Title of Invention

LYSINE BASED COMPOUNDS

Abstract The present invention provides lysine based compounds of the formula; and when the compound of formula I comprises an amino group, pharmaceutically acceptable ammonium salts thereof, wherein n is 3 or 4, wherein R1 may be, for example, (HO)2P(O)-, (NaO)2P(O)-, alkyl-CO- or cycloalkyl-CO-, wherein X may be, for example, F, Cl, and Br, and wherein R2, R3 and R6 are as defined in the specification.. The lysine based compounds have a physiologically cleavable unit, namely R1, whereby upon cleavage of the unit, an HIV aspartyl protease inhibitor is released. The invention is also for pharmaceutical composition comprising the said compound.
Full Text

TECHNICAL FIELD OF THE INVENTION
This invention relates to lysine based compounds which present good solubility, and
bioavailability. More particularly, the present invention relates to lysine based compounds
having a physiologically cleavable unit, whereby upon cleavage of the unit, the compound is
able to release an HIV protease inhibitor. The compounds and pharmaceutical compositions
of the present invention are particularly well suited for decreasing the pill burden and
increasing patient compliance.
BACKGROUND OF THE INVENTION
Inhibito rs o f t he HIV v iral p rotease h ave b een developed relatively r ecently and t heir u se
began only in 1996. Currently, they are considered the most effective drugs against HIV
infection. Unfortunately, m ost c urrent p roteases' i nhibitors a re r elatively large h ydrophobic
molecules that possess rather low bioavailability. A high pill burden is therefore required to
attain the therapeutic dose in a patient. This is a deterrent, which too often results in patient
non-compliance and inadequate treatment results. This situation leads to sub-optimal
therapeutic drug concentration that in turns leads to the development of HIV resistant strains.
Consequently, there is an urgent need to improve the solubility and bioavailability of
proteases inhibitors.
Examples of improved compounds have been developed in the form of prodrugs of aspartyl
protease inhibitors such as described, for example, in US patent no. 6,436,989 to Hale et al,
the entire content of which is incorporated herein by reference. This patent shows a novel
class of molecules characterized by favourable aqueous solubility, high oral bioavailability
and facile in vivo generation of the active ingredient. However, it is well known that HIV has
the ability to develop resistance to the currently available drugs. Thus, there is a need for
alternative HIV protease inhibitors active towards wild-type and resistant viral strains. Thus,
molecules derived from current HIV protease inhibitors showing enhanced solubility and
bioavailability is desirable to fight resistant viral strains.

. A unique class of aromatic derivatives which are inhibitors of aspartyl proteases is described
in US patent no. 6,632,816 to Stranix et al, the entire content of which is incorporated herein
by reference. This patent includes, more particularly, iV,-synthetic amino acid substituted L-
lysine derivatives possessing potent aspartyl protease inhibitory properties. However, it
would be advantageous to improve these derivatives by enhancing aqueous solubility and
bioavailability in order to reduce the pill burden and to favour patient's compliance. Since it
is challenging to generate active protease inhibitors, specifically toward wild-type and
resistant strains, the formation of derivatives of original HIV protease inhibitors such as
inhibitors described in US patent no. 6,632,816 to Stranix et al, known to be active toward
resistant strains represents a viable route with considerable advantages. More particularly,
generation of compounds with enhanced aqueous solubility, bioavailability, time of duration
and formulation properties along with other advantages is desirable in the development of an
effective drug.
SUMMARY OF THE INVENTION
The present invention provides novel lysine based compounds originating from a class of
derivatives that are potent aspartyl protease inhibitors and pharmaceutically acceptable
derivatives thereof. These compounds may readily b e cleaved in vivo to r elease the active
ingredient. The active ingredient has an affinity for aspartyl proteases, in particular, HIV-1
aspartyl protease (US patent no. 6,632,816). The active ingredients also present potent
antiviral activity when tested on non-mutated HIV-1 viral strain (NL4.3 as the wild type
virus) as well as several mutant strains. Therefore, the compounds of the present invention
may be useful as a mean to increase solubility and improving bioavailability of the active
ingredient (protease inhibitor). The compounds of the present invention may be used alone or
in combination with other therapeutic or prophylactic agents for the treatment or prophylaxis
of HIV infection. The compounds of the present invention possess good solubility and
bioavailability and may be orally administered as aqueous solution.
It is the main objective of this invention to provide an improved class of lysine based
compounds that are able to release an aspartyl protease inhibitor, and particularly, HIV

aspartyl protease inhibitors. Lysine based compounds of the present invention may have a
cleavable unit, whereby upon cleavage of the unit the compound is able to release an HIV
protease inhibitor. The present invention also provides pharmaceutical compositions
comprising lysine based compounds described herein.
Therefore the present invention provides in one aspect thereof, lysine based compounds
which upon in vivo physiological conditions (e.g., metabolic, enteric and/or gastrointestinal
conditions, etc.) allow the release of a protease inhibitor (e.g., aspartyl p rotease inhibitor).
The c ompounds o f t he p resent i nvention m ay se rve asm eans for improving the s olubility
and/or bioavailability of the protease inhibitors and therefore may reduce the pill burden and
may favour patient's compliance.
The compounds of the present invention may have, for example, a (e.g., physiologically)
cleavable (e.g., hydrolysable) bond or unit which upon cleavage of the cleavable bond or unit
generates a protease inhibitor (e.g., an active protease inhibitor).
The p rotease inhibitor m ay a ct o n aspartyl p rotease o f HIV-1 i ncluding mutated and n on-
mutated HIV-1 viral strain (e.g., NL4.3) or on protease of HTV-2 (mutated or non-mutated) or
even on protease of related virus (SIV, etc.). The compounds of the present invention may be
used alone or in combination with other therapeutic or prophylactic agents for the treatment
or prophylaxis of, for example, an HIV infection.
The compounds and the pharmaceutical compositions of the present invention may release
the protease inhibitor (active ingredient) in vivo and thereby may inhibit (e.g., in vivo) the
activity of HIV aspartyl protease, an enzyme essential for virus maturation and infectivity.
The compounds and the pharmaceutical compositions of the present invention may possess
higher bioavailability and may also be apt to reduce dosages needed for inhibition and
consequently may improve treatment of HIV-infected patients.
The present invention in accordance with one aspect thereof provides a compound (e.g. a
compound able to generate an HIV protease inhibitor) of formula I:


pharmaceutically acceptable salts and derivatives thereof (e.g., for example, when the
compound of the present invention comprises an amino group, the pharmaceutically
acceptable salt may be an ammonium salt),
wherein n may be, for example, 3 or 4,
wherein X and Y, the same or different, may be selected, for example, from the group
consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to
6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atom;:, F, Cl, Br, I, -CF3, -OCF3, -CN,
-NO2, -NR4R5, -NHCOR4, -OR4, -SR4, -COOR4, -COR4, and -CH2OH or X and Y together
define an alkylenedioxy group selected from the group cons isting of a methylenedioxy group
of formula -OCH2O- and an ethylenedioxy group of formula -OCH2CH2O-,
wherein R6 may be selected, for example, from the group consisting of a straight alkyl group
of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms,, a cycloalkylalkyl
group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the
alkyl part thereof,
wherein R3 may be selected, for example, from the group consisting of H, a straight alkyl
group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl
group of 3 to 6 carbon atoms, and a group of formula R3A-CO-, wherein R3Amay be selected,
for example, from the group consisting of a straight or branched alkyl group of 1 to 6 carbon
atoms (e.g. methyl, ethyl-, propyl, iso-propyl, butyl, iso-butyl, tert-bntyl, tart-butyl-CH2-,
etc.), a cycloalkyl group having 3 to 6 carbon atoms (e.g. cyclopropyl-, cyclohexyl- etc.), a
cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3
carbon atoms in the alkyl part thereof, (e.g. cyclopropyl-CH2-, cyclohexyl-CH2-, etc.), an
alkyloxy group of 1 to 6 carbon atoms (e.g. CH3O-, CH3OH2O-, iso-butylO-, tert-butylO-
(Boc), etc.), tetrahydro-3-furanyloxy, -CH2OH, -CF3, -CH^CF3, -CH2CH2CF3, pyrrolidinyl,

piperidinyl, 4-morpholinyl, CH3O2C-, CH3O2CCH2-, Acetyl-OCH2CH2-, HO2CCH2-, 3-
hydroxyphenyl, 4-hydroxyphenyl, 4-CH3OC6H4CH2-, CH3NH-, (CH3)2N-, (CH3CH2)2N-,
(CH3CH2CH2)2N-, HOCH2CH2NH-, CH3OCH2O-, CH3OCH2CH2O-, C6H5CH2O-, 2-
pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-
isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula,


wherein X' and Y', the same or different, may be selected, for example, from the group
consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to
6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF3, -NO2. -NR4R5, -
NHCOR4, -OR4, -SR4, -COOR4, -COR4 and -CH2OH,
wherein R4 and R5, the same or different, may be selected, for example, from the group
consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to
6 carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms,
wherein R2 may be selected, for example, from the group consisting of a diphenylmethyl
group of formula IV

a naphthyl-1-CH2- group of formula V '

a naphthyl-2-CH2- group of formula VI



a biphenylmethyl group of formula VII

and an anthryl-9-CH2- group of formula VIII

and wherein R1 may be a cleavable unit (e.g., a physiologically cleavable unit), whereby upon
cleavage of the unit, the compound releases a protease inhibitor (an HIV protease inhibitor),
provided that R1 is not H. For example, R1 may be an enzymatically or metabolically
cleavable unit or hydrolysable bond which may be cleaved under enteric and/or
gastrointestinal conditions (pH) or other physiological conditions.
In accordance with the present invention, R1 may be selected, for example, from the group
consisting of (HO)2P(O) and (MO)2P(O), wherein M is an alkali metal (e.g. Na, K, Cs, etc) or
alkaline earth metal (Ca, Mg, etc.).

Further in accordance with the present invention, R1 may be a group of formula R1A-CO-,
wherein R1A may be selected, for example, from the group consisting of a straight or
branched alkyl group of 1 to 6 carbon atoms (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-
butyl, tert-butyl, tert-butyl-CH2-, etc.), a cycloalkyl group having 3 to 6 carbon atoms (e.g.
cyclopropyl-, cyclohexyl- etc.), a cycloalkylalkyl group having 3 to 6 carbon atoms in the
cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, (e.g. cyclopropyl-
CH2-, cyclohexyl-CH2-, etc.), an alkyloxy group of 1 to 6 carbon atoms (e.g. CH3O-,
CH3CH2O-, rso-butylO-, tert-butylO- (Boc), etc.), -CH2OH, CH3O2C-, CH3O2CCH2-, Acetyl-
OCH2CH2-, HO2CCH2-, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,
(CH3)2NCH2-, (CH3)2CHCH(NH2)-, HOCH2CH2NH-, CH3OCH2O-, CH3OCH2CH2O-, 2-
pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, l-methyl-l,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-
quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group
of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group, consisting of
n


a substituted pyridyl group selected from the group consisting of

and a group of formula,

wherein X', Y', R4 and R5 are as defined herein.
The present invention further provides in another aspect a compound of formula II,

phannaceutically acceptable salts and derivatives thereof (e.g., for example, when the
compound of the present invention comprises an amino group, the pharmaceutically
acceptable salt may be an ammonium salt),
wherein n may be 3 or 4,
wherein X and Y, the same or different, may be selected, for example, from the group
consisting of H, a straight allcyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to
6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF3, -OCF3, -CN, -
N02, -NR4R5, -NHCOR4, -OR4, -SR4, -COOR4, -COR4, and -CH2OH or X and Y together

together define an alkylenedioxy group selected from the group consisting of a
methylemedioxy group of formula -OCH2O- and an ethylenedioxy group of formula -
OCH2CH2O-,
wherein R6 may be selected, for example, from the group consisting of a straight a.lkyl group
of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkylalkyl
group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the
alkyl part thereof,
wherein R3 may be selected, for example, from the group consisting of H, a straight alkyl
group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl
group of 3 to 6 carbon atoms, and a grOup of formula R3A-CO-, wherein R3A maybe selected,
for example, from the group consisting of a straight or branched alkyl group of 1 to 6 carbon
atoms (e.g. methyl, ethyl-, propyl, wo-propyl, butyl, iso-butyl, tert-butyl, tert-butyl-CH2-,
etc.), a cycloalkyl group having 3 to 6 carbon atoms (e.g. cyclopropyl-, cyclohexyl- etc.), a
cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3
carbon atoms in the alkyl part thereof, (e.g. cyclopropyl-CH2-, cyclohexyl-CH2-, etc.), an
alkyloxy group of 1 to 6 carbon atoms (e.g. CH3O-, CH3CH2O-, iso-butylO-, tert-butylO-
(Boc), etc.), tetrahydro-3-furanyloxy, -CH2OH, -CF3, -CH2CF3, -CH2CH2CF3, p yrrolidinyl,
piperidinyl, 4-morpholinyl, CH3O2C-, CH3O2CCH2-, Acetyl-OCH2CH2-, HO2CCH2-, 3-
hydroxyphenyl, 4-hydroxyphenyl, 4-CH3OC6H4CH2-, CH3NH-, (CH3)2N-, (CH3CH2)2N-,
(CH3CH2CH2)2N-, HOCH2CH2NH-, CH3OCH2O-, CH3OCH2CH2O-, C6H5CH2O-, 2-
pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-
isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of


a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula,

wherein X' and Y', the same or different, may be selected, for example, from the group
consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to
6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF3, -NO2, -NR4R5, -
NHCOR4, -OR4, -SR4, -COOR4, -COR4 and -CH2OH,

wherein R4 and R5, the same or different, may be selected, for example, from the group
consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to
6 carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms,
wherein R2 may be selected from the group consisting of a diphenylmethyl group of formula
rv


a naphthyl-l-CH2-group of formula V

a naphthyl-2-CH2- group of formula VI

a biphenylmethyl group of formula VII


and an anthryl-9-CH2- group of formula VIII

and wherein R1 may be a physiologically cleavable unit, whereby upon cleavage of the unit
the compound may be able to release a protease inhibitor, provided that R1 is not H.
In accordance with the present invention, R1 may be selected, for example, from the group
consisting of (HO)2P(O) and (MO)2P(O), wherein M is an alkali metal (e.g. Na, K, Cs, etc) or
alkaline earth metal (Ca, Mg, etc.).
Further in accordance with the present invention R1 may be a group of formula R1A-CO-,
wherein R1A may be selected from the group consisting of a straight or branched alkyl group
of 1 to 6 carbon atoms (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, tert-
butyl-CH2-, etc.), a cycloalkyl group having 3 to 6 carbon atoms (e.g. cyclopropyl-,
cyclohexyl- etc.), a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part
thereof and 1 to 3 carbon atoms in the alkyl part thereof, (e.g. cyclopropyl-CH2-, cyclohexyl-
CH2-, etc.), an alkyloxy group of 1 to 6 carbon atoms (e.g. CH3O-, CH3CH2O-, iso-butylO-,
tert-butylO- (Boc), etc.), -CH2OH, CH3O2C-, CH3O2CCH2-, Acetyl-OCH2CH2-, HO2CCH2-,
2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH3)2NCH2-, (CH3)2CHCH(NH2)-,
HOCH2CH2NH-, CH3OCH2O-, CH3OCH2CH2O-, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,

1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-
isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula,


wherein X', Y', R4 and R5 are as defined herein.
In a further aspect, the present invention provides a compound of formula IIa;

pharmaceutically acceptable salts and derivatives thereof (e.g., for example, when the
compound of the present invention comprises an amino group, the pharmaceutically
acceptable salt may be an ammonium salt),
wherein X and Y, the same or different, may be selected, for example, from the group
consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to
6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF3, -OCF3, -CN, -
NO2, -NR4R5, -NHCOR4, -OR4, -SR4, -COOR4, -COR4, and -CH2OH or X and Y together
define an alkylenedioxy group selected from the group consisting of a methylenedioxy group
of formula -OCH2O- and an ethylenedioxy group of formula -OCH2CH2O-,
wherein X' and Y', the same or different, may be selected, for example, from the group
consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to
6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF3, -NO2;, -NR4R5, -
NHCOR4, -OR4, -SR4, -COOR4, -COR4 and -CH2OH,

and wherein n, R1, R3, R4, R5 and R5 are as defined herein.
In an additional aspect, the present invention provides a compound of formula IIb

pharmaceutically acceptable salts and derivatives thereof (e.g., for example, when the
compound of the present invention comprises an amino group, the pharmaceutically
acceptable salt may be an ammonium salt),
wherein X and Y, the same or different, may be selected, for example, from the group
consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to
6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF3, -OCF3, -CN, -
NO2, -NR4R5, -NHCOR4, -OR4, -SR4, -COOR4, -COR4, and -CH2OH or X and together
define an alkylenedioxy group selected from the group consisting of a methylenedioxy group
of formula -OCH2O- and an ethylenedioxy group of formula -OCH2CH2O-,
wherein X' and Y', the same or different, may be selected, for example, from the group
consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to
6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, -CF3, -NO2, -NR4R5, -
NHCOR4, -OR4, -SR4, -COOR4, -COR4 and -CH2OH,
and wherein n, R1, R3, R4, R5 and R5 are as defined herein.
In yet an additional aspect, the present invention provides a compound of formula IIc


pharmaceutically acceptable salts and derivatives thereof (e.g., for example, when the
compound of the present invention comprises an amino group, the pharmaceutically
acceptable salt may be an ammonium salt),
and wherein n, X, Y, X', Y', R1, R3, R4, R5 and R6 are as defined herein.
In another aspect, the present invention relates to a compound of formula IIA;

wherein Y, n, R1, R2, R3, X' and Y' are as defined herein.
In accordance with the present invention, R1 may be, for example, (HO)2P(O) or (NaO)2P(O)..
Further in accordance with the present invention, n may be 4. Y may be, for example, H. R3
may be, for example, CH3O-CO. R2 may be, for example, a diphenylmethyl- group of
formula IV, where X' and Y' may be, for example H,


Therefore, compounds of formula IIA' as well as pharmaceutically acceptable salts and
derivatives thereof are encompassed by the present invention,

such as, for example, compound of formula IIA' wherein R1 is (HO)2P(O) or, compound of
formula IIA' wherein R1 is (NaO)2P(O).
In yet another aspect, the present invention relates to a pharmaceutical composition
comprising at least one compound of formula I, II, IIa, IIb, IIc, IIA, IIA' or combination of
compounds of formula I, II, Ha IIb, IIe, IIA and/or IIA'. The pharmaceutical composition
may comprise a pharmaceutically acceptable carrier. The pharmaceutical composition may
comprise, for example, a pharmaceutically effective amount of such one or more compounds
or as applicable, pharmaceutically acceptable ammonium salts thereof.
For example, pharmaceutical composition of the present invention may comprise one or more
of the following compounds;
-a compound of formula IIa wherein n is 4, R1 is (HO)2P(O), X is 4-NH2, Y is H, X' is H, Y'
is H, R6 is iso-butyl and R3 is CH3O-CO,

- a compound of formula IIa wherein n is 4, R1 is (NaO)2P(O), X is 4-NH2, Y is H, X' is H,
Y' is H, R6 is iso-butyl and R3 is CH3O-CO,
- a compound of formula IIa wherein n is 4, R1 is (HO)2P(O), X is 4-NH2, Y is H, X' is H, Y'
is H, R6 is iso-butyl and R3 is CH3CO,
- a compound of formula IIa wherein n is 4, R1 is (HO)2P(O), X is 4-NH2, Y is 3-F, X' is H,
Y' is H, R6 is iso-butyl and R3 is CH3O-CO,
- a compound of formula IIa wherein h is 4, R1 is CH3CO, X is 4-NH2, Y is H, X' is H, Y' is
H, R6 is iso-butyl and R3 is CH3O-CO,
- a compound of formula IIa wherein n is 4, R1 is 3-pyridyl-CO, X is 4-NH2, Y is H, X' is H,
Y' is H, R6 is iso-butyl and R3 is CH3O-CO,
- a compound of formula IIa wherein n is 4, R1 is (CH3)2NCH2CO, X is 4-NH2, Y is H, X' is
H, Y' is H, R6 is iso-butyl and R3 is CH3O-CO,
- a compound of formula IIa wherein n is 4, R1 is (CH3)2CHCH(NH2)CO, X is 4-NH2, Y is H,
X' is H, Y' is H, R6 is iso-butyl and R3 is CH3O-CO,

- a compound of formula IIb wherein n is 4, R1 is (HO)2P(O), X is 4-NH2, Y is H, X' is H, Y'
is H, R6 is iso-butyl and R3 is CH3O-CO and wherein the naphthyl group is a naphthyl-2-CH2
group,
- a compound of formula IIb wherein n is 4, R1 is (HO)2P(O), X is 4-NH2, Y is H, X' is H, Y'
is H, R6 is iso-butyl and R3 is 4-morpholine-CO and wherein the naphthyl .group is a
naphthyl-1-CH2 group, or
- a combination of any of the above mentioned compounds.
In an additional aspect, the present invention relates to the use of at least one compound of
formula I, II, IIa, IIb, IIc, HA, IIA' or combination of compounds of formula I, II, IIa IIb, IIc,

IIA and/or IIA' or pharmaceutically acceptable salts or derivatives thereof (as well as their
combinations) in the manufacture of a drug (or pharmaceutical composition) for the treatment
or prevention of an HIV infection.
In a further aspect, the present invention relates to the use of at least one compound of
formula I, II, IIa, IIb, IIc, IIA, IIA' or combination of compounds of formula I, II, IIa IIb, IIc,
IIA and/or IIA' or pharmaceutically acceptable salts or derivatives thereof in the treatment or
prevention of an HIV infection in a mammal in need thereof or for delaying the apparition of
AIDS.
In yet a further aspect, the present invention relates to a method of treating or preventing an
HIV infection (or for delaying the apparition of AIDS) comprising administering at least one
compound of formula I, II, IIa, IIb, IIc, IIA, IIA' or combination of compounds of formula I,
II, IIa IIb, IIc, IIA and/or IIA' or pharmaceutically acceptable salts or derivatives thereof to a
mammal in need thereof.
In another aspect the present invention relates to a compound of formula I, II, IIa, IIb, IIc, IIA
or IIA', pharmaceutically acceptable salts or derivatives thereof for use in the treatment or
prevention of an HIV infection.
In yet a further aspect the present invention relates to a method of fabricating a lysine based
compound using any one of the compounds disclosed in US patent no. 6,632,816 to Stranix et
al. or a method of fabricating a compound able to generate any one of the disclosed in US
patent no. 6,632,816 to Stranix et al. upon cleavage of a (in vivo) cleavable unit.
The compounds listed herein are exemplary embodiments of the present invention and it is to
be understood that the present invention is not restricted to these compounds only.
The t erm "pharmaceutically e ffective amount" r efers t o an amount e ffective in treating o r
preventing HIV infection in a patient or for reducing or eliminating symptoms of AIDS. It is
also to be understood herein that a "pharmaceutically effective amount" may be construed as
an amount giving a desired therapeutic effect, either taken into a single or multiple doses or
in any dosage or route or taken alone or in combination with other therapeutic agents. In the
case of the present invention, a "pharmaceutically effective amount" maybe understood as an

amount having an inhibitory effect on HIV (HIV-1 and HIV-2 as well as related viruses (e.g.,
HTLV-I and HTLV-II, and simian immunodeficiency virus (SIV))) infection cycle (e.g.,
inhibition of replication, reinfection, maturation, budding etc.) and on any organism which
rely on aspartyl proteases for its life cycle. An inhibitory effect is to be understood herein as
an effect such as a reduction in the capacity of an organism (e.g. HIV) to reproduce itself
(replicate), to re-infect surrounding cells, etc, or even a complete inhibition (or elimination)
of an organism.
The terms "HIV protease" and "HIV aspartyl protease" are used interchangeably and include
the aspartyl protease encoded by the human immunodeficiency vims type 1 or 2.
The term "prophylactically effective amount" refers'to an amount effective in preventing HTV
infection i n a p atient. A s u sed h erein, t he t erm "patient" refers t o a m ammal, i ncluding a
human.
The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable adjuvant"
and "physiologically acceptable vehicle" refer to a non-toxic carrier or adjuvant that may be
administered to a patient, together with one or more compounds of the present invention, and
which does not destroy the pharmacological activity thereof.
The present invention provides pharmaceutically acceptable derivatives of the compounds of
formula I (such as compounds of formulae II, IIa, IIb, IIc, DA. and HA') and where applicable
pharmaceutically acceptable salts thereof such as, for example, ammonium salts. A
"pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, ester,-
or salt of such ester, of a compound of this invention or any other compound which, upon
administration to a recipient, is capable of providing (directly or indirectly) a compound of
this invention or an antivirally active metabolite or residue thereof.
It is to be understood herein that a "straight alkyl group of 1 to 6 carbon atoms" includes for
example, methyl, ethyl, propyl, butyl, pentyl, hexyl.
It is to be understood herein that a "branched alkyl group of 3 to 6 carbon atoms" includes for
example, without limitation, iso-butyl, tert-butyl, 2-pentyl, 3-pentyl, etc.

It is to be understood herein, that a "cycloatkyl group having 3 to 6 carbon" includes for
example, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclocyclohexyl (i.e.,
C6H11).
Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal
(e.g., magnesium), ammonium and N - (C1-4 alkyl)4+ salts.
The compounds of this invention contain one or more asymmetric carbon atoms and thus may
occur as racemates and racemic mixtures, single enantiomer, diastereomeric mixtures and
individual diastereoisomers. All such isomeric forms of these compounds are expressly
included in the present invention. Each stereogenic carbon may be of the R or S
configuration.
Pharmaceutically acceptable salts of the compounds of this invention include those derived
from pharmaceutically acceptable inorganic and organic acids and bases. Examples of such
acid salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,
butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate,
dodecylhydrogensulfate, dodecylsulfate, ethanesulfonate, formate, fumarate,
glucoheptanoate, glycerophosphate, glycollate, hemisulfate, heptanoate, hexanoate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
malonate, methanesulfonate, 2-naphthylsulfonate, nicotinate, nitrate, oxalate, pamoate,
pectinate, perchlorate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate.
This invention also envisions the quatemization of any basic nitrogen containing groups of
the compounds disclosed herein. The basic nitrogen may be quaternized with any agents
known to those of ordinary skill in the art including, for example, lower alkyl halides, such as
methyl, e thyl, p ropyl a nd b utyl c hlorides, b romides a nd i odides; d ialkyl s ulfates i ncluding
dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl,
myristyl and stearyl chlorides, bromides and iodides, and aralkyl halides including benzyl and
phenethyl bromides. Water or oil-soluble or dispersible products may be obtained by such
quatemization.

It is to be understood herein, that if a "range" or "group of substances" is mentioned with
respect to a particular characteristic (e.g., temperature, concentration, time and the like) of the
present invention, the present invention relates to and explicitly incorporates herein each and
every specific member and combination of sub-ranges or sub-groups therein whatsoever.
Thus, any specified range or group is to be understood as a shorthand way of referring to each
and every member of a range or group individually as well as each and every possible sub-
ranges or sub-groups encompassed therein; and similarly with respect to any sub-ranges or
sub-groups therein. Thus, for example,
with respect to the number of carbon atoms, the mention of the range of 1 to 6
carbon atoms is to be understood herein as incorporating each and every individual
number of carbon atoms as well as sub-ranges such as, for example, 1 carbon atoms,
3 carbon atoms, 4 to 6 carbon atoms, etc.
- with respect to reaction time, a time of 1 minute or more is to be understood as
specifically incorporating herein each and every individual time, as well as sub-
range, above 1 minute, such as for example 1 minute, 3 to 15 minutes, 1 minute to
20 hours, 1 to 3 hours, 16 hours, 3 hours to 20 hours etc.;
- and similarly with respect to other parameters such as concentrations, elements,
etc...
It is in particular to be understood herein that the compound formulae each include each and
every individual compound described thereby as well as each and every possible class or sub-
group or sub-class of compounds whether such class or sub-class is defined as positively
including particular compounds,, as excluding particular compounds or a combination
thereof; for example an exclusionary definition for the formula (e.g. I) may read as follows:
"provided that when one of A and B is -COOH and the other is H, -COOH may not occupy
the 4' position".
It is also to be understood herein that "g" or "gm" is a reference to the gram weight unit and
"C", or " °C " is a reference to the Celsius temperature unit.

The compounds of the present invention may easily be prepared, using conventional
techniques from readily available starting materials. The detailed descriptions of these
approaches are presented, for example, in schemes 1 to 5 discussed below.
Scheme 1 illustrates a generic example for the preparation of the phosphate monoester III
derived from a primary alcohol (see I), a compound of HIV protease inhibitors (see example
1 (step G and H) in the experimental portion of this document for a specific example of this
synthesis).
Note:
a) R2 and R3 are as defined herein.
The synthesis of phosphate monoester III may use a HTV aspartyl protease inhibitor (I, see
US patent no. 6,632,816) as the starting material. The diethyl phosphotriester II was obtained
in good yield upon treatment with diethyl chlorophosphate and sodium hydride in a mixture
of tetrahydrofuran and triethylphosphate. Then, addition of trimethysilyl bromide in
dichloromethane (DCM) gave compound III in good to excellent yields.


Scheme 1A represents another generic example for the preparation of the phosphate
monoester IIIA derived from a primary alcohol (see IA), a compound of HIV protease
inhibitors.
Note:
a) n, X, Y, R2, R3 and R6 are as defined herein.

The synthesis of phosphate monoester IIIA is performed as described for the preparation of
///(scheme 1).
Scheme 2 illustrates a generic example for the preparation of the phosphate monoester ///, a
compound of HIV protease inhibitors, with a different approach starting from (3S)-3-
isobutylamino-azepan-2-one (IV).
Note:
a) R2 and R3 are as defined herein.

As shown in scheme 2, the phosphate monoester derivative III was obtained from (3S)-3-
isobutylamino-azepan-2-one (IV) in a seven-step reaction sequence. Initially, (2S)-3-
isobutylamino-azepan-2-one (IV) was sulfonated with 4-acetamidobenzenesulfonyl chloride
in the presence of triethylamine in dichloromethane to give compound Fin excellent yields.
The derivative VI was obtained quantitatively upon treatment of. V with di-tert-butyl
pyrocarbonate and DMAP in acetonitrile. The reductive ring opening with sodium
borohydride in ethanol lead to key intermediates VII in good yield. The diethyl
phosphotriester VIII was obtained in good yield upon treatment with diethyl chlorophosphate
and sodium hydride in a mixture of tetrahydrofuran and triethylphosphate. The Boc
protective groups were removed upon treatment with HC1 in ethanol to give compound IX
quantitatively (T.W. Greene and P. G. M. Wuts, Protective groups in Organic Synthesis, 3rd
Edition, John Wiley & Sons, Inc. 1999). Then, coupling of the free amino group present on
intermediate IX with a variety of synthetic amino acid in the presence of 1-
hydroxybenzotriazole (HOBt) and l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (EDAC) led to derivative II in good to excellent yields. Finally, addition of
trimethysilyl bromide in dichloromethane (DCM) gave compound III in good to excellent
yields.


Scheme 3 presents the transformation of a diphenylmethyl derivative; (1S',5S)-(1-{5-[(4-
amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexylcarbamoyl}-2,2-diphenyl--ethyl)-
carbamic acid methyl ester (PL -100) into its fluorinated phosphate monoester sodium salt
analog XI. This reaction sequence may be used to produce any other similar compounds

(compounds) made of unsubstituted (or substituted) diphenylmethyl, 1-naphthyl, 2-naphthyl,
biphenyl and 9-anthryl groups described in this invention.
Thus, the treatment of PL-100 with Selectfluor™ in acetonitrile gave derivative X in 38%
yield. The introduction of the phosphate monoester group was performed as described
previously in scheme 1 and 2. First, the diethyl phosphotriester intermediate was obtained in
good yield upon treatment with diethyl chlorophosphate and sodium hydride in a mixture of
tetrahydrofuran and triethylphosphate. Secondly, addition of trimethysilyl bromide in
dichloromethane (DCM) gave the phosphate monoester compound in good to excellent
yields. The final product XI was easily obtained upon treatment of the phosphate monoester
with a solution of sodium hydroxide with good yields.

; Scheme 4 illustrates a generic example for the transformation of a phosphotriester II into its
fluorinated analog XIII in a two-step reaction sequence. This generic example represents a
second approach for the synthesis of fluorinated compounds of this invention. In this case, the
fluorine atom is added to the phosphotriester II instead of the primary alcohol derivative of
general formula I or, more specifically, PL-100 as shown on scheme 3. This alternate

reaction sequence may be used to produce any other similar compounds made of
unsubstituted (or substituted) diphenylmethyl, 1-naphthyl, 2-naphthyl, biphenyl and 9-anthryl
groups described in this invention.
Note:
a) R2 and R3 are as defined herein.
Briefly, treatment of derivative. II with Selectfiuor™ in acetonitrile gave derivative XII in
good yields. Then, addition of trimethysilyl bromide in dichloromethane (DCM) gave the
phosphate monoester compound XIII in good to excellent yields. If desired, the final product
XIII may be easily transformed into the phosphate monoester sodium salt analog as described
before in scheme 3.


Scheme 5 illustrates the synthesis of various ester compounds XVI in accordance with the
invention. The ester compounds are known to be easily cleaved in vivo by esterase enzymes
and, as a result, may release the active ingredient. In this scheme R2 is set as a
diphenylmethyl group. However, this reaction sequence may be used to produce any other
similar compounds made of unsubstituted (or substituted) diphenylmethyl, 1-naphthyl, 2-
naphthyl, biphenyl and 9-anthryl groups described in this invention.
Note:
a) R1A represents the "residue" of the acid molecule that is linked to the free primary alcohol
group present on intermediate XV and is as defined herein.
The compounds XVI are generally obtained in a three-step reaction sequence in high yields.
Esterification of (1S)-{4-[(5-tert-butoxycarbonylamino-l-hydroxymethyl-pentyl)-isobutyl-
sulfamoyl]-phenyl}-carbamic acid tert-butyl ester (VII) with a variety of acid in the presence
of 1-hydroxybenzotriazole (HOBt) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (EDAC) led to the desired esters XIV in excellent yields. The acetyl ester was
obtained quantitatively using acetic anhydride in the presence of N,N-dimethylaminopyridine
(DMAP) in dichloromethane (DCM). Cleavage of the Boc protective group was achieved
quantitatively u pon t reatment w ith t rifiuoroacetic a cid ( TFA) i n D CM. A s econd c oupling
with (2iS)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid is performed on the primary
amino group of intermediate XV with HOBt and ED AC to give the desired compounds XVI
in good to excellent yields. If necessary, catalytic hydrogenation of a benzyloxycarbonyl
group is performed using 10% palladium on carbon to give the final compound XVII.


As it may be appreciated by the person skilled in the art, the above synthetic schemes are not
intended to be a comprehensive list of all means by which the compound described and
claimed in this application may be synthesized but only represent exemplification of
synthesis methods among others. Further methods, will be evident to those of ordinary skill in
the art.
The compounds of this invention may be modified by appending appropriate functionalities
to enhance selective biological properties. Such modifications are known in the art and

include those which increase biological penetration into a given biological system (e.g.,
blood, lymphatic system, central nervous system), increase oral availability, increase
solubility to allow administration by injection, alter metabolism and alter rate of excretion.
As discussed above, the novel compounds may release the active ingredients that are
excellent ligands for aspartyl proteases, for example, HIV-1 protease. Accordingly, these
compounds are, b y r eieasing t he a ctive i ngredient, c apable oft argeting and i nhibiting 1 ate
stage events in the replication, i.e. the processing of the viral polyproteins by HIV encoded
protease. Compounds according to this invention advantageously inhibit the ability of the
HIV-1 virus to infect immortalized human T cells over a period of days, as determined by an
assay measuring the amount of extracellular p24 antigen; a specific marker of viral
replication (see, Meek et al., Nature, 343, pp. 90-92 (1990)).
In addition to their use in the prophylaxis or treatment of HIV or HTLV infection, the
compounds according to this invention may also be used as inhibitory or interruptive agents
for other viruses which use aspartyl proteases, similar to HTV or HTLV aspartyl proteases, in
their life cycle. Such compounds inhibit the proteolytic processing of viral polyprotein
precursors by inhibiting aspartyl protease. Because aspartyl protease is essential for the
production of mature virions, inhibition of that processing effectively blocks the spread of
virus by mhibiting the production and reproduction of infectious virions, particularly from
acutely and chronically infected cells. The compounds of this invention advantageously
inhibit aspartyl proteases, thus blocking the ability of aspartyl proteases to catalyze the
hydrolysis of peptide bonds.
The compounds of this invention may be employed in a conventional manner for the
treatment or prevention of HIV, HTLV, and other viral infections, which involve aspartyl
proteases for their life (replication) cycle. Such methods of treatment, their dosage levels and
requirements may be selected by those of ordinary skill in the art from available methods and
techniques. For example, a compound of this invention may be combined with a
pharmaceutically acceptable adjuvant for administration to a virally infected patient in a
pharmaceutically acceptable manner and in an amount effective to lessen the severity of the
viral infection.

Alternatively, the compounds of this invention may be used in vaccines and methods for
protecting individuals against viral infection over an extended period of time. The
compounds may be employed in such vaccines either alone or together with other compounds
of this invention in a manner consistent with the conventional utilization of protease
inhibitors or protease inhibitors derivatives in vaccines. For example, a compound of this
invention may be combined with pharmaceutically acceptable adjuvants, or delivery systems
conventionally employed in vaccines and administered in prophylactically effective amounts
to protect individuals over an extended period of time against viral infections, such as HTV
infection. As such, the novel compounds of the present invention (upon cleavage of a
physiologically cleavable unit) may be administered as agents for treating or preventing viral
infections, including HIV infection, in a mammal.
The compounds of this invention may be administered to a healthy or HIV-infected patient
(before or after the onset of AIDS symptoms) either as a single agent or in combination with
other antiviral agents which interfere with the replication cycle of HIV. By administering the
compounds of this invention with other antiviral agents which target different events in the
viral life cycle, the therapeutic effect of these compounds is potentiated. For instance, the co-
administered antiviral agent may be one which targets early events in the viral life cycle, such
as attachment to the cell receptor and cell entry, reverse transcription and viral DNA
integration into cellular DNA. Antiviral agents targeting such early life cycle events include
among others polysulfated polysaccharides, sT4 (soluble CD4) and other compounds which
block binding of virus to CD4 receptors on CD4 bearing T-lymphocytes and other CD4(+)
cells, or inhibit fusion of the viral envelope with the cytoplasmic membrane, and didanosine
(ddl), zalcitabine (ddC), stavudine (d4T), zidovudine (AZT) and lamivudine (3TC) which
inhibit reverse transcription. ,For example another protease inhibitor may be used with
compounds of the present invention. Other anti-retroviral and antiviral drugs may also be co-
administered with the compounds of this invention to provide therapeutic treatment for
substantially reducing or eliminating viral infectivity and the symptoms associated therewith.
Examples of other antiviral agents include ganciclovir, dideoxycytidine, trisodium
phosphonoformate, efiornithine, ribavirin, acyclovir, alpha interferon and trimenotrexate.
Additionally, other types of drags may be used to potentiate the effect of the compounds of
this invention, such as viral uncoating inhibitors, inhibitors of Tat or Rev trans-activating
proteins, antisense molecules or inhibitors of the viral integrase. These compounds may also
be co-administered with other inhibitors of HIV aspartyl protease. Furthermore, it may be

found useful to administer compounds of the present invention with any other drug (other
anti-viral compounds, antibiotics, pain killer, etc.,).
Combination therapies according to this invention exert a synergistic effect in inhibiting HIV
replication because each component agent of the combination acts on a different site of HIV
replication. The use of such combinations also advantageously reduces the dosage of a given
conventional anti-retroviral agent that would be required for a desired therapeutic or
prophylactic effect as compared to when that agent is administered as a monotherapy. These
combinations may reduce or eliminate the side effects of conventional single anti-retro viral
agent therapies while not interfering with the anti-retroviral activity of those agents. These
combinations reduce the potential of resistance to single agent therapies, while minimizing
any associated toxicity. These combinations may also increase the efficacy of the
conventional agent without increasing the associated toxicity. Combination therapies
encompassed by the present invention include, for example, the administration of a
compound of this invention with AZT, 3TC, ddl, ddC, d4T or other reverse transcriptase
inhibitors.
Alternatively, the compounds of this invention may also be co-administered with other HIV
protease inhibitors such as Ro 31-8959 (Saquinavir; Roche), L-735,524 (Indinavir; Merck),
AG-1343 (Nelfmavir; Agouron), A-84538 (Ritonavir; Abbott), ABT-378/r (Lopinavir;
Abbott), and VX-478 (Amprenavir; Glaxo) to increase the effect of therapy or prophylaxis
against various viral mutants or members of other HIV quasi species.
Administration of compounds of the present invention may be performed, for example, as
single agents or in combination with retroviral reverse transcriptase inhibitors, or other HTV
aspartyl protease inhibitors. Co-administration of the compounds of this invention with
retroviral reverse transcriptase inhibitors or HIV aspartyl protease inhibitors may exert a
substantial synergistic effect, thereby preventing, substantially reducing, or completely
eliminating viral infectivity and its associated symptoms.
The compounds of the present invention may be administered in such a manner or form
which may allow cleavage of the Ri unit to release a protease inhibitor. The compounds of
this invention may also be administered, for example, in combination with
immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF,

methionine enkephalin, interferon alpha, diethyldithiocarbamate sodium, tumor necrosis
factor, naltrexone and rEPO) antibiotics (e.g., pentamidine isethionate) or vaccines to prevent
or combat infection and disease associated with HIV infection, such as AIDS and ARC.
When the compounds of this invention are administered in combination therapies with other
agents, they may be administered sequentially or concurrently to the patient. Alternatively,
pharmaceutical or prophylactic compositions according to this invention may be comprised
of a combination of one or more compounds of this invention and another therapeutic or
prophylactic agent.
Although this invention focuses on the use of the compounds disclosed herein for preventing
and treating HIV infection, the compounds of this invention may also be used as inhibitory
agents for other viruses that depend on similar aspartyl proteases for obligatory events in their
life cycle. These viruses include, but are not limited to, retroviruses causing ATDS-like
diseases such as simian immunodeficiency viruses, HIV-2, HTLV-I and HTLV-II. In
addition, the compounds of this invention may also be used to inhibit other aspartyl proteases
and, in particular, other human aspartyl proteases including renin and aspartyl proteases that
process endothelin precursors.
Pharmaceutical compositions of this invention comprise any of the compounds of the present
invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically
acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable carriers, adjuvants and
vehicles that may be used in the pharmaceutical compositions of this invention include, but
are not limited to ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such
as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid,
potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or
electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, cellulose-based substances, polyethyleneglycol, sodium carboxymethylcellulose,
polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol
and wool fat.
The pharmaceutical compositions of this invention may be administered orally, parenterally
by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted

reservoir. It is therefore understood herein that oral administration or administration by
injection are encompassed by the present invention. For example, compounds of the present
invention, may, for example, be orally administered in an aqueous solution. The
pharmaceutical compositions of this, invention may contain any conventional non-toxic
pharmaceutically acceptable carriers, adjuvants or vehicles. The term "parenteral" as used
herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular,
intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion
techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for
example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be
formulated according to techniques known in the art using suitable dispersing or wetting
agents (such as, for example, Tween 80) and suspending agents. The sterile injectable
preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the
acceptable vehicles and solvents that may be employed are amino acid, water, Ringer's
solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are
conventionally employed a s a s olvent o r s uspending m edium. F or t his p urpose, a ny b land
fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as
oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are
natural p harmaceutically-acceptable o ils, s uch as o live o il o r castor o il, especially i n t heir
polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain
alcohol diluent or dispersant, such as Ph. Helv. or a similar alcohol.
The phiirmaceutical compositions of this invention may be orally administered in any orally
acceptable dosage form including, but not limited to, capsules, tablets, and aqueous
suspension and solutions. In the case of tablets for oral use, carriers that are commonly used
include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also
typically added. For oral administration in a capsule form, useful diluents include lactose and
dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is
combined with emulsifying and suspending agents. If desired, certain sweetening and/or
flavoring and/or coloring agents may be added.

The pharmaceutical compositions of this invention may also be administered in the form of
suppositories for rectal administration. These compositions may be prepared by mixing a
compound of this invention with a suitable non-irritating excipient which is solid at room
temperature but liquid at the rectal temperature and therefore will melt in the rectum to
release the active components. Such materials include, but are not limited to, cocoa butter,
beeswax, and polyethylene glycols.
Topical administration of the pharmaceutical compositions of this invention is especially
useful when the desired treatment involves areas or organs readily accessible by topical
application. For application topically to the skin, the pharmaceutical composition should be
formulated with a suitable ointment containing the active components suspended or dissolved
in a carrier. Carriers for topical administration of the compounds of this invention include,
but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol,
polyoxyethylene or polyoxypropylene compound, emulsifying wax and water. Alternatively,
the pharmaceutical compositions may be formulated with a suitable lotion or cream
containing the active compound suspended or dissolved in a carrier. Suitable carriers include,
but are not limited to, mineral oil, sorbitan monostearate, polysorbate 6 0, cetyl esters wax
cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical
compositions of this invention may also be topically applied to the lower intestinal tract by
rectal suppository formulation or in a suitable neat formulation. Topically-transdermal
patches are also included in this invention.
The pharmaceutical compositions of this invention may be administered by nasal aerosol or
inhalation. Such compositions are prepared according to techniques well-known in the art of
pharmaceutical formulation and may be prepared as solutions in saline employing benzyl
alcohol or other suitable preservatives, absorption promoters to enhance bioavailability,
fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
Dosage levels of between about 0.01 and about 25 mg/kg body weight per day, for example
form between about 0.5 and about 25 mg/kg body weight per day of the active ingredient
compound are useful in the prevention and treatment of viral infection, including HIV
infection. Typically, the pharmaceutical compositions of this invention will be administered
from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such
administration may be used as a chronic or acute therapy. The amount of active ingredient

that may be combined with the carrier materials to produce a single dosage form will vary
depending upon the patient treated and the particular mode of administration. A typical
preparation will contain from about 5% to about 95% active compound (w/w). For example,
such preparations may contain from about 20% to about 80% active compound.
Upon improvement of a patient's condition, a maintenance dose of a compound, composition
or combination of this invention may be administered if necessary. Subsequently, the dosage
or frequency of administration, or both, may be reduced, as a function of the symptoms, to a
level at which the improved condition is retained. When the symptoms have been alleviated
to the desired level, treatment should cease. Patients may, however, require intermittent
treatment on a long-term basis, upon any recurrence of disease symptoms.
As the person skilled in the art will appreciate, lower or higher doses than those recited above
may be desired. Specific dosage and treatment regimen for any particular patient may depend
upon a variety of factors, including the activity of the specific compound employed, the age,
body weight, general health status, sex, diet, time of administration, rate of excretion, drug
combination, the severity and course of the infection, the patient's disposition to the infection
and the judgment of the treating physician.




EXAMPLES
This section describes the synthesis of lysine based compounds able to release an HIV
aspartyl protease inhibitors as described herein. These examples are for the purpose of
illustration only and are not to be construed as limiting the scope of the invention in any way.
This section presents the detailed synthesis of compounds no. 1 to 10 of this invention.
Materials and Methods
Analytical thin layer chromatography (TLC) was carried out with 0.25 mm silica gel E.
Merck 60 F254 plates and eluted with the indicated solvent systems. Preparative
chromatography was performed by flash chromatography, using silica gel 60 (EM Science)
with the indicated solvent systems and positive air pressure to allow proper rate of elution.
Detection of the compounds was carried out by exposing eluted plates (analytical or
preparative) to iodine, UV light and/or treating analytical plates with a 2% solution of p-
anisaldehyde in ethanol containing 3% sulfuric acid and 1% acetic acid followed by heating.
Alternatively, analytical plates may be treated with a 0.3% ninhydrin solution in ethanol
containing 3 % acetic acid and/or a C AM s olution m ade 0 f 2 0 g (NHLOeMoyC^ and 8.3 g
Ce(S04)2 polyhydrate in water (750 mL) containing concentrated sulfuric acid (90 mL).
Preparative HPLC were performed on a Gilson apparatus equipped with a C18 column, a 215
liquid handler module and 25 mL/min capacity head pumps. The HPLC is operated with a
Gilson UniPoint System Software.
Semi-preparative HPLC conditions for purification of test compounds:
HPLC system: 2 Gilson #305-25 mL pumps, Gilson #215 liquid handler for injection and
collection and a Gilson #155 UV-Vis absorbance detector, all controlled from a Gilson
Unipoint V1.91 software
Column: Alltech (#96053) Hyperprep PEP, C-18, 100 Act, 8 |im, 22 x 250 mm
Flow: 15 mL/min
Solvents: A: H20; B: CH3CN
Gradient: 25% to 80% of B over 40 min
Detector: absorbance; X: 210 & 265 nm

The crude material dissolved in acetonitrile to a concentration of around 50 to 80 nig / 2 mL
were injected in each run. Fractions were collected in amounts of 9 mL pertaining absorbance
was detected at the UV detector.
Unless otherwise indicated, all starting materials were purchased from a commercial source
such as Aldrich Co. or Sigma Co.
Melting points (mp) were determined on a Buchi 530 melting point apparatus in capillary
tubes and were uncorrected.
Mass spectra were recorded on a Hewlett Packard LC/MSD 1100 system using APCI or
electrospray sources either in negative mode or positive mode.
Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AMX-II-500
equipped with a reversed or QNP probe. Samples were dissolved in deuterochloroform
(CDCI3), deuteroacetone (acetone-dg), deuteromethanol (CD3OD) or
deuterodimethylsulfoxide (DMSO-de) for data acquisition using tetramethylsilane as internal
standard. Chemical shifts (*) are expressed in parts per million (ppm), the coupling constants
(J) are expressed in hertz (Hz) whereas multiplicities are denoted as s for singlet, d for
doublet, 2d for two doublets, dd for doublet of doublets, t for triplet, q for quartet, quint, for
quintet, m for rnultiplet, and br s for broad singlet.
DETAILED DESCRIPTION OF THE INVENTION
EXAMPLES:
Specific examples for the preparation of derivatives of general formula I
The following compounds were prepared from L-lysine derivatives using the procedures
summarized in schemes 1,1A, 2, 3, 4 and 5 of this invention.

Example 1. Preparation of (l^^^-^-IS-^-amino-benzenesuIfonylHsobutyl-amino]-
6-phosphonooxy-hexylcarbamoyl}-2,2-diphenyI-ethyl)-carbamic acid
methyl ester (PL-461)
The preparation of the title compound is based on schemes 1 and 2 of this invention.
Step A. Preparation of (35)-3-isobutylamino-azepan-2-one(/F)
L-or-amino-^-caprolactam (22.0 g) was dissolved in cold dichloroethane (DCM, 200 mL).
isobutyraldehyde (12.6 g) was added slowly and stirred until the heat evolved was dissipated
(water forms at the surface). The cold solution was added to 46.5 g of powdered
NaBH(OAc)3 in DCM (0.5 L). AcOH (70 mL) was added to the solution. The slightly turbid
mixture was stirred at 20 °C for 4 h. A 500 mL solution of 2M NaOH was added slowly to
the turbid mixture and the pH adjust to 11 using a concentrated NaOH solution, and then the
mixture stirred for a further 20 min. After extraction, the DCM layer was dried with MgSC>4,
filtered and evaporated. The oil thus obtained crystallizes slowly on standing (27.8 g, 85%)
and was used without further purification in the next step.
jH NMR (CDC13): S 0.93 (d, /= 6.5, 3H), 0.97 (d, J= 6.5, 3H), 1.39 (t, J=-9.8, 1H), 1.47
(m, 1H), 1.78-1.65 (m, 2H), 2.00-1.93 (m, 2H), 2,32-2.2 (m, 2H), 2.38 (t, /= 9.7, 1H), 3.16
(m, 3H), 6.62 (s, 1H (NH)). mp 52-54 °C (hexanes).
A small sample was converted to the S-methyl benzyl urea by adding the solid to a solution
of ^-methyl benzyl isocyanate in MeCN. NMR gives 98% ee
Step B. Preparation of A^a-isobutyl-Ara-(4-acetamidobenzenesulfonyl)-L-a'-ammo-,-
caprolactam (V)
JVa-isobutyl-L-ar-amino-,-caprolactam (IV) (4.1 g free base) was dissolved in DCM (200 mL)
and treated with 4.0 g triethylamine, followed by 4-acetamidobenzenesulfonyl chloride (5.2
g). A 0.1 g portion of dimethylaminopyridine was added and the mixture was stirred 5 h. The
resulting thick slurry was poured into 500 mL 0.5 M HC1 and shaken vigorously. The solid in

the biphasic solution was filtered out and washed with cold acetone to give 7.3 g (87%) of
clean product.
:H NMR (DMSO-4): * 0.93 (d, J = 6.0, 3H), 0.96 (d, /= 6.0, 3H), 1.39 (t, /= 12.0, 1H),
1.85-1.65 (m, 3H), 2.08-2.18 (m and s, 6H), 2.90-2.97 (m, 1H), 3.00-3.06 (m, 2H), 3.35 (dd, J
= .14.2, 8.5, 1H), 4.65 (d, J= 8.7,1H), 6.3 (s, 1H), 7.42 (d, J= 8.8, 2H), 7.6 (d, J= 8.8, 2H).
mp 230-233 °C (EtOH).
Step C. Preparation of (35)-3-{[4-(acetyl-tert-butoxycarbonyl-amino)-
berizenesulfonyl]-isobutyl-amino}-2-oxo-azepane-l-carboxylic acid tert-butyl ester (Boc
activation) (VI)
4.2 g of 7Ya-isobutyl-7Va-(4-acetarnidoberizenesulfonyl)-L-c!r-amiiio-,-caprolactam (V) v/as
suspended in 30 mL MeCN and briefly sonicated to break up any large chunks. To this white
suspension was added 6.7 g (3 eq.) of di-tert-butyl pyrocarbonate in 10 mL MeCN. The
suspension was stirred with a magnetic bar and a 120 mg portion of DMAP was added. The
solution becomes a clear light yellow after a few minutes. TLC (EtOAc) reveals 1 product Rf
0.9 (starting material Rf at 0.4). The solution is poured in distilled water 20 mL and extracted
with ether, dried with Na2S04 and evaporated yielding 6.90 g. A sample was recrystallized
from hexanes.
'H NMR (DMSO-4): * 0.68 (d, /= 6.0, 3H), 0.85 (d, /= 6.0, 3H), 1.39 (s, 10H), 1.47 (s,
9H), 1.85-1.65 (m, 3H), 2.15 (s, 3H), 2.80 (q, /= 4,1H), 3.10-3.36 (m, 2H), 4.01 (d, J= 8.0,
1H), 4.85 (d,J= 8.7,1H), 7.32 (d,/= 8.8,2H), 7.87 (d,J= 8.8, 2H). mp 123-124 °C
Step D. Preparation of (l1S)-4-amino-iV-(5-amino-l-hydroxymethyl-pentyl)-JV-isobutyl-
benzenesulfonamide (WZ-deprotected) (reductive ring opening and deprotection)
A 3.0 g portion of (35)-3-{[4-(acetyl-tert-butoxycarbonyl-amino)-benzenesulfonyl]-isobutyl-
amino}-2-oxo-azepane-l-carboxylic acid tert-butyl ester (VI, step C) is dissolved in 40 mL
EtOH followed by 750 mg NaBH/f. Brief heating with a heat gun gives a clear solution. TLC
reveals one streaky spot after 20 min (EtOAc). The solution is concentrated to a paste, poured
in 40 mL INNaOH and extracted with ethyl acetate, the organic phase dried with NaSCU and

evaporated to give 2.8 g of product intermediate (VII); (15)-{4-[(5-tert-
butoxycarbonylamino-1-hydroxymethyl^^
tert-butyl ester (VII).
The above product intermediate is dissolved in 5 mL EtOH and 5 mL 12 N HC1 is added.
Vigorous gas evolution is observed for a few minutes. After 2 h the solution is evaporated
and rendered basic with concentrated KOH and extracted with EtOAc yielding 1.75 g of a
white powder.
!H NMR (DMSO-d6): * 0.82 (m, 6H), 0.97-1.12 (m, 2H), 1.15-1.30 (m, 3H), 1.57 (m, 1H),
1.84 (m, 1H), 2.40 (t, /= 7.8, 2H), 2.75 (m, 1H), 2.85 (m, 1H), 3.21 (m, 1H), 3.44 (d, J= 6.4,
2H), 5.92 (br s, 2H), 6.59 (d, J= 8.0, 2H), 7.39 (d, /= 8.0, 2H).
Step E. Preparation (2>S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid
To a solution of L-diphenylalanine (241 mg, 1.0 mmol) (Peptech Corp.) in 5 mL IN NaOH
and 0.5 mL saturated Na2C03 (resulting solution at pH 10) was added
methoxycarbonyloxysuccinimide (carbonic acid 2,5-dioxo-pyrrolidin-l-yl ester methyl ester)
(180 mg, 1.1 mmol) dissolved in 5 mL. Afterwards, the reaction mixture was stirred at room
temperature for 2 h. The alkaline solution was extracted once with ether (10 mL) and the
aqueous phase was acidified with IN HC1. This was extracted twice with 20 mL EtOAc, and
the combined organic phases were washed with 50 mL IN HC1. The organic phase was dried
over Nct2S04j filtered and evaporated to an oil, which solidifies to yields 250 mg (83%) of the
desired material. This derivative was used as such in the next step.
Step F. Preparation of (l,S',55)-(l-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-
hydroxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamic acid methyl ester (PL-100)
The title compound was prepared from (15)-4-amino-iV-(5-amino-l-hydroxymethyl-pentyl)-
A^-isobutyl-benzenesulfonamide (J^ZZ-deprotected) (step D) and (2S)-2-
methoxycarbonylamino-3,3~diphenyl-propionic acid (step E) using the coupling procedure
with HOBt and ED AC described in example 3 (step D). The final product was obtained in
67% yield. (121 mg).

LC-MS : 625.3 (M+H)+, 95% pure
*H NMR (CD3OD); 5 0.71-0.85 (m, 2H), 0.88 (d, J =6.3, 5H), 0.91-0.96 (m, 2H), 1.29-1.34
(m, 1H), 1.41-1.52 (m, 1H) 1.82-1.92 (m, 1H), 2.61-2.68 (m, 1H), 2.81-2.85 (m, 2H), 2.94-
3.05 (m, 2H), 3.38-3.40 (t, J = 5.0, 1H), 3.50-3.51 (m, 1H), 3.52 (s, 3H), 4.28 (d, J = 11.0
1H), 4.87 (d, J= 11.0, 1H), 6.69 (d, J= 8.0, 2H), 7.15-718 (m, 2H), 7.20-7.31 (m, 6H), 7.33
(d, J = 7.9, 2H), 7.47 (d, J = 7.5,1H).
I3C NMR (CD3OD): 8 20.0, 20.1,23.3,25.4,28.1,28.5,28.9, 38.1,40.0, 51.2, 51.6, 53.1,
57.2, 57.4, 59.5, 61.9, 62.4,112.6,125.7, 126.2,126.3,127.9,128.1,128.15,128.2, 128.4,
128.7,141.3,141.9, 152.4,155.9,169.9, 172.5.
Step G. Preparation of (l1S,,55)-{l-[5-[(4-amino-benzeriesulfonyl)-isobutyl--amino]-6-
(diethoxy-phosphoryloxy)-hexylcarbamoyl]-2,2-diphenyl-ethyl}-carbamic acid methyl ester
The PL-100 compound (product of step F, 203 mg, 0.325 mmol) was dissolved in dry
tetrahydrofuran (3 mL) and 0.2 mL triethylphosphate under N2 atmosphere. The mixture was
stirred at this temperature for 15 min, followed by the addition of diethyl chlorophosphate
(0.061 mL, 0.423 mmol). Sodium hydride (60% in mineral oil) (17 mg, 0.423 mmol) was
added at 0 °C. The solution was stirred for 1 h at 0 °C and 12 h at room temperature. 20 mL
of Amberlite XAD-2 was added to the solution and the beads were thoroughly mixed with the
solvent. To the mixture was added ice water 2 mL, and the THF evaporated off. The beads
were then washed with distilled water 6 times 100 mL then extracted three times with ethyl
acetate (30 mL). The combined phase was evaporated and the residue was dried under high
vacuum. The crude product was purified by flash chromatography using ethyl acetate/hexane
(8/2), then EtOAc 100% as eluent. The yield of this reaction is 152 mg 61%.
LC-MS: 761.2 (M+H)+, 90% pure
*H NMR (CD3OD): 8 0.68-0.75 (m, 1H), 0.75-0.84 (m, IE), 0.84-1.10 (m, 9H), 1.21-1.50
(m, 8H), 1.88 (m, 1H), 2.58-2.71 (m, 1H), 2.80-2.89 (m, 1H), 2.89-3.08 (m, 2H), 3.49-3.60
(s, 3H), 3.65-3.74 (m, 1H), 3.85-3.95 (m, 1H), 3.97-4.02 (m, 1H), 4.07-4.21 (m, 413), 4.29 (d,

J = 10.8,1H), 6.71 (d, J = 8.0, 2H), 7.10-7.20 (m, 2H), 7.20-7.32 (m, 5H), 7.32-7.45 (m, 3H),
7.50 (d, J = 7.5,2H), 7.86 (br s, 1H).
31PNMR(CD3OD): S 1.62
StepH. Preparation of (l»S',55)-(l-{5-[(4-arniiio-benzenesulfonyl)-isobuty]-arnino]-6-
phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamic acid methyl ester (PL-461)
The product of step G prepared above (152 mg) was dissolved in anhydrous dichloromethane
(3.0 mL). Trimethylsilyl bromide (0.5 mL) was added at 0 °C. The mixture was stirred
during In at this temperature and overnight at room temperature. The solvent was evaporated
and 0.2 mL water was added to the residue. 3 mL EtOH was added mixed and evaporated.
This step was repeated three times and the residue dried in vacuo. Yields 98 mg 70% of the
title derivatives of this first example.
LC-MS: 705.2 (M+H)+, 95% pure
*H NMR (CD3OD): S 0.65-0.73 (m, 1H), 0.75-0.83 (m, 1H), 0.89 (d, J = 5.6, 8H), 1.27-1.38,
(m, 1H), 1.42-4.55 (m, 1H), 1.82-1.94 (m, 1H), 2.57-2.68 (m, 1H), 2.78-2.90 (m, 1H), 2.91-
3.09 (m, 2H), 3.54 (s, 3H), 3.60-3.72 (m, 1H), 3.87-4.05 (m, 1H), 4.00 (m, 1H), 4.29 (d, J =
11.3, 1H), 4.90 (d, J = 11.4, 1H), 6.73 (d, J = 8.0, 2H), 7.13-7.22 (m, 2H), 7.22-7.33 (m, 6H),
7.33-7.45 (m, 2H), 7.51 (d, J = 7.5, 2H).
31P NMR (CD3OD): 5 2.80
Example 2. Preparation of (l^S^Hl-IS-f^-ammo-benzenesulfonylHsobutyl-amino]-
6-phosphonooxy-hexylcarbamoyI}~2,2-diphenyI-ethyl)-carbamic acid
methyl ester sodium salt (PL-462)
70.7 mg of the final product of example 1 is added to 1 mL 0.1 N NaOH and diluted with 1
mL of distilled water. The Solution is then frozen and lyophilized. Yields 67.2 mg (92%) of
the desired material with 95% purity.

'HNMR (CD3OD): (m, 1H), 1.88-2.00 (m, 1H), 2.60-2.70 (m, 1H), 2.79-2.89 (m, 1H), 2.98-3.00 (m, 1H), 3.00-
3.08 (m, 1H), 3.54 (s, 3H), 3.58-3.71 (m, 1H), 3.72-3.83 (m, 1H), 3.84-3.95 (m, 113), 4.28 (d,
J = 11.1, 1H), 4.91 (d, J - 11.0, 1H), 6.70 (d, J = 7.6, 2H), 7.12-7.22 (m, 2H), 7.22-7.32 (m,
6H), 7.33-7.40 (m, 2H), 7.50 (d, J = 7.7, 2H).
3lPNMR(CD3OD): 8 3.13
Example 3. Preparation of (liS',51S)-(l-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-
6-phosphonooxy-hexyIcarbamoyI}-2-naphthalen-2-yl-ethyl)-carbamicacid
methyl ester (PL-507)
The preparation of the title compound is based on scheme 2 of this invention.
Step A. Preparation of (liS)-(4-{[5-tert-butoxycarbonylamino-l-
(diethoxyphosphoryloxymethyl)-pentyl]-isobutyl-sulfainoyl}-phenyl)-carbamic acid tert-
butyl ester (VIII)
2.00 g (3.7 rnmol) (liS)-{4-[(5-tert-butoxycarbonylamino-l-hydroxvmethyl-pentyl)-isobutyl-
sulfamoyl]-phenyl}-carbamic acid tert-butyl ester (VII) (example 1, step D) is dissolved in
0.63 mL triethylphosphate and 10 mL THF at 0 °C under inert argon atmosphere. 0.63 mL
(4.44 mmol) diethylchlorophosphate is added and then 0.25 g (6.2 mmol), NaH 60% in oil is
added in portionwise. The mixture is allowed to warm to room temperature and left to stir for
2 h (LC-MS showed completion after 1 h). To the solution is added 20 mL of Amberlite
XAD-2 resin and the slurry thoroughly mixed and added to 200 mL ice water. After stirring
for 15 min. the resin suspension is filtered and the resin washed several times with distilled
water (500 mL). The desired product is desorbed from the resin with acetone (5 X 50 mL),
EtOAc (5 X 50 mL), the organic phase is then dried over Na2SC>4. After evaporation of the
solvent 2.66 g (89%) of clear oil is obtained. The crude product contains a fraction with two
diethyl phosphates and is used as is in the next step.
TH NMR (CD3OD): 8 0.91 (d, J = 6.3, 6H), 1.11-1.21 (m, 2H), 1.33 (t, J = 6.9,10H), 1.43 (s,
9H), 1.53 (s, 10H), 1.90-1.97 (m, 1H), 2.88-2.96 (m, 3H), 2.96-3.04 (m, 1H), 3.81-3.90 (m,
1H), 3.91-3.99 (m, 1H), 4.01-4.14 (m, 4H), 7.61 (d, J = 8.3, 2H), 7.72 (d, J *= 8.4, 2H).

31P NMR (CD3OD): 8 1.59
StepB. Preparation of (2i5)-phosphoric acid 6-amino-2-[(4-amino-benzenesulfonyl)-
isobutyl-amino]-hexyl ester diethyl ester (IX)
The crude product obtained in the previous step {VIII, 2.66 g) is dissolved in 12 mL EtOH. 4
mL of HC1 cone- is added and heated briefly to 70 °C then left at room temperature for 3h. The
solvent is evacuated and the residue triturated with 50 mL ether. The thick residue is then
dissolved in 3 mL ice water and the pH adjusted to 12 with 50% NaOH. The thick slurry
obtained is extracted with EtOAc (3 X 50 mL) and the organic phase dried overNa2S04.
After filtration of the drying agent the organic phase is evacuated to yield 1.84 g (98%) of the
desired product (IX).
LC-MS: 480.2 (M+H)+, 95% pure.
!H NMR (CD3OD): 5 0.91 (s, 6H), 1.11-1.26 (m, 3H), 1.28-1.43 (m, 8H), 1.45-1.51 (m,
1H), 1.52-1.61 (m, 1H), 1.89-1.96 (m, 1H), 2.56 (t, J = 6.7, 2H), 2.85-2.91 (m, 1H), 2.98-3.11
(m, 1H), 3.79-3.99 (m, 1H), 3.94 (d, J = 5.3, 1H), 4.09-4.11 (m, 4H), 6.69 (d, J = 7.9, 2H),
7.50 (d, J = 7.9, 2H).
31PNMR(CD3OD): 8 1.61
Step C. Preparation of (25)-2-methoxycarbonylamino-3-naphthalen-2-yl-propionic
acid (or L-Moc-2-naphthylalanine)
To a solution of L-2-naphthylalanine (215 mg, 1 mmol) (Peptech Corp.) in 5 mL IN NaOH
and 0.5 mL saturated Na2C03 (resulting solution at pH 10) was added
methoxycarbonyloxysuccinimide (187 mg, 1.1 mmol) dissolved in 5 mL. Afterwards, the
reaction mixture was stirred at room temperature for 2 h. The alkaline solution was extracted
once with ether (10 mL) and the aqueous phase was acidified with IN HC1. This was
extracted twice with 20 mL EtOAc, and the combined organic phases were washed with 50
mL IN HC1. The organic phase was dried over Na2S04, filtered and evaporated to an oil,

which solidifies to yields 200 mg (73%) of the desired material. This intermediate (referred
as the iV-substituted amino acid) was used without further purification in the next step.
Step D. Preparation of (16',5IS)-(l-{5-[(4-amino-benzenesulfonyl)-isobutyl-ainino]-6-
phosphonooxy-hexylcarbamoyl}-2-naphthalen-2-yl-ethyl)-carbamic acid methyl ester (PL-
507)
100 mg L-Moc-2-naphthylalariine (step C) was activated with 100 mg ED AC and 57 mg
HOBt in 1.5 mL DMF for 30 minutes. Then, 100 mg of phosphoric acid 6-arnino-2-[(4-
amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester diethyl ester (step B) was added and left
to stir at room temperature for 1 h. 40' mL of 1M K2CO3 was added to the DMF solution and
left for 10 min. 50 mL of EtOAc was then added and the mixture was then agitated
vigorously. Separation of the EtOAc phase was effected, followed by extraction with 5%
citric acid (50 mL) once, then water (50 mL) 3 times and finally brine. The organic phase was
the separated and evaporated. The residue was taken up in 50 mL DCM and re-evaporated.
The residue was again taken up in 50 mL DCM and 0.5 mL of TMSBr was added. The
solution was left overnight (16 h). The DCM was evacuated and a solution of ice cold
MeOH: Water 1:1 was added, stirred briefly and evacuated. The residue was triturated with
ether then dissolved in IN NaOH. The clear solution was extracted with ether and the
aqueous phase acidified with 6N HC1. The white precipitated was then collected by filtration
and dried in vacuo overnight. Yields 88 mg of the title compound.
LC-MS: 679.8 (M+H)+, 95% pure.
1HNM]R.(CD3OD): 8 0.89-0.98 (m, 8H), 1.15 (m, 2H), 1.35 (m, 1H), 1.45 (m, 1H), 1.88 (m,
1H), 2.84 (m, 2H), 2.98 (m, 1H), 3.01 (m, 2H), 3.24 (m, 1H), 3.56 (s, 3H), 3.60 (m, 1H), 3.81
(m, 1H), 3.99 (m, 1H), 4.39 (t, J = 6.8, 1H), 6.91 (d, J = 8.0, 2H), 7.34 (d, J= 8.0, 1H), 7.45
(m, 2H), 7.58 (d, J = 8.0, 2H), 7.66 (s, 1H), 7.70-7.82 (m, 3H).
31P NMR (CD3OD): 3 2.56

Example 4. Preparation of (2S,2S) phosphoric acid mono-(2-[(4-amino-
benzenesulfonyI)-isobutyl-amino]-6-{2-[(morpholine-4-carbonyl)-amino]-
3-naphthalen-l-yl-propionylamino}-hexyl) ester (PL-498)
Step A. Preparation of (2 propionic acid
To a solution of L-1-naphthylalanine (215 mg, 1 mmol) (Peptech Corp.) in 5 mL IN NaOH
and 0.5 mL saturated Na2CC>3 (resulting solution at pH 10) was added morpholine-4-carbonyl
chloride (150 mg,. 1.0 mmol) dissolved in 5 mL. Afterwards, the reaction mixture was stirred
at room temperature for 2 h. The alkaline solution was extracted once with ether (10 mL) and
the aqueous phase was acidified with IN HC1. This was extracted twice with 20 mL EtOAc,
and the combined organic phases were washed with 50 mL IN HC1. The organic phase was
dried over Na2S04, filtered and evaporated to an oil, which solidifies to yields 125 mg (38%)
of the desired material. This compound was used as such in the next step.
Step B. Preparation of (2S,2S) Phosphoric acid mono-(2-[(4-amino-benzenei;ulfonyl)-
isobutyl-amino]-6-{2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-l-yl-propionylamino}-
hexyl) ester (PL-498)
This compound was made as for the preparation of the product of example 3 (step D) with
100 mg of (2JS)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-l-yl-propionic acid (step A
of this example). The resulting precipitated residue was further purified by reverse phase
preparative HPLC. Yields 41 mg of the final compound.
LC-MS: 734.8 (M+H)+, 95% pure.
!HNMR (CD3OD): 8 0.83-0.98 (m, 8H), 1.00-1.25 (m, 4H), 1.45-1.52 (m, 1H), 1.52-1.66
(m, 1H), 1.88-1.99 (m, 1H), 2.77-2.92 (m, 2H), 2.98-3.16 (m, 3H), 3.40-3.49 (m, 1H), 3.50-
3.56 (m, 6H), 3.67-3.69 (m, 1H), 3.81-3.89 (m, 1H), 3.99-4.05 (m, 1H), 4.59 (t, J = 6.0, 1H),
6.75 (d, J = 8.0, 2H), 7.30-7.60 (m, 7H), 7.75 (d, J = 8.0, 1H), 7.90 (d, J= 7.8, 1H), 8.23 (d,
J=7.8 2H).
31P NMR (CD3OD): 5 2.71

Example 5. Preparation of (25,2iy)-phosphoric acid mono-{6-(2-acetylamino-3,3-
diphenyI-propionylamino)-2-[(4-amino-benzenesuIfonyl)-isobut5'l-amino]-
hexyl} ester (PL-504)
Step A. Preparation (21S)-2-acetylamino-3,3-diphenyl-propionic acid
To a solution of L-diphenylalanine (100 mg, 0.4 mmol) (Peptech Corp.) in 5 mL IN NaOH
and 0.5 mL saturated Na2CC>3 (resulting solution at pH 10) was added acetyl chloride (0.5
mmol) dissolved in 5 mL. Afterwards, the reaction mixture was stirred at room temperature
for 2 h. The alkaline solution was extracted once with ether (10 mL) and the aqueous phase
was acidified with IN HC1. This was extracted twice with 20 mL EtOAc, and the combined
organic phases were washed with 50 mL IN HC1. The organic phase was dried over Na2SC*4,
filtered and evaporated to an oil, which solidifies to yields 70 mg (60%) of the desired
material. This crude intermediate was used as such in the next step.
Step B. Preparation of (25,,26)-phosphoric acid mono- {6-(2-acetylamino-3,3-diphenyl-
propionylamino)-2-[(4-amino-benzenesulfonyl)-isobutyl-amino] -hexyl} ester (PL-504)
This compound was made as for the preparation of the product of example 3 (step D) with
100 mg of (2iS)-2-acetylamino-3,3-diphenyl-propionic acid (this example step A). The final
product was obtained in 30% yield (30 mg).
LC-MS: 689.3 (M+H)+, 95% pure.
lH NMR (CD3OD): 8 0.77-1.04 (m, 9H), 1.10-1.17 (m, 1H), 1.23-1.49 (m, 1H), 1.46-1.57
(m, 1H), 1.78 (s, 3H), 1.88-1.99 (m, 1H), 2.80-2.92 (m, 2H), 2.92-3.08 (m, 2H), 3.63-3.75
(m, 1H), 3.79-3.95 (m, 1H), 4.00 (m, 1H), 4.34 (d, J = 11.3, 1H), 5.19-5.28 (m, 1H), 6.77-
6.85 (m, 2H), 7.10-7.20 (m, 2H), 7.27-7.33 (m, 6H), 7.32-7.41 (m, 2H), 7.49-7.62 (m, 2H).
31P NMR (CD3OD): S 2.70

Example 6. Preparation of (llS',55)-(l-{5-[(4-amino-3-fluoro-benzenesulfony][)-
isobutyl-ammo]-6-phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-
carbamic acid methyl ester (PL-515)
First methodology: The preparation of the title compound is based on scheme 3 of this
invention.
Step A. Preparation of (l-{5-[(4-arm^o-3-fluoro-benzenesulfonyl)-isobutyl-amino]-6-
hyoVoxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamic acid methyl ester (X) (PL-337)
The product of example 1, step F (0.624 g, 1 mmol) is dissolved in 5 mL MeCN at 24 °C.
SelectFluor 0.35 g (1 mmol) is added in one portion and stirred for lh. 1 mL of water is
added and the solution was injected directly into a preparative reverse-phase HPLC. The
product was collected and lyophilized to give 250 mg (38%) yield of a white solid.
LC-MS: 643.3 (M+H)+, 99% pure.
lK NMR (MeOD): S 0.71-0.85 (m 2H), 0.88 (d, J = 6.3, 6H), 0.91-0.96 (m, 2H), 1.21-1.29
(m, 1H), 1.41-1.52 (m, 1H) 1.82-1.92 (m, 1H), 2.61-2.68 (m, 1H), 2.81-2.85 (m, 2H), 2.94-
3.05 (m, 2H), 3.38-3.40 (t, J = 5, 1H), 3.49-3.52 (m, 5H), 4.28 (d, J = 10, 1H), 4.87 (d, J =
10, 1H) 6.90 (t, J = 8.3, 1H), 7.20 (m, 2H), 7.28 (m, 3H), 7.33 (m, 3H), 7.39 (m, 4H).
StepB. Preparation of (l1S',55)-{l-[5-[(4-amino-3-fluoro-benzenesulfonyl)-isobutyl-
amino]-6-(diethoxy-phosphoryloxy)-hexylcarbamoyl]-2,2-diphenyl-ethyl}-carbamic acid
methyl ester
The product of step A was phosphorylated with chlorodiethylphosphate following the
procedure described in example 1, step G. Yields 157 mg, 68%.
LC-MS: 779.3 (M+H)+, 95% pure.
lH NMR (CD3OD): 6H), 1.90 (m, 1H), 2.69 (m, 1H), 2.89 (m, 1H), 2.98 (m, 2H), 3.56 (s, 3H), 3.74 (mi, 1H), 3.93

(m, 1H), 4.03 (m, 1H), 4.12 (q, J = 7.5 and 14.8,4H), 4.32 (d, J = 11.4,1H), 4.92 (d, J - 11.4,
1H), 6.90 (t, J = 8.3,1H), 7.20 (m, 2H), 7.28 (m, 3H), 7.33 (m, 3H), 7.39 (m, 4H).
31PNMR.(CD3OD): 5 1.65
StepC. Preparation of (16',55)-(l-{5-[(4-amino-3-fluoro-benzenesulfonyl)-isobutyl-
amino]-6-phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamic acid methyl ester
(XI) (PL-515)
Deprotection was effected using the procedure described in example 1,. step G. Yields 101
mg.
LC-MS: 723.2 (M+H)+, 95% pure.
:H NMR (CD3OD): S 0.65-0.77 (m, 1H), 0.77-0.85 (m, 1H), 0.85-1.05 (m, 9H), 1.25-1.39
(m, 1H), 1.40-1.52 (m, 1H), 1.82-1.98 (m, 1H), 2.58-2.72 (m, 1H), 2.82-2.92 (m, 1H), 2.92-
3.05 (m, 2H), 3.54 (s, 3H), 3.64-3.75 (m, 1H), 3.80-3.92 (m, 1H), 3.91-4.04 (m, III), 4.29 (d,
J = 11.4, 1H), 7.19 (t, J = 6.6, 1H), 7.13-7.21 (m, 2H), 7.22-7.33 (m, 6H), 7.34-7.38 (m, 2H),
7.39-7.48 (m, 2H).
31PNMR(CD3OD): S 2.1 A
Second methodology: The preparation of the title compound is based on scheme 4 of this
invention.
Step A. Preparation (l1S',5iS)-(l-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-
phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamic acid methyl ester (PL-461)
(2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid ((example 1, step E) 0.9 g, 3
mmol) was activated in DMF (5 mL) with EDAC (1.7 g, 9 mmol) and HOBt (1.2 g, 9 mmol).
To the solution was added 1.17 g of (2>S)-phosphoric acid 6-amino-2-[(4-amino-
benzenesulfonyl)-isobutyl-amino]-hexyl ester diethyl ester (IX) (example 3, step B) and the
mixture stirred for 3 h. 20 g of Amberlite XAD-2 resin was then added and the beads were
left to soak for 10 min. The resin was transferred into a glass filter and washed thoroughly

with distilled water (400 mL) and 200 mL of 1M NaHC03. The beads were then washed with
4 X 50 ml portions of MeOH then EtOAc 200 mL. The organic phase was evaporated. The
residue was adsorbed onto silica gel and passed through a short silica gel column (EtOAc) to
yield 2.4 g (83%) of white solid after evaporation.
NMR identical as in example 1, step H.
Step B. Preparation (16,,5iS)-{l-[5-[(4-amino-3-fluoro-benzenesulfonyl)-isobutyl-
amino]--6-(diethoxy-phosphoryloxy)-hexylcarbamoyl]-2,2-diphenyl-ethyl}-carbamic acid
methyl ester (XII)
The product of step A above, (15,,5)S)-(l-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-
phosphonooxy hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamic acid methyl ester (0.555 g,
0.73 mmol) was dissolved in 5 mL MeCN. Selectfiuor (0.26 g, 0.7 mmol) was added and the
mixture stirred for 30 min. The mixture was purified by reverse phase preparative HPLC and
lyophilized to yield 278 mg (48% yield) white solid.
lH NMR. identical as previous entry, see first methodology above.
Step C. Preparation (lJS,,5^-(l-{5-[(4-amino-3-fluoro-benzenesulfonyl)-isobutyl-
amino]-6-phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamic acid methyl ester
(XIII, in this specific case is compound XT) (PL-515)
The procedure make this derivative was as described in the deprotection step for the
methodology above. Yields 139 mg 70% after reverse phase HPLC.
'H NMR identical as previous entry, see first methodology above.
Example 7. Preparation of (25',2iS)-acetic acid 2-[(4-amino-benzenesulfonyl)-isobutyl-
amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylami]ao)-hexyI
ester (PL-521)
The preparation of the title derivative is based on scheme 5 of this invention.

Step A. Preparation of (2iS)-acetic acid 6-tert-butoxycarbonylanrino-2-[(4-tert-
butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexyl ester {XIV, Ru = CH3)
To a stirred solution of (l»J)-{4-[(5-tert-butoxycarbonylamino-l-hydroxymetl'Lyl-pentyl)-
isobuty]-sulfamoyl]-phenyl}-carbamic acid tert-butyl ester (intermediate product (VII) of
example 1, step D, 97 mg, 0.18 mmol) in anhydrous CH2CI2 (3 mL) was added N,N-
dimethylaminopyridine (22 mg, 0.18 mmol) and acetic anhydride (0.014 mL, 0,18 mmol).
The mixture was stirred at room temperature for 1 hour. The solvent was evaporated. Ethyl
acetate (50 mL) was added and the organic layer was washed with water (30 mL)., then dried
with Na2S04 and concentrated. The residue was purified by flash chromatography eluting
with ethyl acetate. The yield obtained was quantitative (100 mg).
LC-MS: 586.2 (M+H)+, 95% pure
StepB. Preparation of (25)-acetic acid 6-amino-2-[(4-amino-benzenesulfonyl)-
isobutyl-amino]-hexyl ester (XV, RJA = CH3)
This derivative was prepared from (25')-acetic acid 6-tert-butoxycarbonylamino-2-[(4-tert-
butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexyl ester as described in example
15, step B. The yellow solid (66 mg) was used for the next reaction without purification.
LC-MS: 386.2 (M+H)+, 95% pure
Step C. Preparation of (2S,2S)-acetic acid 2-[(4-amino-benzenesulfonyl-)isobutyl-
amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-hexyl ester (XVI, RIA =
CH3) (PL-521)
This derivative was prepared from (2 isobutyl-amino]-hexyl ester (product of step B) as described in example 15, step B. The final
product was purified by flash chromatography with a mixture of eluents hexane/ethyl acetate
(2/8). A yellow solid was obtained in 70% yield (70 mg).
LC-MS: 667.3 (M+H)+, 95% pure

]H NMR (acetone-de): 8 0.85-0.97 (m, MIS), 1.21-1.41 (m, 2H), 1.88-2.00 (s, 3H), 2.59-
2.69 (m, 1H), 2.83-2.90 (m, 1H), 2.90-3.01 (m, 1H), 3.01-3.10 (br s, 1H), 3.45-3.60 (s, 3H),
3.70-3.80 (m, 1H), 3.93-4.00 (m, 1H), 4.00-4.11 (m, 1H), 4.38-4.45 (d, J = 11.0, 1H), 4.89-
4.98 (t, J = 10.0, 1H), 5.43-5.58 (br s, 1H), 6.28-6.48 (d, J = 8.9, 1H), 6.72-6.83 (d, J = 8.0,
2H), 6.85-6.93 (br s, 1H), 7.12-7.22 (t, J = 7.4, 1H), 7.21-7.31 (d, J = 7.0, 4H), 7.31-7.45 (m,
5H), 7.48-7.57 (d, J = 8.0, 2H).
Example 8. Preparation of (25,,21S)-nicotinic acid 2-[(4-amino-benzenesuIfonyl)-
isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-
propionylamino)-hexyI ester (PL-520)
Step A. Preparation of (25)-nicotinic acid 6-tert-butoxycarbonylamino-2-[(4-tert-
butoxycarbonylamino-benzenesulfonyl)-isobutyl-ammo]-hexyl ester (XIV, Ru = 3-pyridyl)
(l^-{4-[(5-tert-butoxycarbonylamino-l-hydroxymethyl-pentyl)-isobu1yl-siilfamoyl]-
phenylj-carbamic acid tert-butyl ester (intermediate product (VU) of example 1, step D, 130
mg, 0.24 rnmol) was dissolved in anhydrous DMF (1 mL) and treated with 0.066 mL (0.48
mmol) of triethylamine followed by EDC (120 mg, 0.65 mmol), HOBt (88 mg, 0.65 rnmol)
and nicotinic acid (27 mg, 0.22 mmol). The mixture was stirred overnight at room
temperature. The product was extracted with ethyl acetate (40 mL) and water (40 mL). The
organic phase was separated and dried with Na2SC>4, then evaporated to give 200 mg of crude
product. This compound was purified by flash chromatography with ethyl acetate as the
eluent. A clear oil was obtained in 100% yield (150 mg).
LC-MS: 649.3 (M+H)+, 95% pure
!H NMR (acetone-d6): S 0.90-1.14 (d, J = 5.9, 6H), 1.31-1.42 (m, 2H), 1.48 (s, 9H), 1.51-
1.55 (m, 2H), 1.59 (s, 9H), 1.62-1.69 (m, 1H), 1.72-1.83 (m, 1H), 3.00-3.11 (m, 2H), 3.11-
3.17 (m, 1H), 3.19-3.27 (m, 1H), 4.15-4.24 (m, 1H), 4.35-4.44 (t, J = 9.1, 1H), 4.50-4.58 (dd,
J = 4.4 and 11.5, 1H), 5.89-5.99 (br s, 1H), 7.53-7.60 (m, 1H), 7.70-7.77 (d, J == 8.2, 2H),
7.80-7.87 (d, J = 8.2, 2H), 8.24-8.31 (d, J = 7.3, 1H), 8.75-8.82 (m, 1H), 8.82-8.88 (m, 1H),
9.12-9.18 (brs, 1H).

StepB. Preparation of (2S)-rncotinic acid 6-amino-2-[(4-amino-benzenesulfonyl)-
isobutyl-amino]-hexyl ester (XV, RIA ~ 3-pyridyl)
The product of step A, (2>S)-nicotinic acid 6-tert-butoxycarbonylamino-2-[(4-tert-
butoxycarbonylamino-benzenesulfonyl)4sobutyl-amino]-hexyl ester (150 mg, 0.23 rnrnol),
was dissolved in CH2CI2 (5 mL) and trifluoroacetic acid (1 mL) was added. The mixture was
stirred during 2 hours at room temperature. The solvent was evaporated and the residue was
extracted with ethyl acetate (40 mL) and NaOH 1M (40 mL) (pH = 10). The organic portion
was separated, dried with Na2S04 and evaporated. The residue (100 mg) was used for the
next reaction without further purification. The yield was quantitative.
LC-MS: 449.2 (M+H)+, 95% pure
Step C. Preparation of (2£,2£)-nicotinic acid 24(4-amino-benzenesulfonyl)-isobutyl-
amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-hexyl ester (PL-520)
The product of step B, (25)-nicotinic acid 6-ammo-2-[(4-amino-benzenesulfonyl)-isobutyl-
aminoj-hexyl ester (100 mg, 0.22 mmol) was dissolved in anhydrous DMF (2 mL) and
treated with 0.062 mL (0.45 mmol) of triethylamine followed by EDC (100 mg, 0.56 mmol),
HOBt (75 mg, 0.56 mmol) and (2>S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid
(56 mg, 0.19 mmol). The mixture was stirred overnight at room temperature. The product
was extracted with ethyl acetate (40 mL) and water (40 mL). The organic layer was separated
and dried with Na2S04, then evaporated to give 160 mg of crude oil. The residue was purified
by flash chromatography with a mixture of eluents hexane/ethyl acetate (2/8). The title
compound was obtained as a clear oil in 20% yield (25 mg).
LC-MS: 730.2 (M+H)+, 95% pure
1HNWtR(acetone-d6): 5 0.80-0.97 (m, 9H), 0.97-1.13 (m, 2H), 1.26-1.40 (m, 1H), 1.40-1.57
(m, 1H), 2.61-2.73 (m, 1H), 2.86-2.98 (m, 2H), 3.00-3.17 (m, 2H), 3.45-3.59 (s, 3H), 3.91-
4.00 (m, 1H), 4.24-4.34 (m, 1H), 4.34-4.47 (m, 2H), 4.90-4.99 (t, J = 9.7, 1H), 6.35-6.44 (m,
1H), 6.68-6.79 (d, J = 7.9, 1H), 6.91-7.00 (br s, 1H), 7.13-7.22 (m, 2H), 7.22-7.31 (m, 313),

7.35-7.48 (m, 4H), 7.49-7.64 (m, 2H), 7.75-7.84 (m, 1H), 8.25-8.36 (m, 1H), 8.76-8.88 (br s,
1H), 9.12-9.26 (brs, 1H).
Example 9. Preparation of (ZiS^^-dimethylamino-acetic acid 2-[(4-amino-
benzeuesuIfonyl)-isobutyl-amino]-6-(2-methoxycarbonyIamino-3,3-
diphenyI-propionyIamino)-hexyI ester (PL-534)
Step A. Preparation of (2iS)-dimethylamino-acetic acid 6-tert-butoxycarbonylamino-2-
[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexyl ester {XIV, RIA =
(CH3)2NCH2-)
This title compound was obtained from (l1S}-{4-[(5-tert-butoxycarbonylamino-l-
hydrox;^methyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamic acid tert-butyl ester
(intermediate product (VII) of example 1, step D) as described example 15, step A using N,N-
dimethylglycine. The clear oil "was obtained in 100% yield (150 mg).
LC-MS: 629.3 (M+H)+, 95% pure
]H NMR. (acetone-de): 8 0.81-0.95 (d, J = 6.1, 6H), 1.18-1.30 (m, 2H), 1.32-1.43 (s, 9H),
1.43-1.52 (s, 8H), 1.52-1.62 (m, 1H), 1.93-2.00 (m, 1H), 2.19-2.29 (s, 4H), 2.69-2.80 (m,
,4H), 2.90-3.05 (m, 6H), 3.60-3.65 (m, 1H), 3.85-3.97 (m, 1H), 3.98-4.08 (m, 1H), 4.08-4.14
(m, 1H), 5.78-5.88 (m, 1H), 7.68-7.80 (m, 3H), 8.80-8.88 (brs, 1H).
StepB. Preparation of (2iS)-dimethylamino-acetic acid 6-amino-2-[(4-amino-
benzenesulfonyl)-isobutyl-amino]-hexyl ester (XV, RIA = (CH3)2NCH2-)
The title derivative was prepared from (26)-dimethylamino-acetic acid 6-tert-
butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-
hexyl ester as described in example 15, step B. The final product (100 mg) was used as such
in the next step.
LC-MS: 429.3 (M+H)+, 90% pure

Step C. Preparation of (2jS',2iS}-dimethylamino~acetic acid 2-[(4-amino-
benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-dipheriyl-
propionylarnirio)-hexyl ester (PL-534)
This title compound was prepared from (2 amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester as described in example 15, step C. The
crude product was purified by LC-preparative. The final compound was obtained in 10%
yield (10 mg).
LC-MS: 710.3 (M+H)+, 92% pure
'HNMRCacetone-de): 8 0.81-0.98 (m, 12H), 1.14-1.30 (m, 2H), 1.31-1.45 (m, 1H), 2.58-
2.77 (m, 2H), 2.79-2.90 (m, 2H), 3.42-3.56 (s, 3H), 3.75-3.85 (m, 1H), 3.99-4.17 (m, 3H),
4.23-4.35 (m, 1H), 4.36-4.45 (m, 1H), 4.86-4.96 (m, 1H), 6.33-6.42 (m, 1H), 6.74-6.83 (m,
1H), 6.85-6.90 (m, 1H), 7.12-7.22 (m, 3H), 7.23-7.31 (m, 4H), 7.31-7.44 (m, 5H), 7.47-7.55
(m, 1H), 7.73-7.80 (m, 1H).
Example 10. Preparation of (25l,25)-2-amino-3-methyl-bufyric acid 2-[(4-amino-
benzenesulfonyl)-isobutyI-amino]-6-(2-methoxycarbonylamino-3,3-
diphenyl-propionyIamino)-hexyl ester (PL-530)
Step A. Preparation of (2iS)-2-benzyloxycarbonylamino-3-methyl-butyric acid 6-tert-
butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-
hexyl ester (XIV, R1A = (CH3)2CHCH(NH2)-)
This title compound was obtained from (15}-{4-[(5-tert-butoxycarbonylamino-l-
hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamic acid tert-butyl ester
(intermediate product (VII) of example 1, step D) as described in example 15, step A using
(25)-2-benzyloxycarbonylamino-3-methyl-butyric acid. The crude product was purified by
flash chromatography eluting with a mixture of hexane/ethyl acetate (1/1). The yield obtained
was 100% (150 mg).
LC-MS: 777.3 (M+H)+, 95% pure

!HNMR (acetone-d6): 8 0.80-1.00 (m,14), 1.13-1.28 (s, 2H), 1.30-1.44 (s, 11H), 1.45-1.56
(s, 10), 1.58-1.67 (m, 1H), 2.87-3.04 (m, 4H), 3.84-3.97 (m, 1H), 3.97-4.12 (m, 2H), 4.12-
4.21 (m, 1H), 4.99-5.14 (m, 2H), 5.78-5.89 (m, 1H), 6.38-6.52 (m, 1H), 7.24-7.34 (m, 1H),
7.34-7.41 (m, 2H), 7.65-7.83 (m, 4H), 8.77-8.86 (m, 1H).
Step B. Preparation of (2iS)-benzyloxycarbonylarnmo-3-memyl-butyric acid 6-amino-
2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester (XV, RiA = (CH3)aCHCH(NH2)-)
This derivative was prepared from (25)-2-benzyloxycarbonylamino-3-methyl-but;yric acid 6-
tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl-
amino]-hexyl ester (product of step A) as described in example 15, step B. The final
compound was obtained in quantitative yield (110 mg) and used for the next step without
purification.
LC-MS: 577.3 (M+H)+, 90% pure
Step C. Preparation of (25',25}-2-benzyloxycarbonylamino-3-methyl-butyric acid 2-
[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-
propionylamino)-hexyl ester
The title compound was obtained from (26)-benzyloxycarbonylamino-3-methyl-butyric acid
6-amino-2-[(4-amino-benzenesulfpnyl)-isobutyl-amino]-hexyl ester (product of step B) as
described in example 15, step C. The clear oil was obtained in 86% yield (120 mg).
LC-MS: 858.3 (M+H)+, 95% pure
StepD. Preparation of (21S',2iS)-2-amino-3-methyl-butyric acid 2-[(4-amino-
benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-
propionylamino)-hexyl ester (PL-530)
To a stirred solution of (21S',2^)-2-benzyloxycarbonylamino-3-methyl-butyric acid 2-[(4-
amino-l3enzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-

propionylamino)-hexyl ester (step C, 120 mg, 0.14 mmol) in anhydrous THF (8 mL), under
nitrogen atmosphere, was added palladium 10% wt. on activated carbon (160 mg). The
mixture was reacted under hydrogen atmosphere overnight, at room temperature. The
solution was filtered and the palladium on carbon was washed with THF (50 mL). The
solvent was evaporated and the residue (110 mg) was purified by flash chromatography using
ethyl acetate as the eluent. The clear oil was obtained in 47% yield (47 mg).
LC-MS: 796.4 (M+H)+, 95% pure
'H NMR (acetone-de): S 0.84-0.97 (m, 12H), 0.97-1.08 (m, 2H), 1.27-1.43 (m, 3H), 1.49-
1.62 (m, 4H), 1.80-1.93 (m, 1H), 1.94-2.00 (m, 1H), 2.36-2.46 (m, 1H), 2.58-2.74 (m, 2H),
2.86-2.96 (m, 3H), 2.99-3.10 (m, 2H), 3.46-3.52 (s, 3H), 3.52-3.60 (m, 2H), 3.75-3.87 (m,
2H), 3.95-4.04 (m, 1H), 4.10-4.18 (m, 1H), 4.37-4.44 (m, 1H), 4.89-4.97 (m, 1H), 5.40-5.48
(m, 1H), 6.30-6.40 (m, 1H), 6.76-6.83 (d, J = 8.2, 1H), 6.87-7.03 (m, 2H), 7.14-7.22 (m, 1H),
7.23-7.34 (m, 3H), 7.35-7.45 (m, 4H), 7.50-7.56 (m, 1H), 7.57-7.65 (m, 1H).
Bioavailability of the compounds
To assess the extent of in vivo cleavage of the phosphate group from the putative compounds,
PL-100, PL-462 (based on PL-100), PL-337 and PL-515 (based on PL-337) compounds were
administered po (50 mg/kg) to male Sprague-Dawley rats and their plasma concentration
measured at different time intervals post-administration.
PL100 is an active ingredient (protease inhibitor) of the following formula;


PL-337 is an active ingredient (protease inhibitor) of the following formula;

The active ingredient has been shown to be efficient against an HTV-1 aspartyl protease (US
patent no. 6,632,816). The active ingredients also present potent antiviral activity when tested
on non-mutated HIV-1 viral strain (NL4.3 as the wild type virus) as well as several mutant
strains.
All test articles (PL-100, PL-462, PL-337 and PL-515) were prepared in different vehicle at
the final concentration of 25 mg/mL. The vehicle composition is as follows: (1) 20% ethanol;
50% propylene glycol; 0.05% w/v Tween 20 and water (Mix); (2) PBS buffer (PBS).
Test articles were administered to male Sprague-Dawley rats at a single oral dose of 50
mg/kg. Each article was tested in three rats. Blood samples (0.2-0.3 mL) were collected at the
post-dose time of 10, 20, 40, 60,120, 180 and 360 minutes. The harvested blood was
centrifuged to isolate plasma. The resulting plasma was separated and stored at -70°C.
Plasma samples together with standards and quality control samples were treated to
precipitate proteins, then analyzed by HPLC-MS, for the presence of PL-462, PL-100, PL-
515 and PL-337.
J


The results demonstrate that PL-462 and PL-515 compounds may be delivered orally in
aqueous solutions. None of the PL-462 and PL-515 compounds, delivered as aqueous
solutions, are detected in the blood samples, which suggests rapid metabolism to PL-100 and
PL-337 the parent drugs.
Aqueous dosing of PL-462 and PL-515 solutions showed equivalent to slightly superior
delivery of PL-100 and PL-337 compared to non-aqueous formulations of PL-100 and PL-
337.
Based on these results, all the phosphorylated compounds described, in the present invention
will demonstrate similar pharmacokinetic properties.
Partition coefficient (LogP) of selected compounds and the corresponding HIV protease
inhibitors (drug) are as follow:


The LogP were measured in a standard fashion by dissolving 1 mg of compound in 0.8 mL of
each octanol and phosphate buffer pH 7.4 (0.04 M KHPO4). The concentration of the
compounds in the phases was detected by LC-MS. This test demonstrates the solubility of the
compounds at physiological pH. The LogP obtained show that the compounds are highly
soluble as compare to the corresponding drugs.
The compounds listed in Table 3 were prepared by following scheme 1, 1A, 2, 3, 4 or 5; and
more particularly as described in each example listed above. The numbers of the compounds
listed in Table3 (Ex. No.) corresponds to the example numbers presented above.




We claim:
1. A compound of formula I

sterioisomers or a pharmaceutically acceptable salt thereof.
wherein n is 3 or 4.
wherein X and Y, the same or different, are selected from the group consisting of H, a
straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon
atoms, a cycloalkyl group of 3 to 6 carbon atoms. F, Cl, Br, I, -CF3, -OCF3, -CN, -NO2,
-NR4R5, -NHCOR4, -OR4, -SR4, -COOR4, -COR4, and -CH2OH or X and Y together
define an alkylenedioxy group selected from the group consisting of a methylenedioxy
group of formula -OCH2O- and an ethylenedioxy group of formula -OCH2CH2O-,
wherein R6 is selected from the group consisting of a straight alkyl group of 1 to 6
carbon atoms, a branched alkyl group of 3 to 6 carbon atoms and a cycloalkylalkyl
group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms
in the alkyl part thereof,
wherein R3 is selected from the group consisting of H, a straight alkyl group of 1 to 6
carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to
6 carbon atoms, and a group of formula R3A-CO-, R3A being selected from the group
consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl
group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms
in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an
alkyloxy group of 1 to 6 carbon atoms, tetrahydro-3-furanyloxy. -CH2OH, -CF3.
-CH2CF3. -CH2CH2CF3, pyrrolidinyl, piperidinyl, 4-morpholinyl. CH3O2C-,
CH3O2CCH2-, Acetyl-OCH2CH2-, HO2CCH2-, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-
CH3OC6,H4CH2-, CH3NH-, (CH3)2N-, (CH3CH2)2N-, (CH3CH2CH2)2N-, HOCH2CH2NH-,
CH3OCH2O-, CH3OCH2CH2O-, C6H5CH2O-, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-

pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-
quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula

wherein X' and Y". the same or different, are selected from the group consisting of H, a
straight alky 1 group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon
atoms, a cycloalkyl group of 3 to 6 carbon atoms. F, Cl, Br, I, -CF3, -NO2, -NR4R5,
-NHCOR4, -OR4, -SR4, -COOR4, -COR4 and -CH2OH,

wherein R4 and R5, the same or different, are selected from the group consisting of H, a
straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon
atoms, and a cycloalkyl group of 3 to 6 carbon atoms,
wherein R2 is selected from the group consisting of a diphenylmethyl group of formula IV

a naphthyl-1-CH2- group of formula V

a naphthyl-2-CH2- group of formula VI

a biphenylmethyl group of formula VII

and an anthryl-9-CH2- group of formula VIII


and wherein R1 is selected from the group consisting of (HO)2P(O), (MO)2P(O) and a
group of formula R1A-CO-, wherein M is an alkali metal or alkaline earth metal.
wherein R1A is selected from the group consisting of a straight or branched alkyl group
of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a
cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to
3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6 carbon atom.
-CH2OH, CH3O2C-, CH3O2CCH2-, Acety l-OCH2CH2-. HO2CCH2-, 2-hydroxyphenyl, 3-
hydroxyphenyl, 4-hydroxyphenyl, (CH3)2NCH2-, (CH3)2CHCH(NH2)-, HOCH2CH2NH-,
CH3OCH2O-, CH3OCH2CH2O-, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-
1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-
isoquinolyl, 2-quinoxalinyl, a phenyl group of formula III

a picolyl group selected from the group consisting of


a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula

2. A compound as claimed in claim 1 defined by formula II,

or a pharmaceutically acceptable salt thereof.

wherein X, Y, X', Y', n, R1, R3, R4, R5 and R6 are as defined in claim 1.
3. A compound as claimed in claim 2. wherein R6 is iso-butyl and n is 3.
4. A compound as claimed in claim 2, wherein R6 is iso-butyl and n is 4.
5. A compound as claimed in claim 4, wherein R1 is (HO)2P(O) or (NaO)2P(O).
6. A compound as claimed in claim 4, wherein R1 is selected from the group of CH3CO, 3-
pyridyl-CO, (CH3)2NCH2CO and (CH3)2CHCH(NH2)CO.
7. A compound as claimed in claim 5, wherein R3 is selected from the group consisting of
CH3CO, CH3O-CO, (CHO2N-CO, 3-pyridyl-CO, 4-pyridyl-CO and 4-morpholine-CO.
8. A compound as claimed in claim 6, wherein R3 is selected from the group consisting of
CH3CO, CH3O-CO, (CH3)2N-CO, 3-pyridyl-CO, 4-pyridyl-CO and 4-morpholine-CO.
9. A compound as claimed in claim 7, wherein X is 4-NH2 and Y is H or F.
10. A compound as claimed in claim 8, wherein X is 4-NH2 and Y is H or F.
11. A compound as claimed in claim 9, wherein R2 is selected from the group consisting of
a diphenylmethyl group of formula IV, a naphthyl-1-CH2- group of formula V, and a
naphthyl-2-CH2- group of formula VI.
12. A compound as claimed in claim 10, wherein R2 is selected from the group consisting of
a diphenylmethyl group of formula IV, a naphthyl-1-CH2- group of formula V, and a
naphthyl-2-CH2- group of formula VI.
13. A compound as claimed in claim 11, wherein X' and Y' are H.
14. A compound as claimed in claim 12, wherein X' and Y' are H.
15. A compound as claimed in claim 2 as defined by formula IIa


or a pharmaceutically acceptable salt thereof.
wherein X, Y. X',. Y', n, R1, R3, R4, R5- and R6, are as defined in claim 1.
16. A compound as claimed in claim 15, wherein R6 is iso-butyl.
17. A compound as claimed in claim 16, wherein n is 4.
18. A compound as claimed in claim 17, wherein R1 is (HO)2P(O) or (NaO)2P(O).
19. A compound as claimed in claim 17, wherein R1 is selected from the group consisting of
CH3CO, 3-pyridyl-CO, (CH3)2NCH2CO and (CH3)2CHCH(NH2)CO.
20. A compound as claimed in claim 18, wherein R3 is selected from the group consisting of
CH3CO, CH3O-CO, (CH3)2N-CO, 3-pyridyl-CO, 4-pyridyl-CO and 4-morpholine-CO.
21. A compound as claimed in claim 19, wherein R3 is selected from the group consisting of
CH3CO, CH3O-CO, (CH3)2N-CO, 3-pyridyl-CO, 4-pyridyl-CO and 4-morpholine-CO.
22. A compound as claimed in claim 20, wherein X is 4-NH2 and Y is H or F.
23. A compound as claimed in claim 21, wherein X is 4-NH2 and Y is H or F.
24. A compound as claimed in claim 20, wherein X is 4-NH2, Y is H, X' is H, Y' is H and
R3 is CH3O-CO.
25. A compound as claimed in claim 24, wherein R1 is (HO)2P(O).
26. A compound as claimed in claim 24, wherein R1 is (NaO)2P(O).
27. A compound as claimed in claim 20, wherein X is 4-NH2, Y is 3-F, X' is H, Y' is H and
R3 is CH3O-CO.
28. A compound as claimed in claim 27, wherein R1 is (HO)2P(O).
29. A compound as claimed in claim 27, wherein R1 is (NaO)2P(O).
30. A compound as claimed in claim 20, wherein X is 4-NH2, Y is H or 3-F, X' is H, Y' is
H and R3 is CH3CO.
31. A compound as claimed in claim 30, wherein R1 is (HO)2P(O).
32. A compound as claimed in claim 30, wherein R1 is (NaO)2P(O).
33. A compound as claimed in claim 20, wherein X is 4-NH2, Y is H or 3-F, X' is H, Y' is
H and R3 is 4-morpholine-CO.

34. A compound as claimed in claim 21, wherein X is 4-NH2, Y is H, X' is H, Y' is H and
R3 is CH3O-CO.
35. A compound as claimed in claim 34, wherein R1 is 3-pyridyl-CO.
36. A compound as claimed in claim 34, wherein R1 is (CH3)2NCH2CO.
37. A compound as claimed in claim 34, wherein R1 is (CH3)2CHCH(NH2)CO.
38. A compound as claimed in claim 34, wherein R1 is CH3CO.
39. A compound as claimed in claim 21, wherein X is 4-NH2, Y is 3-F, X' is H. Y' is H and
R3 is CH3O-CO.
40. A compound as claimed in claim 39, wherein R1 is 3-pyridyl-CO.
41. A compound as claimed in claim 39, wherein R1 is (CH3)2NCH2CO.
42. A compound as claimed in claim 39, wherein R1 is (CH3)2CHCH(NH2)CO.
43. A compound as claimed in claim 21, wherein X is 4-NH2, Y is H or 3-F, X' is H, Y' is
H and R3 is CH3CO.
44. A compound as claimed in claim 21, wherein X is 4-NH2, Y is H or 3-F, X' is H, Y' is
H and R3 is 4-morpholine-CO.
45. A compound as claimed in claim 2 defined by formula IIb

or a pharmaceutically acceptable salt thereof.
wherein X, Y, X', Y' , n, R1, R3, R4, R5 and R6 are as claimed in claim 1.
46. A compound as claimed in claim 45 wherein R6 is iso-butyl.

47. A compound as claimed in claim 46, wherein n is 4.
48. A compound as claimed in claim 47, wherein R1 is (HO)2P(O) or (NaO)2P(O).
49. A compound as claimed in claim 47, wherein R1 is selected from the group consisting of
CH3CO, 3-pyridyl-CO, (CH3)2NCH2CO and (CH3)2CHCH(NH2)CO.
50. A compound as claimed in claim 48, wherein R3 is selected from the group consisting of
CH3CO, CH3O-CO, (CH3)2N-CO, 3-pyridyl-CO, 4-pyridyl-CO and 4-morpholine-CO.
51. A compound as claimed in claim 49, wherein R3 is selected from the group consisting of
CH3CO , CH3O-CO, (CH3)2N-CO, 3-pyridyl-CO, 4-pyridyl-CO and 4-morpholine-CO.
52. A compound as claimed in claim 50, wherein X is 4-NH2 and Y is H or F.
53. A compound as claimed in claim 51, wherein X is 4-NH2 and Y is H or F.
54. A compound as claimed in claim 50, wherein X is 4-NH2, Y is H or 3-F, X' is H, Y' is
H and R3 is CH3O-CO.
55. A compound as claimed in claim 50, wherein X is 4-NH2, Y is H or 3-F, X' is H, Y' is
H and R3 is CH3CO.
56. A compound as claimed in claim 50, wherein X is 4-NH2, Y is H or 3-F, X' is H, Y' is
H and R3 is 4-morpholine-CO.
57. A compound as claimed in in claim 54, wherein the napthyl group

is a naphthyl-2-CH2 group.
58. A compound as claimed in claim 57, wherein Y is H and R1 is (HO)2P(O).
59. A compound as claimed in claim 56, wherein the napthyl group


is a naphthyl-1-CH2 group.
60. A compound as claimed in claim 59, wherein Y is H and R1 is (HO)2P(O).
61. A compound as claimed in claim 51, wherein X is 4-NH2, Y is H or 3-F, X' is H, Y' is
H and R3 is CH3O-CO.
62. A compound as claimed in claim 51, wherein X is 4-NH2, Y is H or 3-F, X' is H, Y' is
H and R3 is CH3CO.
63. A compound as claimed in claim 51, wherein X is 4-NH2, Y is H or 3-F, X' is H, Y' is
H and R3 is 4-morpholine-CO.
64. A compound as claimed in claim 63, wherein the napthyl group

is a naphthyl-1-CH2 group.
65. A compound as claimed in claim 2 defined by formula IIc

or a pharmaceutically acceptable salt thereof.
wherein n. X. Y, X', Y', R1, R3, R4, R5 and R6 are as defined in claim 1.
66. A compound as claimed in claim 65 wherein R6 is iso-butyl.
67. A compound as claimed in claim 66, wherein n is 4.

68. A compound as claimed in claim 67, wherein R1 is (HO)2P(O) or (NaO)2P(O).
69. A compound as claimed in claim 67, wherein R1 is selected from the group of CH3CO.
3-pyridyl-CO, (CH3)2NCH2CO and (CH3)2CHCH(NH2)CO.
70. A pharmaceutical composition comprising at least one compound as claimed in any one
of claims 1,2, 17, 45 or 65, pharmaceutically acceptable salts or combination thereof
and a pharmaceutically acceptable carrier.
71. A pharmaceutical composition as claimed in claim 70, wherein said composition is
useful for treating or preventing HIV infection.


The present invention provides lysine based compounds of the formula;

and when the compound of formula I comprises an amino group, pharmaceutically acceptable
ammonium salts thereof, wherein n is 3 or 4, wherein R1 may be, for example, (HO)2P(O)-,
(NaO)2P(O)-, alkyl-CO- or cycloalkyl-CO-, wherein X may be, for example, F, Cl, and Br,
and wherein R2, R3 and R6 are as defined in the specification.. The lysine based compounds
have a physiologically cleavable unit, namely R1, whereby upon cleavage of the unit, an HIV
aspartyl protease inhibitor is released.
The invention is also for pharmaceutical composition comprising the said compound.

Documents:

02395-kolnp-2006 abstract.pdf

02395-kolnp-2006 claims.pdf

02395-kolnp-2006 correspondence others.pdf

02395-kolnp-2006 description (complete).pdf

02395-kolnp-2006 form-1.pdf

02395-kolnp-2006 form-3.pdf

02395-kolnp-2006 form-5.pdf

02395-kolnp-2006 international publication.pdf

02395-kolnp-2006 international search report.pdf

02395-kolnp-2006 others.pdf

02395-kolnp-2006 pct form.pdf

02395-kolnp-2006-assignment.pdf

02395-kolnp-2006-correspondence-1.1.pdf

02395-kolnp-2006-correspondence-1.2.pdf

02395-kolnp-2006-form-18.pdf

02395-kolnp-2006-form-3-1.1.pdf

02395-kolnp-2006-g.p.a.pdf

2395-KOLNP-2006-ABSTRACT.pdf

2395-KOLNP-2006-AMENDED CLAIMS.pdf

2395-KOLNP-2006-ASSIGNMENT.pdf

2395-KOLNP-2006-CANCELLED PAGES.pdf

2395-KOLNP-2006-CORRESPONDENCE.pdf

2395-KOLNP-2006-DESCRIPTION (COMPLETE).pdf

2395-KOLNP-2006-EXAMINATION REPORT.pdf

2395-KOLNP-2006-FORM 1.pdf

2395-KOLNP-2006-FORM 18.pdf

2395-KOLNP-2006-FORM 2.pdf

2395-KOLNP-2006-FORM 3.1.pdf

2395-KOLNP-2006-FORM 3.pdf

2395-KOLNP-2006-FORM 5.pdf

2395-KOLNP-2006-GPA.pdf

2395-KOLNP-2006-GRANTED-ABSTRACT.pdf

2395-KOLNP-2006-GRANTED-CLAIMS.pdf

2395-KOLNP-2006-GRANTED-DESCRIPTION (COMPLETE).pdf

2395-KOLNP-2006-GRANTED-FORM 1.pdf

2395-KOLNP-2006-GRANTED-FORM 2.pdf

2395-KOLNP-2006-GRANTED-SPECIFICATION.pdf

2395-KOLNP-2006-OTHERS.pdf

2395-KOLNP-2006-PA.pdf

2395-KOLNP-2006-PCT SEARCH REPORT.pdf

2395-KOLNP-2006-PETITION UNDER RULE 137.pdf

2395-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf

2395-KOLNP-2006-REPLY TO EXAMINATION REPORT1.1.pdf

abstract-02395-kolnp-2006.jpg


Patent Number 250461
Indian Patent Application Number 2395/KOLNP/2006
PG Journal Number 01/2012
Publication Date 06-Jan-2012
Grant Date 04-Jan-2012
Date of Filing 23-Aug-2006
Name of Patentee AMBRILIA BIOPHARMA INC.
Applicant Address 1000 CHEMIN DU GOLF, VERDUN, QUEBEC H3E 1H4, CANADA
Inventors:
# Inventor's Name Inventor's Address
1 STRANIX BRENT RICHARD 109, MAYWOOD, POINTE-CLAIRE, QUEBEC H9R 3L7, CANADA
2 PERRON VALERIE 7805 17TH AVENUE, LAVAL QUEST, QUEBEC H7R 6H7, CANADA
PCT International Classification Number C07C 311/37
PCT International Application Number PCT/CA2004/001440
PCT International Filing date 2004-08-02
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA