH O
\ N N \ O N N \ I O
F I/ H OH O H OH 0
H,C CH3 \ , \ I
I
OH O H i I
H N0 OH O 0
H
OH O b N N CH3
F H OH ~
H3C CH3
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OH O H 0
OH 0 H O \ N N1~CHa
\ N NCH3 F,JI / H OH 0
F I/ H OH O
o ~
OH 0 HaC O /
H _ N- \ I O' N N \ I O
H
FI\ ~ OH 0 OH 0 / If
H3C CHa \
\ I /
OH 0 H~O H3C CHa
OH 0 H \ N_ N OH 0 H
\ N N F/ I/ H OH 0 N _ N NH
~/ H H OH 0 O~CH
F~ O H 0 F a
7 ~ H3C CHa
/
OH O \ I H3C CHa
OH 0 H3C CHa \ N _ NNH
H H
I\ H _ NNH F / OH CHa
F~ OH 0 O')-CH
3
f 7
O H / O / O
H3CO~N N \ I O HaCO~N N \ I
H
O OH O / 0 H OH 0
H3C CHa I
f f
o
H3C0\ ^~LN N \ O O H O
0~ OH O b H3CON _ N~OCHa
0 OH 0
H3C CHa
I
0 H 0 N O H O HaCO'lf'-" KH N~,OCH3
H3CO~N NOCH3 0 OH 0
0 H (65 H 0
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HaC / O %O:Ho ~ I I O 0I H O
H a HaCON N
0 H (65 H 0
H3C CHa
0 H 0
O H O HaCO~H = N
H3C0^AN N 0 OH O
j0~ H OH 0
C CH3
0 H3C CHa H7NH
O
H
H3CON N ~ 'NH HaCO~N N O H OH 0 O~CH 0 H OH O
3 O--l-CHa
H3C CH3 O ~ I H3C CH3 ~ O
C0~ N N NH I/ \ I HaC
H3 H = 0 N
O OH O O~CH , N _ CHa
rN
3 H OH 0 O/j-CHa
H3C CHa
p 0 HaC CHa
O NaC CH3 O ~ H _ N NN
O ~ N H I/ OH O O~CH
a
H
I / OH 0 O-~-CH
a
HaC / O 0 0 ~ I HaC CH
I a
v'O" v`H N~OCHa H3CO~H N 'NH
OH 0 0 OH 0 O-~-CH
3
H3C CH3 H3C CHa
/ I
0 H 3C CHa
0 HaC CH HaCO~H _ N N
3
H3CO,r,,_AN N NH 0 OH O O I^CH
O H OH O--CH
a
3
7 ~
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f.::r I!a"; .,1i". " -i...l~ ~~~ :i~ II::;!Ã i!'mi~ ., ` ~u:'~ tr:.{['.~li..
~~;;I! ,1~ l~
P O H3C CH
H3C H 3
O H CH3 O \ H3C CH3 N NH
H = N II "H N N NH O H OH O O~CH3
O OH O H =H O O~CH O O
3 O---CH
3
H3C CH3 > > >
H3CO H3C
y O CH3 H3Cy O O H3C CH3
HN,, N N HN,, N õ'NH
~H OH IOI H =
H C' 'CH O~CH OH O~
3 3 3 H3C CH3 O CH3
H3C CH3 7 f
H'CyO O \ I HC CH3 \ I H'C / C I O
HN,, H = N O' v'H _ N1~OCH3
H3C" 'CH3 OH O OCH3 OH O
7 )
H3C / O \ I O H 3 C / O I O
H N \{ O~H = N
OH LO OH O
H3C CH3 ~ H3C CH3
H3C / 0 {
H3C O O \ I O~N N~
N H OH O
H OH O
, and
Another aspect of the present invention relates to a compound, or a
pharmaceutically acceptable salt thereof, of formula V:
0 R2 0
R3, X'HN~X2R4 I
Rl R5
V
wherein, independently for each occurrence,
Xl is absent, -0-, -S- or -NR-;
X2 is absent, -0-, -S- or -NR-;
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Rl is -OH, -SH or -NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R2 is"hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,
(heterocyclyl)alkyl,
arallcyl or heteroaralkyl;
R3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl,
cycloallcyl,
cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl,
arallcyl or
heteroaralkyl;
R5 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl,
(keto)alkyl,
cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl; and
the stereochemical configuration at any stereocenter is R, S, or a mixture of
these
configurations;
~~0 O ~O
N
provided that when Xl is absent; R3 is not RsA or N-R3A; wherein
R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl,
cycloalkyl,
cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl;
O~i O
and provided that when X2 is absent; R4 is not N 1
R4A or ~N-R4A;
wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl,
(keto)alkyl,
cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl,
arallcyl or
heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is -0-.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein X2 is absent.
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In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent or -0-;
and X2 is
absent.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Rl is OH.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R2 is aralkyl or
heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R2 is aralkyl.
In certain embodiments, the present invention relates to the aforementioned
A1 A2
A3
compound and any of the attendant definitions, wherein R2 is A5 A4 ; and AI,
A2,
A3, A4 and A5 are independently selected from the group consisting of
hydrogen, halogen,
azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino,
nitro,
sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl,
ether,
alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl,
heteroaryl,
trifluoromethyl and cyano.
In certain embodiments, the present invention relates to the aforementioned
Al A2
A3
compound and any of the attendant definitions, wherein R2 is A5 A4 ; Al, A2,
A4
and A5 are hydrogen; and A3 is halogen, azide, alkyl, aralkyl, alkenyl,
alkynyl, cycloalkyl,
hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,
phosphinate,
carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone,
aldehyde, ester,
heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
In certain embodiments, the present invention relates to the aforementioned
A1 A2
A3
compound and any of the attendant definitions, wherein R2 is A5 A4 ; Al, A2,
A3
and A5 are hydrogen; and A4 is halogen, azide, alkyl, aralkyl, alkenyl,
alkynyl, cycloalkyl,
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hydroxyl, alkoxyl, amino, nitro, sulfliydryl, imino, amido, phosphonate,
phosphinate,
carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone,
aldehyde, ester,
heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is alkenyl,
(amino)alkyl,
(amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,
heteroaryl,
(heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is heterocyclyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R4 is
(heterocyclyl)alkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R5 is alkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein XI is absent or -0-; X2
is absent;
R, is OH; R2 is aralkyl; R3 is heterocyclyl; R4 is alkyl, aryl or heteroaryl;
and R5 is alkyl.
Another aspect of the present invention relates to a compound, or a
pharmaceutically acceptable salt thereof, of formula VI:
0 Ph o
R3, X~H N N~R4
RI R
6
vi
wherein, independently for each occurrence,
Xl is absent or -0-;
Rl is -OH or -NH2;
R3 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl,
aralkyl or
heteroaralkyl;
R4 is aryl, (amino)alkyl, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl,
heteroaryl,
arallcyl or heteroaralkyl; and
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O p
~
provided that when XI is absent; R3 is not ~.N R3A or ~ R3A; wherein
R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl,
cycloalkyl,
cycloalkenyl, heterocyclyl, aiyl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl;
/O
Y~--OrO O--
and provided that when X2 is absent; R4 is not N R4A or N-R4A;
wherein R3A is hydrogen, alkyl, alkenyl, (amino)allcyl, (amido)alkyl,
(keto)alkyl,
cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl,
aralkyl or
heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
conipound and any of the attendant definitions, wherein Rl is -OH.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Rt is -NH2.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is -0-.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is heterocyclyl.
In certain embodiments, the present invention relates to the aforementioned
O C)
~.~
compound and any of the attendant defimtions, wherein R3 is or
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is -0-; and R3 is
heterocyclyl.
In certain embodiments, the present invention relates to the aforementioned
0
compound and any of the attendant definitions, wherein Xt is -0-; and R3 is ~-
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R4 is heterocyclyl.
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In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R6 is alkyl.
n certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R6 is -CH(CH3)2.
Another aspect of the present invention relates to a compound, or a
pharmaceutically acceptable salt thereof, of formula VII:
0 R2 H R4
R3.X'~'H~N.NyX2
Rl R5 0
VII
wherein, independently for each occurrence,
Xl is absent, -0-, -S- or -NR-;
X2 is absent, -0-, -S- or -NR-;
Rl is -OH, -SH or -NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,
(heterocyclyl)alkyl,
aralkyl or heteroaralkyl;
R3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl,
cycloalkyl,
cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl,
aralkyl or
heteroaralkyl;
R5 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl,
(keto)alkyl,
cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl; and
the stereochemical configuration at any stereocenter is R, S, or a mixture of
these
configurations;
O-~
N
provided that when Xt is absent; R3 is not R3A or N-R3A; wherein
R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl,
cycloalkyl,
cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl;
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0 O-'~/ p
N
and provided that when X2 is absent; R4 is not R4A or N-R4A;
wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl,
(keto)alkyl,
cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl,
aralkyl or
heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein X2 is absent.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent; and X2 is
absent.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Rl is -OH or -NH2.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R2 is aralkyl or
heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R2 is aralkyl.
In certain embodiments, the present invention relates to the aforementioned
Al A2
A3
compound and any of the attendant definitions, wherein R2 is A5 A4 ; and AI,
A2,
A3, A4 and A5 are independently selected from the group consisting of
hydrogen, halogen,
azide, alkyl, aralkyl, alkenyl, allcynyl, cycloalkyl, hydroxyl, alkoxyl,
amino, nitro,
sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl,
ether,
alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl,
heteroaryl,
trifluoromethyl and cyano.
In certain embodiments, the present invention relates to the aforementioned
A1 A2
A3
coinpound and any of the attendant definitions, wherein R2 is A5 A4 ; AI, A2,
A4
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and A5 are hydrogen; and A3 is halogen, azide, alkyl, aralkyl, alkenyl,
alkynyl, cycloalkyl,
hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,
phosphinate,
carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone,
aldehyde, ester,
heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
In certain embodiments, the present invention relates to the aforementioned
"S', A1 A2
As
compouiid and any of the attendant definitions, wherein R2 is A5 A4 ; AI, A2,
A3
and A5 are liydrogen; and A4 is halogen, azide, alkyl, aralkyl, alkenyl,
alkynyl, cycloalkyl,
hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,
phosphinate,
carbonyl, carboxyl, silyl, ether, alkyltliio, sulfonyl, sulfonamido, ketone,
aldehyde, ester,
heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is alkenyl,
(amino)alkyl,
(amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,
heteroaryl,
(heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is (amido)alkyl or
heterocyclyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R4 is (amido)alkyl or
heterocyclyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein RS is alkyl or aryl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xt is absent; X2 is
absent; RI is -
OH; R2 is aralkyl; R3 is (amido)alkyl or heterocyclyl; R4 is (amido)alkyl or
heterocyclyl;
and R5 is alkyl or aryl.
Another aspect of the present invention relates to a compound, or a
phanizaceutically acceptable salt thereof, of formula VIII:
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O Ph
H
R3.X~H N.NUR4
OH ~R IOI
8
YIII
wherein, independently for each occurrence,
Xi is absent or -0-;
R3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl,
aryl,
heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is aryl, heteroaryl, aralkyl or heteroaralkyl; and
R6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or
heteroaralkyl;
s~0
-_CIr0 / O--~ O
N
provided that when Xl is absent; R3 is not R3A or N-R3A; wherein
R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl,
cycloalkyl,
cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or
heteroaralkyl;
~00 ~ O-~
/'O
N
and provided that when X2 is absent; R4 is not R4A or N-R4A;
wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl,
(keto)alkyl,
cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl,
aralkyl or
heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein Xl is absent.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is (amino)alkyl,
(amido)alkyl or
heterocyclyl.
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In certain embodiments, the present invention relates to the aforementioned
H3C~CH3
V'NH
compound and any of the attendant definitions, wherein R3 is O4-1-OCH3 or
H3CCH3CH3
~
`~ NH
O--l-OCH3,
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R4 is (amino)alkyl,
(amido)alkyl or
heterocyclyl.
In certain embodiments, the present invention relates to the aforementioned
H3C~CH3
VNH
compound and any of the attendant definitions, wherein R4 is 0--l-OCH3 or
H3CCH3CH3
~
`~ NH
O-~-OCH3110 In certain embodiments, the present invention relates to the
aforementioned
compound and any of the attendant definitions, wherein R6 is alkyl or aryl.
In certain embodiments, the present invention relates to the aforementioned
CH3
~--(
~
compound and any of the attendant definitions, wherein R6 is CH3 or
- N-
~
In certain embodiments, the present invention relates to the aforementioned
H3C~CH3
compound and any of the attendant definitions, wherein R3 is OOCH3 , or
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H3CCH3CH3 H3C~CH3 H3CCH3CH3
~
`~. NH `~~'NH NH CH3
O-)-OCH3; R4 is O-~IOCH3 , or O-~IOCH3; and R6 is CH3 or
N
Syntlaesis of Selected Compounds of the Invention. The protease inhibitors I-
VIII
can be synthesized using the synthetic schemes outlined in Figures la-b. The
definition of
each of the variables may be the same as shown in formulae I-VIII above.
Protease inhibitors I, II, V and VI can be prepared using the synthetic scheme
shown in Figure 1 a (top). As shown therein, an epoxide, for example, can be
reacted with
an amine in a stereoselective manner to yield amine 2. Amine 2 is reacted with
sulfonyl
chloride or an acyl chloride to yield 3. Deprotection followed by reaction
with an acid
chloride, for example, yields inhibitor I, II, V or VI.
Protease inhibitor III and IV can be prepared using the synthetic scheme shown
in
Figure 1 a (bottom). Amino acid 5 can be converted to amine 6 using standard
synthetic
procedures. Reaction with an acid yields amide 7. Deprotection followed by
reaction with
an acid chloride yields inhibitor III or IV.
Protease inhibitor IV can be prepared using the synthetic scheme in Figure lb.
As
shown in the scheme, an epoxide, for example, can be reacted with a protected
hydrazine in
a stereoselective manner to yield hydrazine 9, after deprotection. Hydrazine 9
is reacted
with an acid to yield amide 10. Further deprotection yields amine 11 followed
by reaction
with acid chloride yields inhibitor VII or VIII.
As can be seen from Figures la and lb, the R groups of the inhibitors are
determined by choosing suitable reagents and starting material. Similarly, the
stereochemistry of the inhibitors is determined by choosing appropriate
starting material
and reagents.
Phaf maceutical Compositions. The methods described herein include the
manufacture and use of pharmaceutical compositions, which include the protease
inhibitors
described herein as active ingredients. Also included are the pharmaceutical
compositions
themselves. These compositions can be administered using routes of
administration and
dosages similar to those used for known HIV protease inhibitors.
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It will also be appreciated that certain of the compounds of present invention
can
exist in free form for treatment, or where appropriate, as a pharmaceutically
acceptable
derivative thereof. According to the present invention, a pharmaceutically
acceptable
derivative includes, but is not limited to, pharmaceutically acceptable salts,
esters, salts of
such esters, or a pro-drug or other adduct or derivative of a compound of this
invention
which upon administration to a patient in need is capable of providing,
directly or
indirectly, a compound as otherwise described herein, or a metabolite or
residue thereof.
As used herein, the term "pharmaceutically acceptable salt" refers to those
salts
which are, within the scope of sound medical judgment, suitable for use in
contact with the
tissues of humans and lower animals without undue toxicity, irritation,
allergic response
and the like, and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically
acceptable salts of amines, carboxylic acids, and other types of compounds,
are well known
in the art. For example, S. M. Berge, et al. describes pharmaceutically
acceptable salts in
detail in J. Plzannaceutical Sciences 1977, 66: 1-19, incorporated herein by
reference. The
salts can be prepared in situ during the final isolation and purification of
the compounds of
the invention, or separately by reacting a free base or free acid function
with a suitable
reagent, as described generally below. For example, a free base function can
be reacted with
a suitable acid. Furthermore, where the compounds of the invention carry an
acidic moiety,
suitable pharmaceutically acceptable salts thereof may, include metal salts
such as alkali
metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts,
e.g. calcium or
magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid
addition salts are
salts of an amino group formed with inorganic acids such as hydrochloric acid,
hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with
organic acids
such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,
succinic acid or
malonic acid or by using other methods used in the art such as ion exchange.
Other
pharmaceutically acceptable salts include adipate, alginate, ascorbate,
aspartate,
benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate,
camphorsulfonate,
citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,
formate,
fuinarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate,
heptanoate,
hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl
sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate,
nicotinate,
nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-
phenylpropionate,
phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,
taztrate, thiocyanate, p-
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toluenesulfonate, undecanoate, valerate salts, and the like. Representative
alkali or alkaline
earth metal salts include sodium, lithium, potassium, calcium, magnesium, and
the like.
Further pharmaceutically acceptable salts include, when appropriate, nontoxic
ammonium,
quaternary ammonium, and amine cations formed using counterions such as
halide,
hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and
aryl sulfonate.
Additionally, as used herein, the term "pharmaceutically acceptable ester"
refers to
esters that hydrolyze in vivo and include those that break down readily in the
human body
to leave the parent compound or a salt thereof. Suitable ester groups include,
for example,
those derived from pharmaceutically acceptable aliphatic carboxylic acids,
particularly
alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl
or alkenyl
nioiety advantageously has not more than 6 carbon atoms. Examples of
particular esters
include formates, acetates, propionates, butyrates, acrylates and
ethylsuccinates.
Furthermore, the term "pharmaceutically acceptable prodrugs" as used herein
refers
to those prodrugs of the compounds of the present invention which are, within
the scope of
sound medical judgment, suitable for use in contact with the issues of humans
and lower
animals with undue toxicity, irritation, allergic response, and the like,
commensurate with a
reasonable benefit/risk ratio, and effective for their intended use, as well
as the zwitterionic
forms, where possible, of the compounds of the invention. The term "prodrug"
refers to
compounds that are rapidly transfomied in vivo to yield the parent compound of
the above
formula, for example by hydrolysis in blood. A thorough discussion is provided
in T.
Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the
A.C.S.
Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug
Design,
American Pharmaceutical Association and Pergamon Press, 1987, both of which
are
incorporated herein by reference.
Methods of forniulating pharmaceutical compositions are known in the art; see,
e.g.,
Remington: The Science and Practice of Pharmacy, 20th Ed. (Baltimore, MD:
Lippincott
Williams & Wilkins, 2000). Pharmaceutical coinpositions typically include a
pharmaceutically acceptable carrier. As used herein the language
"pharmaceutically
acceptable carrier" includes saline, solvents, dispersion media, coatings,
antibacterial and
antifungal agents, isotonic and absorption delaying agents, and the like,
compatible with
pharmaceutical administration. Supplementary active compounds can also be
incorporated
into the compositions.
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Pharmaceutical compositions are typically formulated to be compatible with
their
intended route(s) of administration. Examples of routes of administration
include
parenteral, e.g., by intravenous, intradermal, or subcutaneous injection; or
mucosal (e.g., by
oral ingestion, inhalation, or rectal or vaginal administration)
administration. Compositions
intended for parenteral administration can include the following components: a
sterile
diluent, such as water for injection, saline solution, fixed
oils,.polyethylene glycols,
glycerine, propylene glycol or other synthetic solvents; antibacterial agents,
such as benzyl
alcohol or methyl parabens; antioxidants, such as ascorbic acid or sodium
bisulfite;
chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as
acetates, citrates
or phosphates and agents for the adjustment of tonicity, such as sodium
chloride or
dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or
sodiuni
hydroxide, as appropriate. A parenteral preparation can be enclosed in
ampoules,
disposable syringes or multiple dose vials made of glass or plastic.
Pharmaceutical compositions suitable for injectable use can include sterile
aqueous
solutions (where the active ingredient is water soluble) or dispersions and
sterile powders
for the preparation of sterile injectable solutions or dispersion. For
intravenous
administration, suitable carriers include physiological saline, bacteriostatic
water,
Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In
all cases,
the composition must be sterile and should be fluid to the extent necessary to
allow
administration via syringe. It should be stable under the conditions of
manufacture and
storage and must be preserved against the contaminating action of
microorganisms, such as
bacteria and fungi. The carrier can be a solvent or dispersion medium
containing, for
example, water, ethanol, polyol (for example, glycerol, propylene glycol, and
liquid
polyetheylene glycol, and the like), and suitable mixtures thereof. The proper
fluidity can
be maintained, for example, by the use of a coating, such as lecithin, by the
maintenance of
the required particle size in the case of dispersion and by the use of
surfactants. Prevention
of the action of microorganisms can be achieved by various antibacterial and
antifungal
agents, for example, parabens, chlorobutanol, phenol, ascorbic acid,
thimerosal, and the
like. In many cases, it will be preferable to include isotonic agents, for
example, sugars,
polyalcohols, such as mannitol, sorbitol, and/or sodium chloride in the
composition.
Prolonged absorption of the injectable compositions can be brought about by
including in
the composition an agent that delays absorption, for example, aluminum
monostearate and
gelatin.
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Sterile injectable solutions can be prepared by incorporating the active
compound in
the required amount in an appropriate solvent with one or a combination of
ingredients
enumerated above, as required, followed by filtered sterilization. Generally,
dispersions are
prepared by incorporating the active compound into a sterile vehicle, which
contains a basic
dispersion medium and the required other ingredients from those enumerated
above. In the
case of sterile powders for the preparation of sterile injectable solutions,
the preferred
methods of preparation are vacuum drying and freeze-drying, which yield a
powder of the
active ingredient plus any additional desired ingredient from a previously
sterile-filtered
solution thereof.
Oral compositions generally include an inert diluent or an edible carrier. For
the
purpose of oral therapeutic administration, the active compound can be
incorporated with
excipients and used in the form of tablets, troches, or capsules, e.g.,
gelatin capsules. Oral
compositions can also be prepared using a fluid carrier for use as a
mouthwash.
Pharmaceutically compatible binding agents, and/or adjuvant materials can be
included as
part of the composition. The tablets, pills, capsules, troches and the like
can contain any of
the following ingredients, or compounds of a similar nature: a binder, such as
microcrystalline cellulose, gum tragacanth or gelatin; an excipient, such as
starch or lactose,
a disintegrating agent such as alginic acid, Primogel, or corn starch; a
lubricant such as
magnesium stearate or Sterotes; a glidant, such as colloidal silicon dioxide;
a sweetening
agent, such as sucrose or saccharin; or a flavoring agent, such as peppermint,
methyl
salicylate, or orange flavoring.
For administration by inhalation, the compounds can be delivered in the form
of an
aerosol spray from a pressured container or dispenser that contains a suitable
propellant,
e.g., a gas such as carbon dioxide, or a nebulizer. Such methods include those
described in
U.S. Patent No. 6,468,798; hereby incorporated by reference.
Systemic administration of a therapeutic compound as described herein can also
be
by transmucosal or transdermal means. For transmucosal or transdermal
administration,
penetrants appropriate to the barrier to be permeated are used in the
formulation. Such
penetrants are generally known in the art, and include, for example, for
transmucosal
administration, detergents, bile salts, and fusidic acid derivatives.
Transmucosal
administration can be accomplished through the use of nasal sprays or
suppositories. For
transdermal administration, the active compounds are formulated into
ointments, salves,
gels, or creams as generally known in the art. The pharmaceutical compositions
can also be
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prepared in the form of suppositories (e.g., with conventional suppository
bases, such as
cocoa butter and other glycerides) or retention enemas for rectal delivery.
In one embodiment, the therapeutic compounds are prepared with carriers that
will
protect the therapeutic compounds against rapid elimination from the body,
such as a
controlled release formulation, including implants and microencapsulated
delivery systems.
Biodegradable, biocompatible polymers can be used, such as ethylene vinyl
acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic
acid. Such
formulations can be prepared using standard techniques. The materials can also
be obtained
commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal
suspensions (including liposomes targeted to infected cells with monoclonal
antibodies to
viral antigens) can also be used as pharmaceutically acceptable carriers.
These can be
prepared according to methods known to those skilled in the art, for example,
as described
in U.S. Patent No. 4,522,811; hereby incorporated by reference.
The pharmaceutical compositions can be included in a container, kit, pack, or
dispenser, optionally with instructions for administration. A kit may comprise
one or more
compounds described herein and/or one or more other therapeutic compounds
and/or a
device for their administration, e.g., a syringe.
Biological Evaluation of Selected Cornpounds of the Invention. HIV protease
inhibitor activities were determined by fluorescence resonance energy transfer
(FRET)
method. (Matayoshi, E. D. et al. Science 1990, 247, 954-958.) Protease
substrate (Arg-
Glu(EDANS)-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Lys(DABCYL)-Arg) was labeled with
the
energy transfer donor (EDANS) and acceptor (DABCYL) dyes at its two ends to
perform
FRET. Inhibitor binding dissociation constant (Ki value) was obtained by
nonlinear
regression fitting to the plot of initial velocity as a function of inhibitor
concentration based
on Morrison equation. (Greco, W. R. et al. J. Biol. Chenz. 1979, 254, 12104-
12109.) The
activities of all the synthesized inhibitors against wild type HIV-1 protease
(Q7K) were
determined in triplicate. Chemical structures of inhibitors and their
inhibitory activities (Ki
values) are presented in the Figures.
Methods of Ti=eatnaent. The methods described herein include methods for the
treatment or prevention of a viral infection, e.g., an HIV, infection and
Acquired
Immunodeficiency Syndrome (AIDS) or AIDS Related Complex (ARC). Generally, the
methods include administering a therapeutically effective amount of a protease
inhibitor
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described herein, to a subject (e.g., a human or other primate) in need
thereof, or who has
been determined to be in need of, such treatment, e.g., a subject who is (or
is determined to
be) infected with HIV. A subject who is likely to be infected with HIV, e.g.,
a person in a
high risk group, may also be treated as indicated herein. Subjects also
include women who
are expecting a child (pregnant women) and in wliom a treatment reduces the
liklihood of
transmission of HIV to the child.
In addition to HIV-1 infections, the methods described herein are also
expected to be
beneficial for treating or preventing HIV-2 infections. Among HIV 1 viruses,
it is expected
that the methods will be effective against any HIV 1 strain, such as those of
group M, 0 and
N, and subtypes A, B, C, D, E, F, G, H, I, J and K and "circulating
recombinant forms" or
CRFs thereof. The compounds described herein may also be used for treating any
other
viral infections in which the viral agent has a protease inhibitor that can be
inhibited by the
compounds described herein.
As used in this context, to "treat" means to ameliorate at least one clinical
symptom
or parameter of HIV infection or preventing it from worsening or preventing
the
transmission of HIV, e.g., from mother to child. For example, a treatment can
result in a
reduction in viral load, and/or an increase in number of CD4+ T cells ("CD4
count").
When a subject has achieved a reduction in viral load, and/or an increase in
CD4 count,
then treatment may also include maintaining the reduction in viral load,
and/or the
increased CD4 count, e.g., preventing a resurgence of viral load and/or a
decrease in CD4
count. These, and other clinically relevant parameters, can be measured using
methods
known in the art. For example, viral load can be measured, e.g., using PCR or
branched
DNA (bDNA) assays known in the art. CD4 counts can be measured, e.g., using
hematology, DYNAbeadsTM (Dynal Biotech/Invitrogen Corp., Brown Deer, WI), flow
cytometry (e.g., FACSCountTM, BD Biosciences, Franklin Lakes, NJ) or enzyme-
linked
immunosorbent assay (ELISA) methods (see, e.g., Lyamuya et al., J. Immunol.
Methods
195(1-2):103-12 (1996); Paxton et al., Clin. Diagn. Lab. Immunol. 2(1):104-114
(1995);
Saah et al. Arch. Pathol. Lab. Med. 121(9):960-2 (1997); Mwaba et al., Lancet
362 1459-60
(2003)). Healthy adults and teenagers generally have a CD4 count of at least
800 cells per
cubic millimeter of blood; a CD4 count below 200 is associated with severe
risk of illness
(e.g., AIDS-related diseases, such as Kaposi's sarcoma or pneumocystic
pneumonia).
Current guidelines suggest treatment for HIV should be started when the CD4
count is less
than about 350 and/or the viral load is greater than about 50,000.
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A "therapeutically effective amount" is an amount sufficient to effect a
desired
therapeutic effect, e.g., a reduction in viral load, and/or an increase in
number of CD4+ T
cells. An effective amount can be administered in one or more administrations,
applications or dosages. A therapeutically effective amount of a composition
may depend
on the composition selected. The compositions can be administered once, one or
more
times per day, and/or one or more times per week; including once every other
day. In
certain embodiments, the compositions will be administered two or three times
per day.
The skilled artisan will appreciate that certain factors may influence the
dosage and timing
required to treat effectively a subject, including but not limited to the
severity of the disease
or disorder, previous treatments, the general health and/or age of the
subject, and any other
indications present. Treatment of a subject with a therapeutically effective
amount of a
protease inhibitor described herein can include a single treatment or a series
of treatments.
Dosage, toxicity and therapeutic efficacy of the compounds can be determined,
e.g.,
by standard pharmaceutical procedures in cell cultures or experimental
animals, e.g., for
determining the LD50 (the dose lethal to 50% of the population) and the ED50
(the dose
therapeutically effective in 50% of the population). The dose ratio between
toxic and
therapeutic effects is the therapeutic index and it can be expressed as the
ratio LD50/ED50.
Compounds that exhibit high therapeutic indices are preferred. While compounds
that
exhibit toxic side effects may be used, care should be taken to select a dose
and
administration schedule that minimizes severe side effects while maximizing
therapeutic
efficacy.
The data obtained from the cell culture assays and animal studies can be used
in
formulating a range of dosage for use in humans. The dosage of such compounds
lies
preferably within a range of circulating concentrations that include the ED50
with little or
no toxicity. The dosage may vary within this range depending upon the dosage
form
employed and the route of administration utilized. For any compound used in a
method
described herein, a therapeutically effective dosage range can be estimated
initially from
cell culture assays. A dose can be further formulated in animal models to
achieve a
circulating plasma concentration range that includes the IC50 (i.e., the
concentration of the
test compound that achieves a half-maximal inhibition of symptoms) as
determined in cell
culture. Such information can be used to determine more accurately useful
doses in
humans. Levels in plasma may be measured, for example, by high performance
liquid
chromatography. In some embodiments, a therapeutically effective amount of a
new
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protease inhibitor described herein ranges from about 0.1 to 10 mg per day, or
about 0.3 to
mg/day.
In some embodiments, one or more of the protease inhibitors described herein
will
be administered in combination with one or more other therapeutic agents,
e.g., as part of a
5 highly active antiretroviral therapy (HAART) regimen that includes one or
more other anti-
retroviral agents. For example, the methods may include administration of one
or more of a
non-nucleoside reverse transcriptase inhibitor (NNRTI), such as efavirenz
(SustivaTM),
nevirapine (ViramuneTM) and delavirdine (RescriptorTM), 8 and 9-Cl TIBO
(tivirapine),
loviride, TMC-125, dapivirine, MKC-442, UC 781, UC 782, Capravirine, DPC 961,
DPC963, DPCO82, DPCO83, calanolide A, SJ-1366, TSAO, 4"-deaminated TSAO, MV150
and MV026048; a nucleoside reverse transcriptase inhibitor (NRTI), such as AZT
(zidovudine, RetrovirTM)/3TC (lamivudine, EpivirTM), emtricitabine (EmtrivaTM)
and d4T
(stavudine, ZeritTM)/3TC, and d-drugs (ddl [didanosine, VidexTM/VidexECTM],
ddC
[zalcitabine, HividTM], d4T), Abacavir, FTC, DAPD, dOTC, and DPC 817; a
nucleotide
reverse transcriptase inhibitor, such as tenofovir (VireadTM) and PMEA; a
fusion inhibitor,
such as enfuvirtide (FuzeonTM), T20, T1249, 5-helix and D-peptide ADS-Jl; an
entry
inhibitor; a co-receptor binding inhibitor, such as AMD 3100, AMD-3465,
AMD7049,
AMD3451 (Bicyclams), TAK 779; SHC-C (SCH351125), SHC-D, PRO-14ORT inhibitors,
such as foscamet and prodrugs; an RNAse H inhibitor, such as SP1093V and
PD126338; a
TAT inhibitor, such as RO-5-3335, K12 and K37; an integrase inhibitor, such as
L 708906,
L 731988 and S-1360; another protease inhibitor, such as amprenavir and
prodrug GW908,
nelfinavir, saquinavir, indinavir, lopinavir, palinavir, BMS 186316,
atazanavir, DPC 681,
DPC 684, tipranavir, AG1776, mozenavir, GS3333, KNI-413, KNI-272, L754394,
L756425, LG-71350, PD161374, PD173606, PD177298, PD178390, PD178392, PNU
140135, TMC114 maslinic acid and U-140690; a glycosylation inhibitor, such as
castanospermine, deoxynojirimycine; or a binding inhibitor, such as dextran
sulfate,
suramine, polyanions, soluble CD4, PRO-542 and BMS-806. Other drugs include
those set
forth at http://aidsinfo.nih.gov/, hereby incorporated by reference.
Other therapeutic agenets that may be coadministered with with one or more
agents
described herein are agents that inhibit metabolic enzymes, e.g., inhibitors
of cytochrome
P450 (CYP450) enzymes. For example, a compound described herein may be
administered, simultaneously or not, with an inhibitor of CYP3A4, e.g.,
Ritonavir, or an
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inhibitor of CYP2C 19, CYP 1A2, CYP2D6, or CYP2C9. Exemplary inhibitors of 2C9
are
described, e.g., in U.S. publication No. 2006.0069042, hereby incorporated by
reference.
The compounds of the present invention may also be administered in combination
with immunomodulators (e.g., bropirimine, anti-human alpha interferon
antibody, IL-2,
methionine enlcephalin, interferon alpha, HE-2000 and naltrexone), antibiotics
(e.g.,
pentamidine isothiorate), cytokines (e.g. Th2), modulators of cytokines,
chemokines or the
receptors thereof (e.g. CCR5) or hormones (e.g. growth hormone), to
ameliorate, combat,
or eliminate HIV infection and its symptoms.
In some embodiments, the methods further comprise administering a second
therapeutic agent, wherein the second therapeutic agent is selected from the
group
consisting of amprenavir (Agenerase ; APV), tipranavir (Aptivus ; TPV),
indinavir
(Crixivan ; IDV), saquinavir (Invirase ; SQV), lopinavir and ritonavir
(Kaletra ; LPV),
fosamprenavir (Lexiva ; FPV), ritonavir (Norvir ; RTV), atazanavir (Reyataz ;
ATZ),
nelfinavir (Viracept ; NFV), brecanavir, and darunavir.
In some embodiments, the methods further comprise administering a second
therapeutic agent, wherein the second therapeutic agent is ritonavir (Kaletra
; LPV).
In some embodiments, the methods further comprise administering a second
therapeutic agent, wherein the second therapeutic agent is selected from the
group
consisting of zidovudine (AZT; Azidothymidine; Retrovir ), didanosine
(Dideoxyinosine;
ddI; Videx ), zalcitabine (Dideoxycytidine; ddC; Hivid ), lamivudine (3TC;
Epivir ),
stavudine (2',3'-didehydro-3'-deoxythymidine; D4T; Zerit ), abacavir succinate
(1592U89
succinate; Ziagen ABC), Combivir (lamivudine & zidovudine; (-)-3TC & AZT),
and
Trizivir (abacavir & lamivudine & zidovudine; ABC & (-)-3TC & AZT).
In some embodiments, the methods further comprise administering a second
therapeutic agent, wherein the second therapeutic agent is selected from the
group
consisting of nevirapine (BI-RG-587; Viramune ), delavirdine (BHAP; U-90152;
Rescriptor ), and (efavirenz; DMP-266; SustivaOO ).
In some embodiments, the methods further comprise administering a second
therapeutic agent, wherein the second therapeutic, agent is T-20 (Fuzeon ;
Enfuvirtide; DP-
178; Pentafuside; GP41 127-162 AA).
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In some embodiments, the methods further comprise administering a second
therapeutic agent, wherein the second therapeutic agent is TMCC114, or TMCC114
in
combination with a reverse transcriptase inhibitor. In some embodiments, the
methods
further comprise administering a second therapeutic agent, wherein the second
therapeutic
agent is Lipinavir, or Lupanivir in combination with a reverse transcriptase
inhibitor.
Combination therapy in different formulations may be administered
simultaneously,
separately or sequentially. Alternatively, such combination may be
administered as a single
formulation, whereby the active ingredients are released from the formulation
simultaneously or separately. Compositions comprising at least two inhibitors
described
herein and/or one or more other protease inhibitors and/or other therapeutic
agents are also
provided herein. In certain embodiments the compounds of the invention can be
combined
with one or more of any anti-HIV compounds (e.g. those listed in Figures 6a-
k). Additional
compounds which may be combined with one or more of the inventive compounds,
and
further discussion of combination therapy can be found in Yeni, P. G. et al.
JAMA 2004,
292(2), 251-265; Pozniak, A. et al. Business Briefing: Clinical Virology &
Infectious
Disease 2004, 1-7; and Chittick, G. E. et al. Antimicrobial Agents and
Chenzotherapy 2006,
1304-1310; all of which are hereby incorporated by reference.
Definitions. All definitions, as defined and used herein, should be understood
to
control over dictionary definitions, definitions in documents incorporated by
reference,
and/or ordinary meanings of the defined terms.
The indefinite articles "a" and "an," as used herein in the specification and
in the
claims, unless clearly indicated to the contrary, should be understood to mean
"at least
one."
The term "HIV" is known to one skilled in the art to refer to Human
Immunodeficiency Virus. There are two types of HIV: HIV-1 and HIV-2. There are
many
different strains of HIV-1. The strains of HIV-1 can be classified into three
groups: the
"major" group M, the "outlier" group 0 and the "new" group N. These three
groups may
represent three separate introductions of simian immunodeficiency virus into
humans.
Within the M-group there are at least ten subtypes or clades: e.g., clade A,
B, C, D, E, F, G,
H, I, J, and K. A"clade" is a group of organisms, such as a species, whose
members share
homologous features derived from a conunon ancestor. Any reference to HIV in
this
application includes all of these tupes and strains.
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As known to one skilled in the art, "retroviruses" are diploid positive-strand
RNA
viruses that replicate through an integrated DNA intermediate (proviral DNA).
In
particular, upon infection by the RNA virus, the lentiviral genome is reverse-
transcribed
into DNA by a virally encoded reverse transcriptase that is carried as a
protein in each
retrovirus. The viral DNA is then integrated pseudo-randomly into the host
cell genome of
the infecting cell, forming a "provirus" which is inherited by daughter cells.
The retrovirus
genome contains at least three genes: gag codes for core and structural
proteins of the virus;
pol codes for reverse transcriptase, protease and integrase; and env codes for
the virus
surface proteins. Within the retrovirus family, HIV is classified as a
lentivirus, having
genetic and morphologic similarities to animal lentiviruses such as those
infecting cats
(feline immunodeficiency virus), sheep (visna virus), goats (caprine arthritis-
encephalitis
virus), and non-human primates (simian immunodef ciency virus).
The term "heteroatom" is art-recognized and refers to an atom of any element
other
than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen,
oxygen,
phosphorus, sulfur and selenium.
The term "alkyl" is art-recognized, and includes saturated aliphatic groups,
including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl
(alicyclic)
groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl
groups. In
certain embodiments, a straight chain or branched chain alkyl has about 30 or
fewer carbon
atoms in its backbone (e.g., Ci-C30 for straight chain, C3-C30 for branched
chain), and
alternatively, about 20 or fewer. Likewise, cycloalkyls have from about 3 to
about 10
carbon atoms in their ring structure, and alternatively about 5, 6 or 7
carbons in the ring
structure.
Unless the number of carbons is otherwise specified, "lower alkyl" refers to
an alkyl
group, as defined above, but having from one to about ten carbons,
alternatively from one
to about six carbon atoms in its backbone structure. Likewise, "lower alkenyl"
and "lower
alkynyl" have similar chain lengths.
The term "aralkyl" is art-recognized and refers to an alkyl group substituted
with an
aryl group (e.g., an aromatic or heteroaromatic group).
The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated
aliphatic groups analogous in length and possible substitution to the alkyls
described above,
but that contain at least one double or triple bond respectively.
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The term "aryl" is art-recognized and refers to 5-, 6- and 7-membered single-
ring
aromatic groups that may include from zero to four heteroatoms, for example,
benzene,
naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole,
oxazole, thiazole,
triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the
like. Those aiyl
groups having heteroatoms in the ring structure may also be referred to as
"aryl
heterocycles" or "heteroaromatics." The aromatic ring may be substituted at
one or more
ring positions with such substituents as described herein, for example,
halogen, azide, alkyl,
aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro,
sulfhydryl, imino,
amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,
sulfonyl,
sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic
moieties, -
CF3, -CN, or the like. The term "aryl" also includes polycyclic ring systems
having two or
more cyclic rings in which two or more carbons are common to two adjoining
rings (the
rings are "fused rings") wherein at least one of the rings is aromatic, e.g.,
the other cyclic
rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or
heterocyclyls.
The terms ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and
1,4-
disubstituted benzenes, respectively. For example, the names 1,2-
dimethylbenzene and
ortho-dimethylbenzene are synonymous.
The terms "heterocyclyl", "heteroaryl", or "heterocyclic group" are art-
recognized
and refer to 3- to about 10-membered ring structures, alternatively 3- to
about 7-membered
rings, whose ring structures include one to four heteroa toms. Heterocycles
may also be
polycycles. Heterocyclyl groups include, for example, thiophene, thianthrene,
furan, pyran,
isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole,
pyrazole,
isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine,
indolizine, isoindole,
indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,
naphthyridine,
quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,
phenanthridine,
acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine,
furazan,
phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine,
morpholine,
lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones,
and the like.
The heterocyclic ring may be substituted at one or more positions with such
substituents as
described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl,
cycloalkyl,
hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate,
carbonyl,
carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a
heterocyclyl, an
aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
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The terms "polycyclyl" or "polycyclic group" are art-recognized and refer to
two or
more rings (e.g., cycloallcyls, cycloalkenyls, cycloalkynyls, aryls and/or
heterocyclyls) in
which two or more carbons are common to two adjoining rings, e.g., the rings
are "fused
rings". Rings that are joined through non-adjacent atoms are termed "bridged"
rings. Each
of the rings of the polycycle may be substituted with such substituents as
described above,
as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,
hydroxyl, amino, nitro,
sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl,
ether,
alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or
heteroaromatic
moiety, -CF3, -CN, or the like.
The term "carbocycle" is art-recognized and refers to an aromatic or non-
aromatic
ring in which each atom of the ring is carbon.
The term "nitro" is art-recognized and refers to -NO2; the term "halogen" is
art-
recognized and refers to -F, -Cl, -Br or -I; the term "sulfhydryl" is art-
recognized and refers
to -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" is art-
recognized and
refers to -S02 ."Halide" designates the corresponding anion of the halogens,
and
"pseudohalide" has the definition set forth on page 560 of "Advanced Inorganic
Chemistry"
by Cotton and Wilkinson.
The terms "amine" and "amino" are art-recognized and refer to both
unsubstituted
and substituted amines, e.g., a moiety that may be represented by the general
formulas:
-N(R51)(R50) or [-N(R50)(R52)(R53)]+, wherein R50, R51, R52 and R53 each
independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m-R61, or R50
and R51 or
R52, taken together with the N atom to which they are attached complete a
heterocycle
having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a
cycloalkyl, a
cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the
range of 1 to 8.
In other embodiments, R50 and R51 (and optionally R52) each independently
represent a
hydrogen, an alkyl, an alkenyl, or -(CH2),,; R61. Thus, the term "alkylamine"
includes an
amine group, as defined above, having a substituted or unsubstituted alkyl
attached thereto,
i.e., at least one of R50 and R51 is an alkyl group.
The term "acylamino" is art-recognized and refers to a moiety that may be
represented by the general formula: -N(R50)-C(=O)R54, wherein R50 is as
defined above,
and R54 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m R61, where m
and R61 are
as defined above.
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The term "amido" is art recognized as an amino-substituted carbonyl and
includes a
moiety that may be represented by the general formula: -C(=O)N(R50)(R5 1),
wherein R50
and R51 are as defined above. Certain embodiments of the amide in the present
invention
will not include imides which may be unstable.
The term "alkylthio" refers to an alkyl group, as defined above, having a
sulfur
radical attached thereto. In certain embodiments, the "alkylthio" moiety is
represented by
one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2),t,-R61, wherein m and
R61 are defined
above. Representative alkylthio groups include methylthio, ethyl thio, and the
like.
The term "carboxyl" is art recognized and includes such moieties as may be
represented by the general formulas: -C(=O)-X50-R55 or -X50-C(=O)-R56, wherein
X50 is
a bond or represents an oxygen or a sulfur, and R55 and R56 represents a
hydrogen, an
alkyl, an alkenyl, -(CHa)m R61 or a pharmaceutically acceptable salt, R56
represents a
hydrogen, an alkyl, an alkenyl or -(CH2)m-R61, where m and R61 are defined
above.
Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula represents
an
"ester". Where X50 is an oxygen, and R55 is as defined above, the moiety is
referred to
herein as a carboxyl group, and particularly when R55 is a hydrogen, the
formula represents
a "carboxylic acid". Where X50 is an oxygen, and R56 is hydrogen, the formula
represents
a"formate". In general, where the oxygen atom of the above formula is replaced
by sulfur,
the formula represents a "thiolcarbonyl" group. Where X50 is a sulfur and R55
or R56 is
not hydrogen, the formula represents a "thiolester." Where X50 is a sulfur and
R55 is
hydrogen, the formula represents a "thiolcarboxylic acid." Where X50 is a
sulfur and R56
is hydrogen, the formula represents a"thiolformate." On the other hand, where
X50 is a
bond, and R55 is not hydrogen, the above formula represents a "ketone" group.
Where X50
is a bond, and R55 is hydrogen, the above formula represents an "aldehyde"
group.
The term "carbamoyl" refers to -O(C=O)NRR', where R and R' are independently
H, aliphatic groups, aryl groups or heteroaryl groups.
The term "oxo" refers to a carbonyl oxygen (=O).
The terms "oxime" and "oxime ether" are art-recognized and refer to moieties
that
may be represented by the general formula: -C(R75)(=NOR), wherein R75 is
hydrogen,
alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH2)n,-R61. The
moiety is an "oxime"
when R is H; and it is an "oxime ether" when R is alkyl, cycloalkyl, alkenyl,
alkynyl, aryl,
aralkyl, or -(CH2)n,-R61.
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The terms "alkoxyl" or "alkoxy" are art-recognized and refer to an alkyl
group, as
defined above, having an oxygen radical attached thereto. Representative
alkoxyl groups
include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is
two
hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of
an alkyl that
renders that alkyl an ether is or resembles an alkoxyl, such as may be
represented by one of
-0-alkyl, -0-alkenyl, -0-alkynyl, -O-(CH2)n; R61, where m and R61 are
described above.
The term "sulfonate" is art recognized and refers to a moiety that may be
represented by the general formula: -S(=O)20R57, in which R57 is an electron
pair,
hydrogen, alkyl, cycloalkyl, or aryl.
The term "sulfate" is art recognized and includes a moiety that may be
represented
by the general formula: -OS(=O)20R57, in which R57 is as defined above.
The term "sulfonamido" is art recognized and includes a moiety that may be
represented by the general formula: -N(R50)-S(=O)20R56, in which R50 and R56
are as
defined above.
The term "sulfamoyl" is art-recognized and refers to a moiety that may be
represented by the general formula: -S(=O)2N(R50)(R51), in which R50 and R51
are as
defined above.
The term "sulfonyl" is art-recognized and refers to a moiety that may be
represented
by the general formula: -S(=O)2R58, in which R58 is one of the following:
hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
The term "sulfoxido" is art-recognized and refers to a moiety that may be
represented by the general formula: -S(=O)R58, in which R58 is defined above.
Analogous substitutions may be made to alkenyl and alkynyl groups to produce,
for
example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls,
iminoalkenyls,
iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or
alkynyls.
The definition of each expression, e.g., alkyl, m, n, and the like, when it
occurs more than
once in any structure, is intended to be independent of its definition
elsewhere in the same
structure.
The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl,
phenyl,
trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and
methanesulfonyl, respectively. A more comprehensive list of the abbreviations
utilized by
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organic chemists of ordinary skill in the art appears in the first issue of
each volume of the
Journal of Organic Chemistry; this list is typically presented in a table
entitled Standard List
of Abbreviations.
It will be understood that "substitution" or "substituted with" includes the
implicit
proviso that such substitution is in accordance with permitted valence of the
substituted
atom and the substituent, and that the substitution results in a stable
compound, e.g., which
does not spontaneously undergo transformation such as by rearrangement,
cyclization,
elimination, or other reaction.
The term "substituted" is also contemplated to include all permissible
substituents
of organic compounds. In a broad aspect, the permissible substituents include
acyclic and
cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and
nonaromatic
substituents of organic compounds. Illustrative substituents include, for
example, those
described herein above. The permissible substituents may be one or more and
the same or
different for appropriate organic compounds. For purposes of this invention,
the
heteroatoms such as nitrogen may have hydrogen substituents and/or any
permissible
substituents of organic compounds described herein which satisfy the valences
of the
heteroatoms. This invention is not intended to be limited in any manner by the
permissible
substituents of organic compounds.
For purposes of this invention, the chemical elements are identified in
accordance
with the Periodic Table of the Elements, CAS version, "Handbook of Chemistry
and
Physics", 67th Ed., 1986-87, inside cover.
EXEMPLIFICATION
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.
Example 1 -- Synthesis of protease inhibitors containing a hydrox e~thylamine
(HEA core
The designed inhibitors with a hydroxyethylamine (HEA) core isostere can be
synthesized in four steps starting with commercially available chiral epoxide
(1S,2S
enantiomer) 12. Ring opening of epoxide 12 with various primary and secondary
amines
provided compounds 13. Reaction of 13 with various sulfonyl chlorides gave
compounds
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14. After deprotecting the Boc group, the resulting amines 15 were coupled
with either (R)
or (S) isomer of activated carboxylic acids to provide the designed inhibitors
16 (Figure
7A).
Example 2 -- Synthesis of protease inhibitors containing cyclic carbamates: HE
Series
The synthesis of protease inhibitors containing hydroxyethylene (HE) isostere
starts
with the synthesis of the core 17, which was obtained from L-phenylalanine in
5 steps.
After coupling of R4X2CO2H to 17, the dibenzyl protection was removed and the
free
aniine 19 was coupled to the an activated acid to provide inhibitors 20
(Figure 7B).
Example 3 -- Synthesis of protease inhibitors containing cyclic carbamates:
Aza-HEA
Series
The synthesis of protease inhibitors containing aza-hydroxyethylamine (Aza-
HEA)
isostere is outlined in Figure 8. The ring opening of chiral epoxide (1S,2R
enantiomer) 21
with CBz protected hydrazine derivative 22 provided compound 23. Deprotection
of CBz
followed by the coupling with R4X2CO2H gave compounds 24. Removal of the Boc
protection and coupling with R3X1CO2H provided the desired inhibitors 27.
Example 4 -- Synthesis of designed HIV- 1 protease inhibitor libraries
The syntheses of designed protease inhibitor libraries can be carried out
using the
general reaction scheme described herein.
Example 5 -- Inhibition of HIV- 1 Protease
HIV 1 protease inhibitor activities were determined using a standard
fluorescence
resonance energy transfer (FRET) method, using a protease substrate that
becomes
fluorescent upon cleavage of a specific peptide sequence separating a
fluorescent donor and
a nonfluorescent acceptor. Protease substrate 1 was labeled with energy
transfer donor
(EDANS) and acceptor (DABCYL) at its two ends, respectively (see, e.g.,
Maggiora et al.,
J. Med. Chem. 35:3727-3730 (1992); Shakhsher and Seitz, Anal. Chem.
62(17):1758-1762
(1990); Wang et al., Tetrahedron Lett. 31(45):6493-6496 (1990); the labeled
substrates are
available from Molecular Probes/Invitrogen (cat. No H2930)). The general
methodology is
described in Science 247:954 (1990).
Measurements were performed on a PTI fluorescence spectrophotometer.
Excitation and emission wavelengths were set at 340 and 490 nm, respectively.
All
incubations were carried on at room temperature for 10-20 min. Protease
concentration was
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around 50 nM and substrate concentration was fixed at 1mM. Ki was obtained by
fitting
the plot of initial velocity as a function of inhibitor concentrations based
on Morrison
equation. The results are shown in the Figures.
INCORPORATION BY REFERENCE
The contents of all cited references (including literature references, issued
patents,
published patent applications and GenBank Accession numbers as cited
throughout this
application) are hereby expressly incorporated by reference. When definitions
of tenns in
documents that are incorporated by reference herein conflict with those used
herein, the
definitions used herein govern.
EQUIVALENTS
Those skilled in the art will recognize, or be able to ascertain using no more
than
routine experimentation, many equivalents to the specific embodiments of the
invention
described herein. Such equivalents are intended to be encompassed by the
following
claims.
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