ANTIVIRAL AGENTS

AGENTS ANTIVIRAUX

English Abstract

The present invention provides a method of treatment or prophylaxis of
hepatitis B virus in a subject comprising administering an effective amount of
a compound of formula (1) or a pharmaceutically acceptable derivative, salt or
prodrug thereof. In addition, there is provided compounds of formula (1) and
pharmaceutical compositions thereof. Further, methods of preparing compounds
of formula (1) are disclosed.

French Abstract

L'invention concerne un procédé de traitement ou de prophylaxie du virus de l'hépatite B chez un patient, qui consiste à lui administrer une dose efficace d'un composé de formule (I) ou d'un dérivé, d'un sel ou d'un promédicament de celui-ci pharmaceutiquement acceptable. De plus, l'invention concerne des composés de formule (I) et des compositions de ceux-ci pharmaceutiquement acceptables. Elle concerne enfin des procédés de préparation de composés de formule (I).

Claims

-51-
CLAIMS
1. ~A method of treatment or prophylaxis of hepatitis, B virus in a subject
comprising~
administering to said subject an effective amount of a compound of formula (1)
or
a pharmaceutically acceptable derivative, salt or prodrug thereof:
<IMG>
wherein X is OH, OR9 or halo:
R and R1 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6 cycloalkyl, aryl, or together with the carbon atom to which they are
attached
form a saturated or unsaturated C3-6carbocyclic ring;
R2 and R3 are independently selected froth H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl or together with the bond between the carbon atoms to which
they
are attached form a double bond;
R4 and R5 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl, OH, OR9, halo or NR10R10, or together with the bond between
the
carbon atoms to which they are attached form a double bond;
R6 and R7 are independently selected from H, C2-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl, OH ar OR9;
R8 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl,
C3-6cycloalkyl, OH, OR9 or halo;

-52-
R9 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, C(=O)R11 or
S(O)2R12
or OR9 is an amino acid residue;
each R10 is independently selected from H and C1-6alkyl;
R11 is C1-21alkyl, C2-21alkenyl, C2-21alkynyl, C3-6cycloalkyl, C3-
6cycloalkylC1-6alkyl,
aryl or arylC1-6alkyl; and
R12 is C1-6alkyl, C2-6alkenyl, C1-6alkynyl or aryl.
2. A method according to claim 1 wherein the compound of formula (1) is a
compound of formula (2):
<IMG>
R and R1 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl, aryl, or together with the carbon atom to which they are
attached
form a saturated or unsaturated C3-6carbocyclic ring;
R2 and R3 are independently selected from H, C1-6alkyl, C2-6alkenyl. C2-
6alkynyl,
C3-6cycloalkyl or together with the bond between the carbon atoms to which
they
are attached farm a double bond;
R4 and R5 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl, OH, OR9, halo or NR10R10 or together with the bond between the
carbon atoms to which they are attached form a double bond;
R9 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, C(=O)R11 or
S(O)2R12
or OR9 is an amino acid residue;

-53-
each R10 is independently selected from H and C1-6alkyl;
R11 is C1-21alkyl, C2-21alkenyl, C2-21alkynyl, C3-6cycloalkyl, C3-
6cycloalkylC1-6alkyl,
aryl or arylC1-6alkyl; and
R12 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl or aryl.
3. The method of claim 1 wherein the compound of formula (1) is selected from
the
group consisting of:
8-hydroxy-3,3-dimethyl-3H naphtho[2,1-b]pyran-7,10-dione,
8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione,
9-bromo-8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-6]pyran-7,10-dione,
9-bromo-8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione,
9-bromo-3,3-dimethyl-8-(4-methylbenzensulfonyloxy)-1,2-dihydro-3H-naphtho[2
,1-b]pyran-7,10-dione,
9-bromo-3,3-dimethyl-8-(4-methylbenzenesulfonyloxy)-3H-naphtho[2,1-b]pyran-7
,10-dione,
8-acetoxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10)-dione,
2,9-dibromo-1,8-dihydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,1
0-dione,
8,9-dichloro-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b[pyran-7,10-dione,
7,8,10-triacetoxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran,
9-Bromo-8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione.
9-Bromo-8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione,
9-Bromo-3,3-dimethyl-8-(4-methylbenzenesulfonyloxy)-1,2-dihydro-3H-
naphtho[2,1-b]pyran-7,10-dione,
9-Bromo-3,3-dimethyl-8-(4-methylbenzensulfonyloxy)-3H-naphtho[2,1-b]pyran-
7,10-dione,
8-Bromo-3,3-dimethyl-9-(4-methylbenzenesulfonyloxy)-3H-naphtho[2,1-b]pyran-
7,10-dione,
8-Bromo-3,3-dimethyl-9-(4-methylbenzenesulfonyloxy)-1,2-dihydro-3H-
naphtho[2,1-b]pyran-7,1o-dione,
8,9-Dichloro-3,3-dimethyl -1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione,


Sodium 3,3-dimethyl-7,10-dioxo-7,10-dihydro-3H-benzo[f]chromen-8-olate;
Sodium 3,3-dimethyl-7,8-dioxo-7,8-dihydro-3H-benzo[f]chromen-10-olate
8-Hydroxy-3-methyl-3-phenyl-3H-benzo[f]chromene-7,10-dione, and
8-Hydroxy-3,3-Biphenyl-3H-benzo[f]chromene-7,10-dione.
4. A method according to claim 1 wherein the compound of formula (1) is
selected
from the group consisting of:
8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione,
8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b)pyran-7,10-dione).
5. The method of claim 1 wherein the compound of formula (1) is a compound of
formula (3);
<IMG>
wherein X is OH, OR9 or halo
R and R1 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl, aryl, or together with the carbon atom to which they are
attached
form a saturated or unsaturated C3-6carbocyclic ring;
R2 and R3 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl or together with the bond between the carbon atoms to which
they
are attached form a double bond;

-55-
R4 is selected from H, C1-6alknyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl,
halo or
NR10R10 or together with R5 and the bond between the carbon atoms to which R4
and R5 are attached, form a double bond;
R5 is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl,
OH, OR9,
halo or NR10R10 or together with R4 and the bond between the carbon atoms to
which R4 and R5 are attached, form a double bond;
R6 and R7 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl, OH or OR9;
R8 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl,
C3-6cycloalkyl, OH, OR9 or halo;
R9 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, C(=O)R11 or
S(O)2R12
or OR9 is an amino acid residue;
each R10 is independently selected from H and C1-6alkyl;
R11 is C1-21alkyl, C2-21alkenyl, C2-21alkynyl, C3-6cycloalkyl, C3-
6cycloalkylC1-6alkyl,
aryl ar arylC1-6alkyl; and
R12 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl or aryl.
6. A method according to any one of claims 1 to 5 further comprising
administering a
second therapeutic agent.
7. A compound of Formula (1) or a pharmaceutically acceptable derivative, salt
or
prodrug thereof:

-56-
<IMG>
wherein X is OH, OR9 or halo;
R and R1 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl, aryl, or together with the carbon atom to which they are
attached
form a saturated or unsaturated C3-6carbocyclic ring;
R2 and R3 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,~
C3-6cycloalkyl or together with the bond between the carbon atoms to which
they
are attached form a double bond;
R4 and R5 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl, OH, OR9, halo or NR10R10 or together with the bond between the
carbon atoms to which they are attached form a double bond;
R9 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl. C(=O)R11 or
S(O)2R12
or OR9 is an amino acid residue;
each R10 is independently selected from H and C1-6alkyl;
R11 is C1-21alkyl, C2-21alkenyl, C2-21alkynyl, C3-6cycloalkyl, C3-
6cycloalkylC1-6alkyl,~
aryl or arylC1-6alkyl; and
R12 is C1-6alkyl, C2-6alkenyl, C23-6alkynyl or aryl;
with the proviso that when R and R1 are both methyl and R is OH or OR9, R5 is
not
selected from OH, OR9 or NHR9.
8. ~A compound according to claim 7 wherein the compound of Formula (1) is a
compound of formula (2);

-57-
<IMG>
R and R1 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl, aryl, or together with the carbon atom to which they are
attached
form a saturated or unsaturated C3-6carbocyclic ring;
R2 and R3 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl or together with the bond between the carbon atoms to which
they
are attached form a double bond;
R4 and R5 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl, OH, OR9, halo or NR10R10 or together with the bond between the
carbon atoms to which they are attached form a double bond;
R6 and R7 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl, OH or OR9;
R8 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl,
C3-6cycloalkyl, OH. OR9 or halo;
R9 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, C(=O)R11 or
S(O)2R12
or OR9 it an amino acid residue;
each R10 is independently selected from H and C1-6alkyl;
R11 is C1-21alkyl, C2-21alkenyl, C2-21alkynyl, C3-6cycloalkyl, C3-
6cycloalkylC1-6alkyl,
aryl or arylC1-6alkyl; and
R12 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl or aryl,

-58-
9. ~A compound according to claim 7 wherein the compound of formula (1) is
selected
from the group consisting of:
8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione,
8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione,
9-bromo-8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione,
9-bromo-8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione,
9-bromo-3,3-dimethyl-8-(4-methylbenzenesulfonyloxy)-1,2-dihydro-3H-naphtho[2
,1-b]pyran-7,10-dione,
9-bromo-3,3-dimethyl-8-(4-methylbenenesulfonyloxy)-3H-naphtho[2,1-h]pyran-7
,10-dione,
8-acetoxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione,
2,9-dibromo-1,8-dihydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,1
0-dione,~
8,9-dichloro-3,3-dimethyl-1,2-dihydro-3H-naphtho(2,1-b]pyran-7,10)-thione,
7,8,10-triacetoxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran,
9-Bromo-8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione.
9-Bromo-8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione,
9-Bromo-3,3-dimethyl-8-(4-methylhenzenesulfonyloxy)-1,2-dihydro-3H-
naphtho[2,1-b]pyran-7,10)-dione.
9-Bromo-3,3-dimethyl-8-(4-methylbenzenesulfonyloxy)-3H-naphtho[2,1-b]pyran-
7,10-dione,~~
8-Bromo-3,3-dimethyl-9-{4-methylbenzenesulfonyloxy)3H-naphtho[2,1-b]pyran-
7,10-dione,
8-Bromo-3,3-dimethyl-9-(4-methylbenzenesulfonyloxy)-1,2-dihydro-3H-
naphtho[2,1-b]pyran-7,10-dione,
8,9-Dichloro-3,3-dimethyl -1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10)-dione,
Sodium 3,3-dimethyl-7,10-dioxo-7,10-dihydro-3H-benzo[f]chromen-8-olate;
Sodium 3,3-dimethyl-7,8-dioxo-7,8-dihydro-3H-benzo[f]chromen-10-olate;
8-Hydroxy-3-methyl-3-phenyl-3H-benzo[f]chromene-7,10-dione, and
8-Hydroxy-3,3-diphenyl-3H-benzo[f]chromene-7,10-dione.

-59-
10. ~A compound according to claim 7 wherein the compound of formula (1) is
selected
from the group consisting of:
8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione,
8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione).
11. ~The compound of claim 7 wherein the compound of formula (1) is a compound
of
formula (3):
<IMG>~
wherein X is OH, OR9 or halo
R and R1 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl, aryl, or together with the carbon atom to which they are
attached
form a saturated or unsaturated C3-6carbocyclic ring;
R2 and R3 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C3-6cycloalkyl or together with the bond between the carbon atoms to which
they
are attached form a double bond;
R4 is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl,
halo or
NR10R10 or together with R5 and the bond between the carbon atoms to which R4
and R5 are attached, form a double bond;

-60-
R5 is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl,
OH, OR9,
halo or NR10R10 or together with R4 and the bond between the carbon atoms to
which R4 and R5 are attached, form a double bond;
R6 and R7 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-
6alkynyl,
C2-6cycloalkyl, OH or OR9;
R8 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl,
C3-6cycloalkyl, OH, OR9 or halo;
R9 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, C(=O)R11 or
S(O)2R12
or OR9 is an amino acid residue;
each R10 is independently selected from H and C1-6alkyl;
R11 is C1-21alkyl, C2-21alkenyl, C2-21alkynyl, C3-6cycloalkyl, C3-
6cycloalkylC1-6alkyl,
aryl or arylC1-6alkyl; and
R12 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl or aryl,
12. A pharmaceutical composition comprising a compound according to any one of
claims 7 to 11 and a pharmaceutically acceptable carrier, diluent or
excipient.

Description

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
_1_
ANTIYIRAT. AGENT
Field of the Invention
The present invention relates to the use of naphthapyrans as agents in the
treatment md/or
prophylaxis of hepatitis B, gharmaceutical compositions for use in such
therapy and novel
naphthopyrans,
Background of the Invention
Infection with human hepatitis B virus is a major public health problem
because of the
ahilit.y of the virus to cause acute and chronic itltcctians. Cbrotuc
hepatitis B vi.ivs
infection (hereinafter refewed to as "t~BV") causes serious liver disease in
humans and
frequexitly rasults izi cirrhosis and hcpataccllular carcinoma. Currently
there is do
completely effective therapy for the successful management of chronic HBV
infections.
The >250 million chronic HBV carriers throughout the wand are un~~bla to
beneru from
the commercial vaccine presently available.
Currcnt.ly available therapies far HBV are only partially effective and may be
accompanied
2Q by deletericaua side effects. In addition, many patients develcap antiviral
resistance resulting
in tha loss of efficacy. Accordingly, a nu;d exists for new cffcctiva
treatrnants for HBV.
It has now boon discovered that compounds caf Fc>rmuia (1) are active agents
against
hepatitis B virus.
Summ;~ry of the Inventitm
According to one aspect of the present invention there is provided a method of
treatment or
praphytaxis of hepatitis; B virus in a subject comprising administering to
said subject an
3p effective amount UL's compound of Formula (1 ):

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
R
Ra
X
t1)
whcrain X is OH, ORS or halo;
R and R1 are uidependently sclcctcd from H, C~.nalkyl, Cz~salkenyl,
C~.~,alkynyl,
C~.~oycloalkyl, aryl, ur together with the carhon atom to v~hich they are
attached form a
saturated or unsaturated C3_ticarbocyclic ring;
R? and R;~ are independently selected from Vii, Ct~a11cy1, C2.6alhcnyl,
C~.~alkynyl,
C3.6cyc1oa1kyl or togcdtcr with the bond between th.~ carbon atcams to v~i~ich
they are
attached form tt double hand;
R.t and RS arc indcp~;ndcntly selected from H, C, fialkyl, G~.oalkenyl,
C~.balkynyl,
C~.~cyclualkyl, OH, Ot~v, halo or NRloRlo or together with the bottd between
the carbon
atoms to which they arc attached farm a double hnnd;
R~ and Et~ are independently selected from H, Ci~;alkyl, Cz.c,alkenyl,
C~.,~alkynyl,
C~.~;oyclo~tll:yl, OH ur ORu;
Rs is iudepeuctently scls:eted from H, C~.~;alkyl, CzfiaElkenyl, C~.~alkynyl,
t:~.6cycloalkyl,
OH, ORv or halo;
R~ is C,.E;alkyl, CZ.fi~tlkenyl, Cz.halkynyl, C~-ocycloalkyla aryl, C(=O)R~~
or S(t~)~R~~ or ORy
is an amino acid rcsiduc;
each 12,~ is independently selected from H and Ci.~;alh.y3;
R" is C~.~ralkyl, CZ.~,:~Ikenyl, C~ ztaJkynyl, C3.ficycloalk.yl,
C3~cyclaaIkylC,.~alkyl, aryl or
arylCr.~alkyl; and
R~2 is Ci.dalkyl, Czfialkenyl, C~.~alkynyl c>r aryl.

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
-3-
According to a further aspect of the present invention there is provided a use
of a
compound of Formula (1) in the manufacture of a medicament for the treatment
or
prophylaxis of hepatitis B virus.
According to yet a further aspect of the prevent invention there is provided a
method of
treatment or prophylaxis of hepatitis B virus comprisuig administering au
effective amount
of a compound of Formula (1) and a :second therapeutic agent.
According, tc7 anc7ther aspect c7f the invention there is provided a compoutld
of rormula (1)
with the proviso that when R and Rt are both methyl and R:~ is OH or ORu, R5
is not
selected Frcym OH, ORy arNHRi{~.
According tc7 another aspect <7f the present invention tl~e1'e is provided a
phartnaecutieal
composition comprising a compound of Formula (l)and a pharmaceutically
aceeptahle
l5 cal-ier, excipient c7r adjLlvant, with the proviso that in the compound of
Formula (1) when
R and Rt are both methyl and R4 is OH or OR.>, R5 is not selected from OH,
p129 or
NFil~~a.
According to the present invention the compounds of rorrzlula (1) may be
presented in the
form of a pllu'tnaccutically acceptable derivative, ;;alt car prcldrug.
1)4txtilCd Tleryc;rigtion
Throughout this specification and the elainl5 which follow, tmless the context
requires
otherwl:;e, the we?rd "compriae", and variat10n4 StlCh a5 ~~cotnpriscs~~ aLld
~~COITlprislll~~', Wlll
be understood to imply the inclusion of a stated integer car step or group of
integers or steps
but. not the exclusion of any other integer or step or group of iritea~rs car
steps.
The reference to any prior art in thin specification is not, aitd should not
be takon as, an
acknowlcd,gtncnt or any form of suggestion that that prior art forms part of
the common
general knowledge in Australia.

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
_q._
f1s used herein, the tcrtn "halo" or "halogen" refers tea tluoriuc (fluoro),
clL1ari31e (chloro),
bromine (brarno) Or ipdin~ (i0ila).
As used herein, the term "alkyl" either used alone or in compound terms such
as NH(alkyl)
or N(alkyl)2, refers tea manavalcnt straight chain ar branched hydrocarbon
groups, having 1
to 3, 1 to 6, 1 to 10 or 1 to 21 carbon atoms as appropriate. For example,
suitable alkyl
groups include, but are not iinutcd to methyl, ethyl, propyl, isvprc>pyl, n-
butyl, sec-butyl,
tert-butyl, pentyl, 2-tnethylhutyl, 3-mcthylbutyl, n-hexyl, 2-, 3- or ~-
methylpcntyl,
2-ethylbutyl, xt-beryl or 2-, 3-, 4-- ar 5-methylpentyl.
As used herein, the term "alkenyl" refet~s to straight chain or branched
hy~i~acarbon groups
haviry one or mare double bonds between carbon atoms, Suitable aLkenyl groups
include,
but are nco limited to ethenyl, propcnyl, isopropenyl, bycnyl, penfenyl and
hexcnyl.
The term "alkytiyl" as used herein, refers to straight chain or branched
hydrcacarbon groups
cc>ntainirtg one car mare triple bands. Suitable alkynyl group:, inc:ludc, bud
are not limited
to ethynyl, grapynyl, but,ynyl, pentynyl and he~enyl.
Tlte term "cyclaal>;yl" as used herein, refers to cyclic hydrocarbon grvup5.
Suitable
2U c:ycloalkyl groups include, but are. not limited to cycloprapyl,
cyclcabutyl, cyclopentyl and
cyclohexyl.
T'he term "aryl" as u.~;ed hereist, refers to C~-Cm aromatic hydrocarbon
group, far example
phony! yr naphthyl.
The term "heteroc;yelyl" when used alone or in compound wards inclu dcs
monvcyclic,
polycyclic, fused ar conjugated hydrocarbon residues, preferably C~.b,wha:reiu
one or more
carbon atoms (and where apprc}priatc, liydrogen atomwttached thereto) are
replaced by a
heteroatom so as to provide a non-aromatic residue. Suitable heteroatvr~s
include, O, N
3C1 and S. Where two or mare carbon atoms are replaced, this may he by tyro ar
mare of the
same heteroatom ar by different heteroatcarw. Suitable examples of
hctcrocyclic groups

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
-5-
may iitc.lude pyrrolidinyl, pyrrolinyl, piperidy~1, piperaainyl, moyhc~lino,
indolinyl,
imiazolidinyl, , pyrazc~lidinyl, thiomtarpholino, dioxa.nyf,
tatrahydrofuranyl,
tetrahydropyranyl, tctrahydrc~pyrrolyl etc.
Each alkyl, alkenyl, alkynyl, cyeloalkyl, aryl or heterocyclyi group play he
optionally
substituted with Ct-aalkyl, OH, C)C~-3alkyl, halo, CN, NO~, CpaH,
GOzC~_.~alkyl, CONH2,
CONH(Cr_:#alkyly, CON(Cl.saikyl)2, trifluorcamethyl, NHS,, NH(alkyl) or
N(alkyl)~. For
example, an optionally substituted aryl group may be a 4-.methylphenyl or 4
hydroxyphenyl group, and all optionally substituted alkyl ~ro.up may be 2-
hydroxyethyl,
trifluoromethyl hr difluoromethyl.
As used herein, the term "amino acid residua" refers to an a-a:n~ino acid or a
~3-amino acid
wl5ich is att<~tched to the naphthopyrandione etrttcture, pretcrably throw the
carboxylic
acid group of the amitxo acid. The amino acid may be a L- or D- isomer and may
have a
l5 naturally occurring side chain or a halt-naturally occurring side chain.
The amino acid
may also be further substituted in the a-position hr the [~-position with a
group selected,
froth -C1-C6alky~!, -C2,-G~alhenyl, -C.2-C~alk,ynyl, -(CH~)aCUIt3, -
(CHZjc,lt," -F031~1,
-(CH~~,hetercx;yclyl or -(~H~)naryl where R;, is -nH, -NHS, -t~tHCt-C~alkyl, -
OCt-Caafkyl
or -Cy-C3alkyl and Rb is -CaH, -,SH, -SCE-C3alkyl. -OCt-Caalkyl, -C3-
C~cyeloalkyl,
-C;~-C~,cyclaalkenyl, -NHS, -NHC1-C~alkyl ur -NHC(C=NH)N kl~, n is 0 or an
integer from
1 to 6 and where each alkyl, a1lcenyl, alkynyt, cyclaalkyl, cycloaLlLenyl,
aryl or heterocyclyl
group may tie substituted with ono car more groups selected froth -OH, -NH,,
-NHCI-C3alkyl, -OCt-C~alkyl, -~1~1, -SCi-C3alkyl, -COSH, -CO?Ct-C~alkyl, -
CONl~f2 or
-CONHC,-C,~all~yl,
Tho ierrn "cx-amino acid" as used herein, refers to a ccampound having an
amino group and
a carboxyl group in which the amino group and the cart-ax'yl group arc
separated by a
single carbon atom, the a-carhop atoiu. An a-amino acid includes naturally
occurring and
non-naturally nccurriltg ~.-amino acids and their D-isatners and derivatives
thereof such as
3U salts or derivatives where functional groups are protected h~ suitable
protecting groups.
The c~-atninu acid may also be funher substituted in the a-pe~sition with a
group selected

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
-
from -C~-Ctoalkyl, -Cz-Cloalkenyl, -Cz-Cloalkynyl, -(CHz)"Cc'aR;,, -
(CFi2)ul~h, -PQsH,
-(CHz)peterooyclyl or -(CHz)naryl where Ra is -UH, -NHz, -NFiCt-C3alkyl, -OC1-
C;~alkyl
car C1~-C;alkyl anti Rb is -Oli, -SH, -SCE-~,".;~alkyl, -OCt-G;~alkylr -C;~-
CtzcYGloalkyl,
-C3-C72CyG1oalkCIlyI, -NHz, -NF-iC~-C3alkyl or -NHC(C=NH)NHy, n i,a 0 ur an
integer frc>m
S to 1t) and where each alkyl, alkenyl, alhynyl, cycloalkyl, aycloalkenyl,
aryl or
hctercx;yclyl group may be substituted with one or more groups selected From -
OH, -NHz,
-hiHC~-C~alkyl, -OCt-C3alkyl, -,S H, -SCE-C:~alhyl, -COzH', -CChCvCaalkyl, -
CONHz or
-CO1V HC ~-C3alkyl.
As used herein, the term "~-amine acid" refers to an amino acid that diffexs
from an
oe-amino acid in that there arc two (?) carbon atoms separating the c~rbaxy!
terminus and
the amino termitms. As such, (3-anvnca acids with a speciFic side chain can
exist as the R ar
,S enantiomcrs at either c~f the tx (C2) carbon or the. p (C3) carbon,
resulting in a total of 4
pcassible isomem for any given side chain. The side chains rnay be the sumo as
those of
1S naturally occurring a,-amine kids or may be the side chailis of non-
naturally occurril~g
~unina acids,
ca~H . 3 i GO2N
H2N ~ Ha_N
R R
R R
CC32H ~t72H
H:N 3 H2N
Furthermore, the ~i-amino acids may have mono-, di-, tri- or tetra-
substit.utican at the C2
and C3 carbon atoms. Mono-substitution ntay he at the C2 or C3 carbon atom.
Di-substitution includes two sub,stitucuts at the C2 carbon atom, twcv
substituents at the C3
carbon atom or one suhstituent at each c~F the C2 and C3 carbon a"t.oms. 'f ri-
substitution
includes two substituents at the C2 carbon atom and onP ,substituent at the C3
carbon atom

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
-
or two suh;,tituents at the C3 carbon atom, and one suhstituent at the C2
carbon atom,
Tetra-substiri~tion provides fcyr twc~ aubstituents at the C2 e~3rbon atom and
two substituenta
at the C:3 carhcm atom. Suitable substituents include -C~-C~alkyl, -C~-
Chalkcnyl,
-C~-C~alhynyl, -(CH2)aGORa, -(Cllz)nRh, -pO~H, -(CHn)"hete;rocyclyl or -
(CHL),~aryl where
R~ is -OH, -NI-t~, -NHC~-C~alkyl, -OCy-C3alkyl or -Ct-Caall'yl and l~h is -OH,
-SH,
-SCE-C3alkyl, -OC1-C3ah;.yl, -C3-(:~cycloallcyl, -Cs-C~,cycloalkenyl, -NH2, -
i~lHCt-C3alkyl
or -NHC(C=NH)NHz, n is 0 car an irite~er Crow 1 to 6 and where each alkyl,
alkenyl,
alkynyl, cyele~alkyl, eyeloalkenyl, aryl or heterocyclyl a coup rn~y be
substitutc;d with one
or rnarc groups selected from -OH, -NHS, -NHC1-C3alh-yl, -OCS-C~aikyl. -SH,
1U -SGt-C~alkyl, -COSH, -CO~Ct-Csahyl, -CONH~ or -CON1~CC,-Csalkyl.
The term "non-naturally occurring amino acid" as used herein, refera tea amino
acids havutg
a aide chain that does not occur in the nahiral 1y occurring Lra-alzlitto
acids. Ehatnples of
non-natural amino acids and dcrivative.s include, but are not limited to, use
of norleucinc,
4~atr~ino butyric acid, 4-amine-3-hydroxy-5-phenylpcntanoic acid, 6-
anlinohexanoic acid,
t-butylglyeine, norvalinc, phenylelycine, ornithine, aareosine, 4-amino-3-
hydroxy-6-
methyllicptanoic acid; 2-thienyl alanine andkar D-isomers of amino acids.
It' will also be recognised that the ecnngounds of formal (1} may possess
asymmetric
centres and are therefore capable of existing in more than one ,atereoisnmeric
form. The
invention thus also relates to c.ompounda in auhatantiaily pure isomeric farm
at one or
.more asymmetric centre:, e~., ~,~aater than aboLtt 90°'o cc, such as
about 95~'n or 97°lo ee or
greater than 99~n ee, as well as mixtures, including racemic mixtures,
thereat. Such
reamers may be prepared by asymmetric synthesis, For example using chiral
intermediates,
~5 or by chiral resolution.
The term "phartttaeeutieally acceptable derivative" may include any
pharntaeeutieally
acceptable salt, hydrate or prcxirug, or any criher c;c~mpuund which upon
adminstmtion to a
subject, is capable of providing (direc;tly or indirectly) a compound of
formula (1 ) or'an
3U antivirally active metabolite or rc~iduc tltcrcof,

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_g_
suitable pharmaceutically acceptable salts include, hut are not limited to,
salts of
pharmaceutioally acceptable inorganic acids such as hydrochloric, sulphuric,
phospliori~:.,
nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of
pharmaceutically
acceptable organic acids such as acetic, prapionic, butyric, tarcario,
malefic, hydrerxymaleic,
futnaric, malic; citric, lactic, mucic, gluconac, benzoic, succinic, oxalic,
phcnylacetio,
methartcsulphonic, toluenesulphonic, bcnzenesulphonic, salicylic, sulphanilic,
aspattic,
glutamic, edetic, stearic, palmitic, oleic, lauric, pantvthertic, tannic,
ascorbic and valer~c
acids.
Ha~se cats i.ttclude, but are not limited tu, those fcarmod with
pharmaceutically acceptabf 1e
catioits, such as sodium, potassium, lithium, calcium, magnesium, zinc,
anuttoniurn,
allcylamntoniurn such as salts formed front triethyiamine, alkcaxyamn~onium
such as tho-~e
fcac-mcd with ethanolamine itrtd salts formed frcsnt ctltylenediwttine.
cholitte or amino ac.ict:;
such as arg,itiille, lysiuc or histidine.
,g.'jSiG nilC0~~11-containitlg groups may he quartemised with sucdt agents as
lower alkyl
halide, such as methyl, ethyl, prc~pyl, and butyl chlorides, bromides <utd
iodides; diall~yl
sulfates like dimethyl and diethyl sulfate; and others.
2C1 Tlte term "prodrug" is used in its breadewt sense and encarnpasses those
derivatives that ire
converted in viva to the compounds of the invention. Such derivatives wcndd
readily ocour
to those skilled in the art, and include, for example, compounds in which a
free hydrc~xy
group is converted into a group, such a.~ an ester, carbonate or carbarnate,
which is capable
of hein~ converted in v~vn back to a hydroxy grcaup. A prodrug may include
modifications
of OclC of metre of the functional groups of, a compound of formula (1). Far
example.
similar to tltc apprc7ach described in US 5,672,607, antiviral naphthopyran
prodrugs haYZn;
enhanced water-solubility (c.g., which are better for parenterally administ~cd
ccampositions) may be prepared by chemical reduction of the quirtone
functionaiities to the
ecyrrcsponding quinals, hollowed by reacticm with phc~aphorous oxyeltloride to
dive the
3U corresponding phosphoric acid esters. Elftcr in viz~u administration of a
camposit=tan
eoutaining such a solubifiz~i alttiviral naphtopyrart prodrub, the prodrua
will be readily

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
_g.
hydrolysed to the corresponding quinnl, which thereafter will oxidize to re-
form in v8vn the
active parent antiviral naphthopyrandione. Likewise, other kinds of
derivatives may be
prepared frcym the reduced quinal derivatives of the antiviral
naphthopyrandione; these can
also serVG a~s prcxirugs fc~r use in therapeutic campoaitians. For example,
other types of
eaterification (e.g.. acetylation) may be used to prcxluce antiviral
naphthopyran prodrugs,
such as far example 7,$,10-tri3cetoxy-'~,3-dimethy!-3H'-naptha12,1-b~pyran.
Again, after
in viva adn~ini5tration the prodrug would be readily hydrolysed and oxidized
t.o its parent
active antiviral naphthopyran compound.
1U In a brat aspect, there is provided a method of treatment or prophylaxis of
hepatitis D virus
in a subject camprisuig administering to said :subject an effective amount of
a compound of
Formula (1);
Rg
X
('1 )
wherein ~ is OH, OR9 or halo;
1~ and Rt arc independently selected from ) 1, Cy.~aikyl, C~.Eaikenyl, CZ
~,alhynyl,
C3~cycloall~;yl, aryl, or toaethcr with the carbon atom to which they arc
attached form a
saturated or unaawrated C3.ticarbQCyclic ring;
R2 and kz are independently selected Pram H, Ci.~alkyl, C2_~alkenyl,
C~.~alkynyl,
C~.~oyclcaalkyl or to~cther with the hc3nd between the carhop atori~s to which
they are
2O attached form a Bauble hand;

CA 02561896 2006-09-29
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-10-
R.r and RS are independently selected from H, C, fiallsyl, C2.6alkenyl,
C2.Galkynyl,
Ca_ccycloalkyl, OH, ORS, halo or NRlaft~" or together with the band he.tween
the carbon
atoms to which they arc attached form a douhJe bond;
R6 and R~ are independently selected Crom Ft, C~.~alhyl, C2~salJ;enyl, C.
~alkynyl,
C3_c,CyClOalkyl., OH cyr OR9;
Rs is independently selected from H, Ci alkyl, Cz.c,ulkcnyl, Cz.~alkynyi,
C3.~cyclcyalkyl,
QH, ORS or halo;
R~ is C,_nalkyl. C~_5allrenyi, C2.~alkynyl, C3_~cyc.loalkyf, aryl, C(=O)R,1 or
S(O~R~2 or ORS
is an amino acid residue;
1U each R,n is indenenrlcntly selected from H and Cl.~a11~y1;
R~i iv C1_~ialkyl., C~.~~alkenyl, Cz_~yalkynyl, C~.bcycfc~akyl,
G;c.ncycloalkylCl.sall:yl, aryl or
arylCj.~alk.yl; and
Rig is Ci.salkyl, C~.6alkenyl, C~.balkynyl or aryl.
1 S Ln another aspect there i;; pravlded a eomPcnuid of Formula (.1 ), with
the proviso that when
R and R, arc both methyl and R is CJC-1' or ORq, R5 is not selected from OH,
Qfty or NHRy.
In a preferrc,d etnh«dffment ono or more of the following definitions apply;
X is OH, Of:,~.,~alkyl or halo;
20 lZ and R~ are indegendcndy selected from H or C~_aalkyl or tc~~cther with
the carbon atom
to which they are attached form a saturated or unsahtrated C~_ecarhncyclie
ring;
Rz and R~ are each hydrofieu;
R4 and 1~5 arc independently ae1ceted from H, OH, OR9, or halo or tcyethcr
with tltc bond
between the carbon atoms to which they are attached form a douhle bond;
25 Rc, ~d R7 are >zidenendently selected from H, OH, C~.~alkyl, Ci.tyalloxy;
Rs is H, OH, ORy, C,.balhyl or halo;
R9 is C(=O)Rt1 car S(O)~:R~z;
R,~ isC~.~lalkyl;
R,z is Cj.c,alkyl, phenyl or tosyl.
3U
Preferred compounds of the. inventican include those of formula (Z):

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
-11-
(Z)
wherein I~, R~, Rz, R;3, R4 and R5 are dcflned as for formula {1).
Preferred compounds of the invcntican include:
8-hydroxy-3,3-dimcthyl-3H-naphtha[2,l-h]pyran-7,10-dionc;,
8-hydroxy-3,3,dimethyl-1,2-dihydrca-3H-naphtho~ 2,1-h]pyran-7,10-dicanc,
~-6romQ-8-hydroxy-3,3-dirnethyi-1,2-di hydra-3 H-naphthc>[2,1-~]lryran-7,10-
dione,
9-bromo-8-hydroxy-3,3-dime.tlyl-3Fi-naphthea[2,1-tx]pyran-7,10-dione,
9-brama-3,3-dimethyl-8-(4-nzethylbcnzsnesulfonyloxy)-1,2-dihydra-311-
nsphtho~2,1-b]py
can-7,10-dinne,
9-brain.o-3,3-dimethyl-8-(4-rnethylbcnzenestMfanylaCy)-3H naphtha[?,1-6]lryran-
7,10-
dione,
S-ac;ctoxy-3,3-dimethyl-;1H naphtha[2,1-b]pyran-7, y 0-dione.
2,9-dihrorna- l ,8-dihydroxy-:i,3-diznethyl-1,2-dihydra-~ H-naphtha[2,1-
b]pa~ratt-7,10-dione,
t3,~-dichloro-3,3-dimcthyl-1,2-dihydra-3l'~-naphtha(2,1-b~pyrazi-7,10-diane,
7,8,1 U-tri srctnxy-3,3-dimethyl-3H-naphtha[2,1-b]pyran,
9~Bromo-8-hydroay-3,3-dimethyl-3H-naphtha[2,1-b[Pyran-7,10-diane.
9-~rmna-8-hydroxy-3,3-dimethyl-3H-naphtha [2,1-b]p y~ran-'1,10-thane.
9-Bromc~-3,3 ndimethyl-8-(4.methylbena,enesulfonylaxy)-1,2-dihydrc5-.3H-
naphtha~?,1-
2U h]pyran-7,1U-dionc.
9-Brarrto-3,;~-dimethyl-8-(4-methylhenzcnesulfanylaxy)-3H-naphtha[2,1-b[py~ an-
7,1U-
diane,

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-12.
8-l3rorno-3,3-di methyl-9-(4-methylhenzenesulfnnylax y)-3l~-naphtholz,1-
h]pyran-7, 7 0-
diane.,
$-Br«mo-3,3-dimethyl-9-(4-methylhenzenesulfanyloxy)-1,2-dihydrn-3fi-
naphtha[2,1-
blpyran-7,10-dione,
$,9-Dicltloro-3,3-dimethyl-1,2-dilaydra-3N-naphtha'2,1-h]pyran-7,tC?-dione,
radium 3,3-dimethyl-'~,1C)-dioro-7,10-dihydro-3H-benzo[f]chromen-8-alate;
Sadium 3,3-dirnethyl-7,$-dioao-7,8-dihydro-3H~benzo[f]chromen-1U-date
8-Hydroxy-3-methyl-3-phenyl-3H-henzv[f]cluamene-7,10-dione, and
8-Hydrcaxy-3,3-Biphenyl-3H-benco[~]chromene-7,J 0-dione,
1 ()
I~referably the. wmpaund of Formula ( 1 ) is:
$-hydraxy-3,3-dirrtethyl-3N-nnphthu[2,1-h]pyran-7,1U-dione (compound (1)),
8-hyd~~c~xy-3,3-dimethyl-1,2-dihydro-;3H naphthop~.,1-b]pyran-'~,10-dione
(campound (2)).
In anather embodimeilt the compounds of the invention include those of formula
(3):
R
Rg
X
(-1)
wherein R, fti, R2, R;t, Rs, R~, R7, Rs, and ~C are as defined far formula ( 1
) and t~~ is
selected frcam H, C~_~alkyl, C2.~alkenyl, C~.Galkynyl, C3.~cycloalkyl, halca
or hlR~aRuo or
together with RS axed the bond between the carbon atoms to which R4 and R; arc
attached,
farm a double hand.

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
-13-
~:ompounda of Formula (1) may be prepwed using the methods dcpicteri or
described
herein or known in the a.crt. It will he understood that minor trLOditications
to methods
described herein or known in the art may be required to synfheaise particular
compounds
of Formula (1). General synthetic procedures applicable to the synthesis of
compounds
rmay be found in standard references such as Cvrnprerhcatsive C)rganic
7ra~~,efnrrnatian,s, R.
C. Larock, 1 g89, VCH Publishers and Advanced Urgc~oir, Chemistry, J. March,
4th Edition
(1992), Wiley W terScience, rznd references therein. It will also be
recognised that certain
reactive groups may require protection and deprotection during the synthetic
process.
f0 Suitable pmtccting and deprotecting methcxis for reactive functional groups
are known in
the art. for example in Protective Grutcps in C)rb~arcic Syntla~si~s, '1'. W.
Greene ~ P. Wutz,
John Yvilcy & Son, 3'~ Edition, 19<~~.
The cor~~pounds of the present inventicm may be pre;parcd according to the
general
procedure of scheme 1.

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- 14-
~chenae 1
Rz
.r~'~ R3 F
R
.~'~ "~ Rg Ry O
(4)
die ~ ~'~'. 'O H
Rr
v ,. r
F
R
(6)
R
R~
Rs Rs
---
OH
(7)

CA 02561896 2006-09-29
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-1.5-
An appropriately substituted 2,6-dihydroxynaphthalene (3) is reactt;d with an
apprcapriately
substituted enal or enone (4) in the gresenee of a suitable base to efCu;t
cyclisation and
provide. a naphthopyranai (5). The naphthopyranol is then oxidised by a
suitable oxidant
to the corresponding intermediate orthc~quinone (f), before being reduced by a
suitable
reducing agent and further oxidised by a suitable oxidant to the desired
uaphthopyrandicane
(7). Further modification of the substikuents on the naphthopyrandione may be
effected
using chemical approaches 1'nown to those skilled in the art for the
gcneratian of the
desired suhstilucnt or aubstituenta. Those skilled in the art may utilise
Conventional
approaches to protect and deprotcct certain Functional groups during the
reaction sequence.
Such ntctho~cis arc well known in the art and include Cor example those
described by
Grc;cne a,nd Wutz (supra), The re:~ction seyucnce described in Ex~tnplea 1 and
2 exemplify
the preparation of compounds (1) and (2) and provide att example of how the
reaction
sequence oC Scheme 1 is utilised. These skilled in the art will appreciate
that a wide
variety of reaction conditions, including solvent,, bases, oxidising agents,
reducing agents,
temperature and time of the reaction, may be utilised to effect the desired
transformation.
A substituted c.none auc;h as (4) may, dependant upon the exacrt nature of the
reagents and
conditions used, add to the substituted 2,f~-dihydroxynaplithalene (3) in the
opposite
orientation to that shown in Scheme '1 and still provide a naphthopyran
product, Such a
~.Q reaction is shown in Scheme 2, and provides naphthopyranol (8).
Naphthopyranol (8) may
be isomerised to provide a naphthopyranol efCtetively c~C general formula (5),
which may
then be subject tc~ Cmther reaction in t~ccordmce with the general prcxedures
of Scheme 1
to prc>vidc cscmpounds of Formula (l).

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
- ltd -
S~;hem~ 2~
R R2
z
P1~ R3 Rt r/ R3
"o"
HO ~,,. ...,' Rs '4a) H /' ~"~ Re
r.
p ~ V R6 ~ v
R7 R7
(3) ($?
(5)

CA 02561896 2006-09-29
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_17_
Alternative synthetic procedures which provide compounds of Fornmla (1) are
ahawn in
Schemes 3 and ~~. In Scheme (3) an appropriately substituted butye (9) is
reacted with an
appropriately substitute.il hydroxy tctralone (10), ~'he group L is a.ny
suitable leavinb
group and includes groups ouch as a promo, chloro, and hydroxyl. Ideaction
hetwcen the
tetralone and the butyne may be acid or base catalysed to provide naphthopyran
{17). In
some cases the reaction may be conducted in one pot however an intermediate (1
1) rttay be
isolated, Intermediate (11) may ccynvcn.iently be cycliaed far example by
heating in the
presence c~f a suitable base, such as diethylaniline. The cyclised product
(1?) is then
oxidised to afford the quinonc (13) which may then be further modified to
provide other
1U compounds of Formula (1).
Scheme (4) outline a similar reaction seduence to that of Scheme (3) which
would start
with an appropriately substituted hydroxy naphthalene. This is based upon work
reported
by Bigi et al., J. Clrg. Chem., ~2, 7024-7027 (1997). The cyclised
naphthapyran (:15) could
be treatad as per compound (5) of Scheme (1) to provide compounds of the
inventiUn.
Many other methods of preparing hanzopyrana have been reported itt the
chemical
literature and those skilled in the art may adopt these methods to provide
compounds of the
present invention, sec for ex~urlplc, lshino ec al., Syn. Comm., 31, 439-44g
(200'1).

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- 18-
Scheme 3
H3
L R
R R3 Ri
HO ~ Rs Ri ~g~ !. R0
Rd
A~ p
(10)
R
I~~) (~2)
r
R~

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
_ yg
~4heme 4
Ra
R~
Hd Re R Ra R
~'"'', R, (9, ,,.~ ~ -,~,, s
R~ ~'. !' off R \ ~ off
a
R7 R7
(74)
(i 5)
Further mudifrcatian may include derivatisation of double bonds. For example,
when R~
and R$ together v~~ith He bond between the carhc~n atoms to which they are
attached form a
douhle. bond, tire double bond may he derivatise~i by addition, oxidation or
reduction
reactions. r1n example of possible de=rivatisation of such ~ douhle bond is
given in ~chcrne
5. Follr~wing xcductive acetylaticati to protect the quinone portion of the
compound,
epo~idation of the pyran doable bond, subseriuent ring opening of floe epoxide
with an
1U amine, and dcprnteotion and axidati~n to regenerate the quiuane may he
effected. Those
skilh;d in tire art could readily deterr~iine appropriate reagents <urd
conditions to effect such
transformations.

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
_ ~Cl
Scheme S
a
R
Y~duciiva acetylatlOn
;r-
epoxida!ion
a'
p~'1' t~J'"r f~~
H
hydrdysis
---
A person skilled in tl~te art would be able to modify such a reaction scheme
by using
different re~gcnts to open tY;.e epoxide, using asymmetric ePoxidation
catalysts and varying
the nature of the substituants.
As used herein, the tcnxt "effective smaunt" relates to an amount of compound
which,
oxidation
p;~

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-21-
when administered according to a desired dosing regimen, pruvidew tha desired
hepatitis B
virus treatment or therapeutic activity, or disease prevention. Dosing may
occur at
iy.~ais of minutes, hours, days, wee);s, months oar years or cotitiuuously
cover any one of
these periods. A therapeutic, or treatment, effective mount is an amount of
the compound
which, when administered according to a desired dosing regimen, is sufficient
tea at least
partially attain the desired therapeutic effect, or delay the crnsct of, or
uihihit the
pxagression ~C or halt or partially or fully reverse the onset or progression
of hepatitis B
virus. A prevention effective amount is an amount of compound which when
administered
ac~carding to the de:;ired dasina regimen is :;ufticient to at lcaat
pairtially prevr;nt, or delay
IU the onset caC a particular disease or condition.
Yet another aspect of the preaent invention provides a use of a compound oC
Formula ( 1 ) in
the preparation of a mcdicame.nt far treating car preventing hepatitis I3
virus.
Suitable dosages may lie within the range of about (1.l ng par kg c>C bcxiy
weight to 1 g per
kg of body weight per dosage. The dosage is preferably in the range of ! p.g
to 1 g per kg
tat body weight per dosage, such as is in the range c~C 1 tog t.o J g per kg
of body weight per
daaage. In one embodiment, the dosage is in thr: range of 1 mg to SOU mg per
kg of body
weight per dcasage. W another embodiment, the dcasage i;; in the range of 1 mg
to 250 mg
2f1 per ~g of body weight per dosage. In yet another preferred e.mbadiment,
the dosage is in
the range of 1 rng to 10U mg per kg of body weight pt~r dosa6e, ;,ooh a,5 up
to 5U tzig per kg
of heady weight per doaage. In yet another e.tnbadirue.nt, the dosage is in
the range of l~tg
to img per kg of body weight per dosage.
Suitable dosage amounts and da;;ing, regimema can be determined by the
attending
physician and may dap~nd on the. severity of the eotiditic~n as vvcll as the
general age.
health and weiyt of the subject.
The active ingredient may be administered in a jingle Base or a series of
doses. While it is
possible for the active ingredient to be administered alone, it is preCerahle
to present it as a
eurnpasition, preferably as a pharniaceutieal ccympoaition.

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-22-
Accardinb to a further embodiment there is provided a xnethad of treatment or
prophylaxis
of hepatitis 1~ virus c,~ompri:~ing administering an effective amount csf a
compound of
Formula (1 ) and a second therapeutic agent.
When adrwinistered as a combination, the compound of Formula {1) and the
second
therapeutic agent may be administered simultanwusly, separately or
sequentially.
The second therapeutic agent may be a known antiviral ar aintiretrovirai agent
car another
'1U pharmaceutical used in the treatment «f viral infections. Representative
examples of
Suitable aecand tlcraPeutic. agents include imtnunornodutators,
inmiunostimulcuzts and
autihiotics. Exemplary untiviral agents include acyclovir, val-acyclovir,
pcncicluvir,
famciclovir, ganciclavir, foaewnet, ribavirin, interferon-alpha. F'EC~-
interferon-alpha,
latnivudine, adcfovir, thymosul alpha 1, entccavir, tclbivudine,
emtricitabine, elvucitabine,
MCC-478, hepavir B, hilV-210, valtorcitabine, Hcpe?C-B, 7idavudine,
didanosine,
zalcitabine, stavudine, lamivudine, abacavir, tenofovir. emtricitabine,
saduinavir, indinavir,
nelfinavir, amprenavir, ritonavir, azatanavir, nevirapine, delavirdine>
ofaviren~, enfurvitide,
trizivir, combivir, kalctra, MIV310, nu»cnavir, 5PD754, ~PD'746, T1249,
TMC125,
TMC114, VX-175, tipranavir other non~nuGleoside reverse transcriptase
iiihibitnrs and
proteaae inhibitors, Exemplary imn~unomodulat4rs and imnlunwtimulants include
ulterfcron alpha, 1'EG-interferon, thymosin alpha I, Hcpe31-B, )'IBV
immunoglcabulin,
HBV monoclonal antibodies, and vaccines suCl1 as Eng,erixB, Havrix, H-B-Vax
II, it~fanrix
hcp ~, twinrix. !h-eferably the second therapeutic agent is an agent suitable
far the
treatment car prophylaxis of hepatitis L1 virus in a subject. Such therapeutic
agents include,
but are not limited to interferon-alpha, IyEG-interferon-alpha, lamivudine,
ade.fovir,
thymosin alpha 1, entccavir, tclbivudule, emtricitabime, elvucitahine, MCC-
47A, hcpavir B,
MrV-21d, valtoraitabine, and HepeX-fi.
Mill another aspect of the present invention relates t« a pharmaceutical
composition
3(~ comprising a compcaund of Formula (1) and a Pharmaceutically acceptable
carrier, dilucnt
or excipient.

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The formulation of such compositions is well known to those skilled in the
art. The
~on2pOSil10i1 m:.ty contain phaxmaccutiGally acccptahle additives such a.~;
carriers, dilucnts
or excipier,<is. These include, where appropriate, all canve'ntlonal solvents,
dispersion
agents, fillers, solid carriers, coating agents, antifungal and antihucterial
agents, dermal
penetration agents, surfactants, isotonic and absorption agents and the like.
it will he
understood that the compositions of the invention may also include other
supplementary
physicalogically active agents.
1Q The carrier must he pharmaeeutic;ally acceptable in the sense of Ding
compatible with the
other ingredient;, of the composition and not injurious to the subject.
Compositions
include those suitable far oral, rcet.al, inhalutionai, nasal, traaasdermai,
topical (including
buecal and sublingual), vaginal ur parentcral (includin g subcutaneous,
ititramuscuiar,
intraspinal~, intravenous and iutradermal) administratinn_ The curnposi.tions
may
1~ conveniently be presented in unit dosage form and may be prepared by any
rnethcxis well
known iw the art of pharmacy. Such methods include the ;;tc:p of bringing into
assoc.-iation
the active ingredient with the carrier which constitutes unc or more
ac;e;cssury ingredients.
In Qeneral, the compositions are. prepared by uniformL.y and: iriticnately
hringi.ng into
association the active inGredient with liquid earrier~; or finely divided wlid
couriers or bath,
'~0 and then if rtec:~SSAry shaping the. product.
J~~pcuding an the di.;ease or condition to be treated, it rnay or may not he
desir~.bla fur a
compaurid of Formula ( 1 ) to crass the bloodlbrain harrier, Thus the
compositions for use
in the present invention rrlay he formulated to be water or lipid soluble.
'~ S
Cort~positions of the present invention suitable for oral administration may
be presented as
discrete units such as capsulea, sachets or tablc;ts each containing a
predete.rmuied amount
of the active ingredient; as a powder car granules; as a solution i~r a
stcspensicsn i.n an
aqueous or nun-aqueous liquid; or as an oi!-in-water liduid emulsion ur a
water-in-oil
30 liquid emulsion. The active ingredient may also he pre~;ented as a bolus,
eleetuary or
paate.

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WO 2005/095376 PCT/AU2005/000453
A tablet may be made by compression or moulding, optionally with one or mcare
accessory
ingredients. Compressed tablets nnay bc. prepared by compressing in a suitable
machine
the active ingredient in a free-flowing form such as a powder or ~Tranules,
optionally mixed
with a binder (eg ine.rt dituent, preservative, disihte~aitt (eg. sodium
starch glycolate,
cross-linked polyvinyl pyrralidone, cross-linked sodium curhoxymethyl
cellulose))
surface-active or dispersing agent. MUUlded tablets may he made by moulding in
a
suitable machine a mixture of the powdered compound moiste:nod with an inert
liquid
diluent. The tablets may optionally be coated or scored and may be Cormulated
so as to
1L1 provide slaw or contrcyllcd release of the active ingredient therein
usinY, far example,
hydrnxypropylrnethyl celfidose in varying prcapartions to provide the desired
release
praFile. Tablets may optionally be provided with an cnt.eric coating, to
provide =elcase in
parts of the gut other than the stomach.
Compositions suitable for topical administration in the mouth include
lc~;~enges campriying
the active ingredient in a flavoured base, usually sucrose ~~trd acacia or
tragacanth gurrl;
pastilles comprising the active inb edient in an inert basis such ;as gelatin
and Glycerin, or
sucrose and acacia gum; and mouthwashes eomprving the active ingredient in a
suitable
liquid carrier,
Tlc compounds of >~ortnula. (I} may also he administered intranasally or via
inhalation, for
csample by atomiser, aercasol or nebulizer means.
ComPc~sitions suitable for topical administration tc~ the skin ma.~ cotnprisa
the compounds
dissolved or suspended in any suitable carrier or base and may be in the form
of Inti:ons,
gel, creams, pastes, ointments and the like. Suitable carriers include mineral
ail, propylene
glycol, polycaxyethylene, pcalyoiypropylene, emulsifying wax, sorbitan
nnonostearatc,
polysarbate 60, cetyl eskers v~ax, cetearyl alcohol, 2-octyldadecanal, henzyl
alcohol and
water. 'fransderntal devices, such as patches, may also be used to
adrtzini;;tar the
ccmpaunds of thr; invention.

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-25-
Compositions for rectal administration rnay be presented as a suppository with
a suit4~ble
carriex base comprising, for example, cocoa butter, gelatin, glycerin ar
polyethylene
glyccal.
S Compcfsitions suitable for vaginal administration may be presented as
pcssaries, tampons,
creams, gels, pastes, foams or spray formulations containing in addltiUI1 to
the active
ingredient such carriers as arc known in the ~u~t to be appropriate.
Compasitiar~s suitable for par~nteral administration include aqucau;; and non-
aqueous
isotonic sterile injection solutions which rnay corltaill ants-oxidants,
buffers, bactericides
and salutes which render the composition i:;otaruc with the blcaod of the
intended recipient;
and aqueauw and non-aqueous sterile suspen ,sicans which may include
suapendi.ng agents
and tllsCkeIllIIg agents. The compositions may he presented in unit-dose Qr -
multi-dose
sealed containers, far exau~ple~ ampoules and vials, and may be ;;torcd in a
freeze-dried
(lyophilised) condition requiring only the addition of the sterile liquid
carrier, for example
water for injections, irtymediately prior to use. Extemparancous injection
aalutiaw and
;;uspensinns may be prepared from sterile powders, gn"anule:; and tablets pf
the kind
previously described.
Preferred unit dosage eompca~itio~ are those containing a daily dose or unit,
daily
sub-dose, as heroin above described, or an appropriate fraction thereof, of
the active
ingredient.
It should be understood that in addition to the active ingredients
pat~ticularly' mentioned
above, the compositions c>f this invention may include other agents
canvention~al in tile art
havin4 regard to the type of corzlpaslttUn 11 question, far example, those
suitable far oral
administration may include such further agents as bircdeus, sweeteners,
thickeners,
flavouring agents, disintegrating agents, coating agents, preservatives,
lularicants andJar
tint delay agents. Suitable sweeteners include sucrose, lactose, glucose,
a.~;partanle or
saccharine. Suitahle disintegrating agents include corn starch,
methyleellulose,
pcalyvisiylpyrrolidone, xantharx gum, bcntanite, alginic acid or agar.
Suitable flavouring

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. 26, _
agents include peppermint oil, ail of wintergreen, cherry, orange or raspberry
ilavauring,
Suitable coating agents include polymers or copolymers of acrylic acid andlur
methacrylic
acid srtdlor their esters, waxes, fatty alcohols, zein, shellac ar gluten.
5uitahle
preservatives include sodium benzoate, vit<~min E, alpha-toeophe.rol, aveorbic
acid, methyl
paraben, propyl parahen ar sodium bisulphite. Suitable lubricants include
magnesium
stearate, stearic acid, sodium Qleatc, sodium chloride or talc, Suitable tune
delay agents
include glyce.ryl rnanostearate or glyceryl distearate.
'those skilled in the art will appreciate that the invention described herein
is auseeptiblc t~
variations and rnodiCieatiow other th,~n those specifically described. It is
to be tmelerstocxi
that the invention iu.cludes all xuch variations and modiL"rcations which fall
within the spirit
and scope. The invention also include,; all of the steps, featmcs,
compositions and
compounds referred to ur indicated in this specifieatican, individually or
collectively, and
airy and all combinations of any two or n~nre of said steps ur features,
The invention will now be described with reference to the following examples
which ale
included far the purpose of illustration only and are not intended to limit
the generality of
the invention hcreinbctore deserihed.
EXANO'Lt:B
Example 1
Compound y:9-l~ydroxy-3,3-~Iimetlayr-3H-ncr,~h~"ft.vj2,1-b,jpyra~t-?',ro-dione
Step 1: 3,9-pimethyl-31'-I-~tuphthujZ,l-bJPyr'an-$~ol
' A mixture of 2,6-dihydraxynaphthaient (50.0 g, 0.312 moi), 3.methyl-2-
butenal (:10 xn_L,
26.24 g, 0.312 mol) and pyridine (38 mL, 37,02 g; 0.468 mal) were heated under
retlux fbr
3.5 h. 'the mixture was cooled to room temperature, diluted with
dichlaromethane (500
mL), filtered through a sintered glass funnel (porosity 3) then washed with
aqueous
hydrc~hlouc acid solution (1 hi, 2 x 25U mL) and water (1 x 25U mL). The
organic layer
u~as eatlvcter3 with a solution of aqueous sodium hydroxide (2 M, 1 x 250 mL
and 1 x 125
mL) and the combined aqueous extracts eooied in an ice~salt hath, acidilied
(mith stirring)

CA 02561896 2006-09-29
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- 27 -
with aqueous hydrochloric acid ;;elution (5'v~ mL~i1 a creamy-white
precipitate formed (pH
2). The saiid wits stirred Cor an additional 1l) mur with ccaoling, collected
by filtration,
washed with water and dried under high vacum at 4i7 °C to affnrd the
desired crude
product as a t~luffy white-grey solid (43.9 g, fit .°~o). The crude
product was used in the.
S subsequent reactian withcaut further purification.
Rccrystallised from diethyl etherlheRane m.p. 12~-123°. S ('f~ (300
MHz, CI~Cf3) 1.47, s;
2xCH3;4.77,s,01'-1;5.71,d,J10.2Hz,H2;6.9t?,d,J10.2Hz,H1;7.U~,,d,J8.7Ha:,HS;
7.U$, s, H7; 7.10, dd, J $.7, 2.7 Hz, H9; 7.4$, d, J 8.7 H~, H6; 7.85, d, J
8.7 flz, H10. m/z
(F.S+, 1Ut) V) 471 (2M+H+H?CJ, 100rra), 24S (M+-H+1 (z0, 62), 227 (M+H, ~3).
Step 2: 3,3-Taimethy6-~H'-r:aphthoj2,l-bJpy~rar~-T,S-dio~ee
To an oxygen saturated xolutian of 3,3-dimethyl-3JI-naphta[2,1-bJpyran-8-al
(3.0 g, 1:i
mmol) in acetonitrilc (70 mL) was uddcd catalytic amounts of
N.N-Bis(salicylidenc)ethylenediamineocobalt(11~ hydrate, ([Co(II)(Salen~])
(3U0 mg, 0.91
mmol, 7 mal~t~), a.nd oxygen was bubbled tltraugh the mixture until the
reaction was
deemed completed (generally 4.5 h) by TLC Chexanc-ethyl acetate 4:1) or HPLC.
The
carangelbrcawn reaction mixture was diluted with ethyl acetate and the entire
mixture
filtered tltraugh a plug of flash silica (11 x 7 cm) to remave,thc catalyst.
The plug was
2U washed with ethyl acetate until the eluent was zicarly cc~lrrurlcss. The
solvent concentrated
ire uacun and the residue dried under high vaeumm tea afford the desired crude
product ais an
ornn,~a solid (2.73 g, 8fi~'o). The crude pruc3uct was used in the subsequent
rcactian
wiillout further purification.
The product was reerystalliscd from etliyl acJetatclhexanes to afford red
needles; m.p.
189-193° 6 (tH) (3U() MHz, CDCI3) 1.5U, s, 2 x CHs; 5.92, d, J 1U.4 H2,
H2, 6.43, d, J 10.4
Hz, H1; 6.71, d, J I0.5 Hlz, H9; 6.84, d, J f3.G 3iz, H5; 7.72, d, J 1U.S Hz,
H1U; 7,97, d, J
8.6 Hz. H6. nr/z (ES+, 30 V) 263 (M+Na, 9TH), 242 (M+1-1+1, 19), 241 (M+H,
100).
Step 3: 9-Flydrory-3,3~dimethyl-3H-naphthuj~,l-bJPyran-7,1U-diano
A solution of 3,3-dimethyl-3H-naphtha[2,1-b ~pyraii-7,8-dicme {4.59 g, 19.1 nu-
nol) in

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
_~g_
toluene (340 mL) wa.5 washed twice with a solution of sodimn dithionitc (24.9
~, 0,143
'mol) in water (250 ntL,). The yellow organic layer was theLZ added ui one
portion to a
oxygen saturated solution csf potassium fir!-butaxide (12.19 g, 11S mmol) in
tert-hutanol
(110 mL) and the resulting mixture was stirred at room tempc~ature with oxygen
bubbling
. for an additional 30 min (MOTE: longer periods appears to result in reduced
yield). Tltc
resultant dark red solution was acidified with aqueous hy~irr~c~loric acid
solution (ittitially
2 M then 5 M) until the colour turns yellowlorange (pH -- 1), then water (~ 40
n1L) was
added to dissolve the fc~rmcd salt, and the layer, separated. Tl~.e organic
phase was washed
with water (1 x $5 mL), and then extracted with a ;,atmated aqueous radium
hydrogen
carbonate solution (5 x 85 mL). The combined aqueous extract;; were
transferred hack isito
the separating funnel and allowed to settle fur 1 h (to ;;eparat~ further
axnaunts e~f toluene)
and the layers acparated main. The combined hale extracts were cooled in an
ice-salt bath,
carefu!!y acidified (aducous hydrochloric acid, 5~.4, ~ 80 ntLy drapwisc Over
30 min with
stirring until the colour turns pale yellowish (pH ~ I-2)- The resultant
precipitate was
further cuolcd in the ice-salt hath with stirring, the aolid collected, washed
with water
0100 mL) tea remove coloured impurities, and the arangelhrow solid was
rccrystalli.scd
(absolute ethanol) to afford the desired product as orange coloured crystals
(1.U4 g, ~l~la),
m.p. 208° c~ ('H) (300 MHz, CDC13) 1.48, s, 2 x CH;~; 5.94, d, J 10.5
Hz, H2; 6.23, s, H9;
7.U3, d, .T 8.4 Hz, H5; 7.83, d, J 10,5 Elz, H1; 7.99, d, J 8.4 Hz, lib, m~,z
(ES+, 100 V) 27~
2U (M+Na, ) 00~'Io), 257 (M+H, 45), l 59 (46), 137 (49), S6 (44), 59 (SO).
LYample 2
Conapaasnd 2: SY-HydrOxy-3,3-dBmetlryl-1,2-ddhydra-3H-naphthrrj2,l-b,JPyran-
7,1U-diu~le
A mixture of R-hydroxy-3,3-dintcthyl-3H-napht1ta12,1-h]pysan-7,y0-clione (132
mg, U,52
mmc.~l) and platinum (I V) pride ( 1 S mg) in ethyl acetate ~ 15 mL) was
stirred under an
~it~nosphere of hydrcagen for 7 h, The resulting mixture was stirred in air
for 1 h then was
filtered through a pad of diatomaceous earth. The pad was cwasUed with ethyl
acetate then
the filtrate. and washings were combined and cocnetratcd irz yac~uu to give a
green solid
(128 mg, 9670). Reciystallisation from ethyl acetatelhexane~ using activated
e;harcaal gave
3U 8-hydroxy-3,3-dimethyl-1,2-dihydra-3H-naphtho[2,l,blpyra~~7,1U-thane rn,p.
'183.5-187°.
S (~H) (;300 MHz, C;f~CI.;) 1.37, a, 2 r CND; 1.85, t, J 6.$ Hc, 2 x H2; 3.30,
t, J 6.S E-Iz, 2 x

CA 02561896 2006-09-29
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_2~_
H1; 6.20, s, 1i9; 7.U3, d, J 8.6 Hz, 115; 7.98, d, J 8.6 Hz, H6. xrtl4 (ES+,
30 V) 259 (M+H,
77°!0), 174 (88), 1,'.59 {1U0).
Cx~rttple 3
Cr~rrspaurrd 3: 8-rlcetaxy~3,3-dirrret):yl-3H rraphtho(2,f-bJpyran~7,10-rlione
CQncentratcd acclphuric acid (1 drop) was added tcf a stirred arangc
suspension of
i~-hydrc~xy-3,3-dimetl~yl-3F1-naphthoi2,1-b~pyran-7,1()-dione (855 mg, 3.34
nrrno!) in
acetic anhydride (1() mL) and the mixture was placed in an oil bath (oil bath
ternnerautre
100° C). The rtvxture immediately heca.me han~ogeneous red~blaclC.
After 10 min the
1U mixture was cooled (icelwater bath) and, water (5U mL) addsd. Prc~duct~~
were eztracted
with ethyl acetate (1S0 mL), the organic phase seg~~rated, dried (NazSC~,~)
aizd filtered .
.through a silica laJug, washing the plug with ethyl acetate until ncs Cmther
~e~lour eluted.
The filtrate was concentrated irt vercua and the residue wav cried overnight
under vacuum
to uCJ:ard the title. compound as a reel solid (965 mg, 97'/0), ~H NMR. (3(X.1
MHz, C:DCI~) c5
1.48 (tiH, s, 2 x CH;;). 2.37 (3H, s, COCH,~), 5.94 (1H, d, J 10.5 H(z, H2),
6.34 ( 1 H; s, H9),
7.07 (11-1, d, J &.4 Hz, H5), 7.73 (1H, d. J 10.5 Hz, Hl), 7.97, f 1k1, d, J
~.4 Hz, H6).
Ex~mplc 4
C'nmpaund4: 7,S,lD-triacetoxy-;i,3-din:etltyx-3H-naphtf:of ,1-bJpyratt
A stirred solution of $~hydruxy-:1,3-dirncthyl-3H-naphtho ] 2.,1-b~pyTan-7,1(1-
dione (110
mg, U.93 n~rnol) in acetic at~lzydride (3 mL) and pyridine (4 inL) was heated
in an ail batli
at 6U°C for 15 mug. 2iric powder (530 mg) was added inE one portion and
the mixture
became pale yellow. After 15 mixl heatiztg, the rni~ture was cooled to room
temperature
and filtered thrayh a sinter (porosity 4), with ethyl acetate washings. The
filtrate was
poured onto icelwater (20 tol.) and acidiCicd with aqueous hydrochloric acid
sc~lution(2.0
tv>). The organic phase was scp,.~ratcd and the aqueous phase washed with
ethyl acetate (3
x SO mL). The ec~rrtbined organic phases were dried (NazSQ~), filtered and
concentrated in
vatrcsu. 'fhe resulting solid was reu~rystaali,sed from echanal ~o afford the
title compound a.s
a culourJeas solid (96 mg, Sf~°la). 1H NMR. (3UU MHz, ~:C~C13) & 1.46
(6H, s, 2 x CH3),
3t? 2.:11 (3H, a, COC,H3), 2.~7 (3H, s, COCH3), 2.43 (3H, s, C~7CH3), 5.64 (11-
1, d, J 10.1 Hz,
H2), 7.11 (1H, s, 1:19), 7.'12 (1H, d, d 9.0 Hz, H6), 7.23 (1H, d, 3 1U.2 ~Iz,
Ei.l), 7.b7 (1H, d,
J 9.0 Hz, H5).

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-30-
Example 5
Cvrrapound 5: ~-Rromo-$~hydroxy-3,3:dimethy!-3H~nnphtbu[2,1-h]gyran-7,10-dione
O
OH ~ ' ' , OH
~ ' 8r
A solution of hramine (354 mg, 2.21 moral) ll1 dry dichlnramcthane (4 ml~~ was
added
dropwisa to a cooled (0° C) solution of A-hydra~y-3,3-dimethyl-1,2-
dilydro-3H-
naphtho[2,1-h]pyrW -7,10-thane (506 mg, 1.~6 rnrnol) in dry dichlarometh~c (4
mL)
containing 3 drops of glacial acetic acid. 'The cooling bath was removed and
flee mixture
Gvaa stirred at roam temperature far 20 ruin then aaneentratc:d iir vacuo to
afCo~rd ~-hramo-
1Q 3-hydrary-3,3-dimethyl-1,2-dihydra-3H-naghtho[2,I-hjpyrau-?,1f)-dune as a
t~right
aratygc powder (C:iS rng, 96%): m.p. 213-216° C (Found; C, 53.5; H,
4,0, ClSHoBrU~s
reduires C, 53,4; H, 3.~ ~~o). V~,~x 3316m, 1660x, 1642x, l3fi~4.;, I?.~bs,
12fi2s, 1174m,
1114x, 1(?-~8s cm~l. ~H NMR. (3Uta MHz, C:DCl_~) 5 1.38 (6H, a, 2 x C113),
1.5:? (2H, t, J =
6.8 Hz, ~I2), 3,32 (2H, t. J = 6.S 1 fz, Hl), 7.06 (1H., d, J- $.fi i-lz, H5),
8.00 (Lff, d, J= ~.C
Fee, Hfi). »zlz (FSI~ 33~ (M[s~Br]+H), 3;i7 (M(~'~Br]+.H).
Fxamplc b'
Co»rporcnrl 6; 4-Bramo-$-)rydroxy-3,3-dinrethyl-3H.naphthoE2,1-b)pyran-
7,~(l~dione
Cnrrtporsnd ~'; 2,,p~dibromo-l,8-dihydroxy-3',3-dirnetlawl-1,2.dit~ydro-
3H~nap~tho(2,1-
bJpyrrxn-?,Yt7-diorre '

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
-31 -
a a
OH
p ',~,' ~ ~,' ' Br
0 . -r' a,
podium hydride (42 rng, 80% dispersion in ail, 1.40 ~unol) was washed with dry
hexane
then the supernatant was removed. The residual solid was dried mtdcr a stream
of
nitrogen. A solution of 8-hydroxy-3,3-dimerhyl-3H-uaphtho[2,1-h]pyran-7,1U-
dione (327
mg, 1.28 moral) in tetrahydrofuran (S mL) was added arid the resulting
solution was stirred
at room temperature for 10 min. This was cooled to c)° C and a~
solut.ion of bromine (265
mg, 1.66 moral) in dry dichloromc;thane (3 ml.) was added. The. mixture was
allowed to
warm to room temperature and stiwed for 2U min, after which t he solvents were
ccane~entratcd in vcacuo to afford a brown residue.. Flash chromatography (20-
50~k~ ethyl
aeet<~tolhexane with 1 ~lo glacial acetic acid) afforded 9-bromo-~3-hydrax.y-
3,3'-dimethyl-:1i~I-
naphthca[2,1-b]pyran-7,10-dionc as an orange-broE~~n solid (43 mg,
10°l°). {Found. M+I-t,
334.9909, 336.9857. C151i1zBr0~+T~qllires 334.9919, 33b.99C~t?). 1H NMR (30i)
MHz,
CDC:l3) b 1.49 (6H, s, 2 x CHs), 5.99 (11-1, d, J= 10.2 Hz, H2), 7.05 {1H, d,
J= 8.4 Hz,
H5), 7.75 ( t H, bs, OH), 7.82 (1H, d, J = 1 Q.2 Hz, Hl), 8.(~1 (133, d, J =
8.4 Hz, 1i6). rrrlz
(ESl*) 337 (M~snr~+H), 33S (ML79Br1+f~f).
Also recovered from the flasli chromatography coltunn was crude cowpcaimd 6
contaminated with a product of py~ran ring bromination (compound 7). This was
subjected
2U to preparative HPh.C (isocratic 60%A, 40r"oB) and gave a co~n.pound
sus~ctcd of being
2, ~-dihrumo-l , 8-dijrydrc~.xy-3, 3-dimeihyl-.1, 2-di~tydrrr-3H-
nrrp~t.t~to(2,1-b)~yrutt-7, I Q-c~inne
(3 mg, 0.5°ln), m.p. 202.5-ZOS° (Found: M+Ei, 412.9011,
414.5981. 416.8)61.
LC~SHt~~r~05 - HBO i~ reduires 412.9024, 414.9005, 416.8y87]. v~,;"~ 3475w,
1664m,
1582m, 1370rn, 12S4s, 1262s, 1184m, 11.22m, lOlfim cni'. ~ (tH) (300 MHz,
CDC13)

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
. 3~, _
1.69, s, CHs; 1.66, s, CH3; 4.42, d, ,l 3.8 Hz, H2; 4.73, ba, OH; 5.6Q, d, J
3.f3 Hz, i 11; 7.22,
d, ,l 8.7 Hz, H5; 8.13, d, J 8.7 Hc, H6. m/~ (ES*, ?0 V) 457 (MI'~~ sr][
s~Br)'~'Na, 13'%'0), 455
(M[slBr~J'''Br]+Na, 31), 453 (M[~eBrJ[~qBrl+Na, 22), 435 (M(a'Br][B,BrJ~-H,
7), 433
(M[siBrJ~'~Br]+H, 18), 431 (M[~QBr)[~~Br1+f(, 12), 417 (IvI(s~l3r][siBr]-
Ii~O+H, 16), 415
(!1Z[siBrJ[ 7gBr]-H=Q+H, 36), 413 (M[~sBr]1''ol3r]-H20+H, 2U), ;i36 (M-L "Br
+H~Oj+H,
1 (X1), 334 (M-( s~ Br +H20 J+H, 10U).
Examgle 7
Compound ~'; 9-Brom~r3,3-rlimethyl-b'~(.~-rrcethylbenze~eculJ'onyln.~yrl,2-
dihydro-~H-
1(? napftthaj2,1-b]pyrat:-x,10-dipue
Carnpor'nd ~: 9-D'romp-3,3-dimethy!-F.(4-m.ethylben~e~aesr~lfonyloxy)-
3H~nupletf~u[2,1-
BJpyran-?,yrJ~diune
O p a
n ~ + ~ ~. ~ 0
tJ ~ Br ~O '~ 6r0 I ,~' ~ 6r
O O ~ O
Pyridine (0.4U mL 4.95 nlmol) «~as ~ddcd to a cooled. (0° C), stirred
saluticm of >-bromo-8-
2U hydroxy-3,3-dimethyl-1,2-dihydro-3f1-napiltho[2,1-bJpyran-7,10-thane (550
mg, 1.63
mmol) in dry dichloromethane (10 mL") under nitrogen. A solution e~f 4-
methylbenzenesulfonyl chloride (3SU mg, 1.84 mmul) in dry dichlorconothane (8
nn:) was
added dropwise, then stirring was continued for 1.5 h at U° C:.
Diisopru~~ylcthylamiue (2.5
mL, 14.4 rnmol) was added and stirring was continued far a further 3 h when
aqueaas

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
-33-
hydrochloric acid solution (2,0 M) was added. Products were extracted with
diehlcaromethane and ethyl acetate, and the combined extracts dried, filtered
and
concentrated in vucwo to afford a brown solid (798 mg). 'frituration of this
with ethyl
acetatelhcxane gave, a yellow solid (fil0 mg) which by'H Nlv~ speotrc~scopy
contained
~l()~'o of the unsaturated pyran (compound 9).
A sample of the above yellow solid (560 mg) was dissolved in ethyl acetate (3U
mL) atLd
platinum (JV) oxide (25 mg) was added, The resulting mixture was stirred under
am
atmosphere of hydrogen Cor S.5 h after which it was filtered through a pad of
~:elite~~' arid
lU the filtrate was stirred in air at rocam temperature overnight.
Concentration ir: ~~acua gave a
brown scatid which ec~ntaixied ~5% of the unsaturated gyran (camgound a) by 1H
NM R
spectroscopy. The about hydrngt~nation was repeated on this solid using
nlatuiuu~ (l~)
oxide (69 mg) in ethyl acetate (35 mi.) under hydrca~en at roe?m ternperah.ire
overnight.
The mirturc was filtered through a pad caC Celite~' and tire filtrate
concentrated in t~acun to
afford a brown residue (5S0 m~;). Thi;; wan dissolved in acetonitrile; (45 mL)
and a solution
of eerie annnonium nitrate (617 mg) in water (2(? mL) was added dropwise. The
resulting
mixture was atirred at roam temperature for ~ h and water (35 mL,) was added.
Tic
resulting precipitate was collected by filtration; washed with watar, hexane
and dried under
vacuum for '~ h at 4U° C to give 9-hromo-3,3-dim~thyl~S-(4-
methylhemenesulfonyloxy)-
2U 1,2-dihr~dra-3N-nnphtJ~oi~,1-h]pyran-7,1U-dione as a brown solid (3UU m~,
41°fn): rc~.p.
lUy-115° C (Found: C, 5~,fi; H, 4.1. C2~HlgBr(36a reduires C, 53.8; fa,
3.9 °l<r). v="~
1fi72s, 1580m, 1:~70s, 13U'2a, 1288s, 1222m, 1202m, 1174s, 994x, 718s cm-t. 1H
NMR
(30U MHz, CD(:l~) S 1.37 (6H, s, 2 x (:H~), l,li7 ('~H, t, J = 6.3 Hz, H2),
2.5U (3I-f~ s,
ArCH3), ;i.27 (2H, t, J = fi.3 Hz. H 1), 7.11 ( 1 H, d, J = 8.4 Hz, H~), 7.41
(2H, d, J = 7.8 )F lx:,
113'), 7.95 (3H, app d, J - 8, 1 J lx, 2 x H~' and H6), , rr:J: (ESI~) 493
(M~'''13r~+H), 491
(~,l C~9$r)+H),

CA 02561896 2006-09-29
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_g.4-
Example 8
rC'~nmpoccnd 9: 9~Brvmo-3,~-dimethyl-8-(~meti:yltrenzcnesrclfvnyloxy)-3H
naphtJro(2,1-
hjpyrn~-7,1 ~-df one
O O
aH ~. -.a
~ ~ ~ ~,
o ~' Br ~' 0 ~ ~r°
o ~ o
Pyridine (0.15 mI~ 1.85 rnmol) wa:; addcci to a cooled (0° C), stirred
solution caf 9-b.~omo-8-
llydroxy-3,3-dimethyl-3F1-naphtha[2,1-bJpyran-7,10-dione (23S mg, U.70 rrnnol]
in dry
dichlororucthane (5 mF.,) under nitrogen. A solution of .~-
methylbcnzenesulfonyl chloride
(0.148 mg" t).78 mmol) in dry dichloromethane (4 mL) war added dropwise, and
stirring
was continued for 1 h at 0° C. Diisopropylethylatnine ( 1.0 mL, 5.74
mmcal) was aided and
stirring was cx>ntit~ued for a further 3 h when aqueous hydrochloric acid
solution (1.0 M)
was added. Products were extracted with dichloromethanc and ethyl acetate, and
the
combined extracts dried, filtered and concentrated ira vac~~o to afford a
brown sold. Fla'~11
chromatography (ethyl aectatelhexane 3:7) afforded 9-bromo-3,3-dimet=hyl-8-(4-
metliylbenzene>.sulfouyloxy)-3H-naphthca[2,1-bJpyran-7,10-dione a,s a brawn
solid. (97 mg,
28°,%): m.p. 167-168° C (Found: M+I C, 490.998, 468.99~J.
C~HtsBrO~,St requires 490.999,
4&9.001). v~,3=1672s, a3$8m, 1288s, 1218rn, 1172s, 1112m, 1018m, 1(?174tti,
732x, 706m.
fi88 crn t. 'Ii NMR (300 MHO, CI7Cia) ~ 1.49 (6H, s, 2 x CH;x), 2.5U (3H, s,
ArCH~), b.00
( 1 H, d, J = 10.5 Hz, H2), 7.10 (1H, d, J = 8.4 Hz, H5), 7.41 (2H, d. J = $.1
Fi2, I-i3'), 7.69
(lII, d, J 1U.5 = H~, Hl), 7.9$ (2H, d, J = $,1 H~, H2'), $.00 (1H, d, J= $.4
H~, Hfi). >rrlz
~LS1*) 491 (MiXlllr]-~H), 4~9U (ML~9Br]+H+1)

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
_~j.
Fxamglc 9:
iG'nrnpnr~nd 10: 8-.f~rn»to-3,3~dintethyl-9-(4-methylbenzenesrslfortylox,)-3H-
napht~arr[2,1-
hJgyrrYn-T,10-thane
Step 1
3,3-Dimethyl-3h-naphtho(2,1-b jpyran-y-of
HO ~ .' C7H ''~
--'----~- O ,~ ,' O H
A u~izturc of 2,7-dihydraxynaghthalene (33.2 ~, 207 n~rnul), 3-methyl-2-
butenal (20.U mL,
2()7 Lnmol) and pyridine (17.0 mL) was heated at 110° C Cor 2(.) h
tinder nitrogen. 'I'he
mixture was caalcd to room temperature and diluted with diethyl ether (150
mL). 'fhc
organic phase was aeparateJ and wahhed suc;ccssively with aducoua sulphuric
acid aolution
(5°~u, 150 1n1~), water (150 rtlL), aqueous sodium hydrtycn carhanate
solution (5~I>, 150
mL) and water (150 ntL). The organic phase was dried, filtered and
concentrated n vucuo
to afford 3,3-dir~ncthyl-3H-.naphtha[2,1-b]pyran-9-of as a buff coloured solid
(43.1 g,
92c~o): ~H lVIvIR (300 MHz, CDCI:a) h 1.48 {6H, s, 2 x CH3), 4.99 (111, br s,
~JH), 5.57 (1H,
d, .l = '10 Hz, H2), 6.84-6.93 (3H, m, H'1, H5, H8), 7.23 ( 1 f-C, d, J 2.3 =
Hz, H10), 7.55 ('lFi,
2U d, J = 8.8 Hz, H6), 7.63 (1F1, d, J = 8.8 Hz, H7). rn/z (FAB, 3NBAlMeOH)
227 (IvtfH,
6.S~o),
Step 2
'25 3,3-Dimethyh3fl-naphtho[2,1-hipyran-9,10-dione

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
-36-
0
0 .,,~ ,,,~ OH O ."" 0
..- ~ .r'
N, N'-Bis(salicylidene)ethylenediaminacol~alt(II) hydrate (4,5 g, 14 mnal) was
added to a
stirred solution of 3,3-dimetlay!-3H-naphthoi2,1-b~pyr.~n-9-of (43.2 g, 1~)0
mmol) in
acetonitrilc (1.0 L) and oxygen buhbled throu4h the mixture with reaction
progress
monitored by HPL,C. Further portions of the catalyst (4.1g, 3.4 ~ and 2.7 g)
were added.
after 18,5 h, 24.5 h and 44.5 h respectively. After 112 h in total, H !LC
shc~wt;d no starting
naphthal and the mixture was filtered though a silicon pad (S x 12 cm),
washing the pad
with ethyl a4etate until na further red valour eluted. Thc. filtrate was
concentrated in aacun
1() and the resulting re:,idue recryst~afliacd from ethyl acetatelhexane to
afford 3,3-dimethyl-
3H-naphtha[2,1-b]pyran-9,1U-dione as maroon needlas (14.5 g, :i2~'o): m.p. 1U9-
11U° C:.
1H NMR (30Q MHO,, CDC1;~) S 1.46 (6H, s, 2 x CH3), 6.(70 (1H, d, J -_ 10.3 Hz,
H2), 6.27
( 1 H, d, J = 1U Hc, H8), 6.98 (1 H, d, J = 8.2 Hz, 1iS), 7.U9 (1H, d, J = 8:?
Hz, lrifi), 7.32
(1H, d, J= 1t).3 Hz, H1), rru''; (FAS, 3NBAIMcOt-1) 242 (M+H+l, 52~Yo),
Step 3
9-Hydroxy,3,3-dixnethyl-3H-naphtha[2,1-h]pyran-7,10-dione
O ''~' fi
o ..o o ~, off
-~a
0~ d
A wlution of 3,3-dimethyl-3H-naphtha[2,1-b]pyn-9,10-dione (14.5 g, 6(,1.3
xztnu~l) in
toluene (850 mL) was washed twice with a salation of sodium dithionite (84 g)
in water
(8S0 mL). The rcsuiting pale yellow solution was LhGll added to a solution of
poOassium
2 r tort-hutaxide (37.U g, 33U nunol) in ~c~rt-butanol (37U mL) saturated with
oxygen. The

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- 37 -
resulting mixture was stirred at ambient temperature fc~r 30 min, after which
aqueous
hydrochloric acid solution (1.U M, 2SCl mL) was added. The organic phase was
separated
and extracted with saturated aqueous sodium hydrogen carhcmate (3 x 250 ml,).
'flhe
combined aqueouw extracts were cooled (icelwater bath) and acidified with
concentrated
hydrochloric acid. The resulting precipitate was collected by filtration and
washed with
water (1.U L) and dried under vacuum for 2 h at 40° C to afford 9-
hydroxy-3.3-dimethyl-
3H-naphtha[2,1-b]pyran-7,1U-dione as an orange solid (7.10 g, 46%): ~H NMR
{300 MHz,
CI7Cls) S 1.47 (6k-f, s, 2 x CH3), 5.99 (1H, d. J = 1. d.4 Hz, H2), 6.25 (1H,
s, Hb), 7.1 1 {1H,
dd, J = $.4, 0.6 H~, HS), 7.47 (1H, s, Uk l), 7.7f~ (dd, .l = 10.4. 0.6 Hz,
H1), 7.97 (1H, d, J
1 (T 8.5 HE, H6. m/z (FAk3, ;~t~lB.4/MeQH) 258 (M+H+1, 5(,)c'ln), 257 (MPH,
100).
Stop 4
8-Brorno-~3,3-dimethyl-9-{4-methylbenzcncsulfonyloxy)-3 H-naphtha['2,1-h]pyran-
7,1 U-
dione
0
o ', o w. a ,S'o
aH -~-~ o ,.. off -~.- Q
'''' I ~r
Br
0 o a
Sodium hydride {12 mg, 8Uro dispersion in oil, 0.40 moral) was added to a
solution of 9-
hydrc~xy-3,3-dimcthyl-3H-naphthca[2,1-b]pyran-7,10-dione (1U0 mg, 0.3.9
rnruol) in
tetrahydrofuran (2 mL) and the mixture wa's stirred at room temperature for 10
min. The
suspension wa;; cooled to 0° C, and a solution i~f bromino (70 tog,
U,44 mmcal) in
dichlc~romethane (1 mL,) was added. The orange solution was allowed to warn t
Co rOOil1
temperature then stirred far 20 rzlin. Aqueous hydrochloric acid solutiurt
(1.0 Ivl) was
added and the product was extracted with dichl<>rcamethane and ethyl acetate.
The
conihined organic phases were dried, filtered and concentrated in vacuo to
give a brown
t~eaidue (129 rng, 99°ln).

CA 02561896 2006-09-29
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-3g_
Pyridine (25 pL, 0.31 mmol) was added to a cooled (0° G), stirred
solution of the above $-
brnmo-9-hydroxy-3,3-dimethyl-;1H-naplttho~2,1-h]pyran-7,1U-diore (25 mg, 0.07
mrnol)
in dry dichlorc~rnethane (1 mL), A solution caf 4-mcthylt}emenest~lfotlyl
chloride (17 mg,
U.09 mmol) in dry dichloromethane (1 mL) was added dropwise, then stirring was
cc>ntinucd far 1 h at 0° C. L7iiaopropylethylamine (115 ltl.w O.fi6
mmol) was added and
stirring was continued far a further :~ h when aqueous hydrochloric acid
solution (1.0 M)
was added and the mixture extracac;d with dichloromcthane and ethyl acetate.
The
combined organic phases were dried, filtered and concentrated in vacaso to
afford 8-bromo-
3,3-dimctlyl-9-(4-methylbenz~nesutfonylo~y)-3H-naphtho(2,'1-b]pyran-7,10-
dio~~e as a
t'0 brown solid (35 mg, 95~'e): m.p. 151.5-184° C (Found: C, 54.0: H,
3.5. C~~HI~Bt~J~S
requires C, 54.U; lI, 3.5 'w). v,n;~~ 1678m, 1382x, 1294;;, l2SSS, 11&3m,
1128m, lUb2m,
98fim, 8Q6n, 6826. 564m crri t. 'H ~1MR (300 MHz, C.DCl3) b 1.49 (fih, a, 2 x
CH3), 2.5f)
(3H, s, AtCII;~), 5.98 (1H, d, ,! = 10.5 Hz, H2), '7.09 (1H, d. J _- 8.4 h~,
H5), 7.41 (2H, d, J
= 8.3 1~I7, H3'), 7.70 (1I-i, d, .1=_ 1U.5 ~i~, H1), 7.95 (2H, d, J= S.3 Hz,
N2'), 8.04 (1H, d, ,!
8.4 Hz, Hb), rrrlz (FAT') 491 (M[gtBr]+H), (My'a~r]+H)
hxample y0
Compound 11; 8-l3romo-3,3~dimet~.yf-,~-(~-rraetjty~~enZenesulfunyloxy)-I,2-
dil~ydra-31f-
naphthnj~,l-b]pyrmr.~?,.IO-rlzane
2~l
.,.. 0 ' '~ O ' /
o ,~~o o ,~~o
f
Br I .-
Br
0 Q
Platinum (IV) oxide (25 mg) was added to a solution of 8-bromo-3,3-dimethyl-9-
(4-
methylhen~onesultoz~ylnxy)-3H~uaphthc~[2,1-h]pyran-7,Ip-dionc (19y mg, 0.41
mtnol)
in ethyl acetate (S mL) and the resulting suspension alas stirred under an
atmosphere of

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
- 39 -
hydrogen fc~r 28 h. The reaction wa,s ftlter4d through a pad of C.elite'~ acid
the filter
cake was vVashcd with ethyl acetate and dic;hlorometlmne. The filtc-ata and
washinøs~
were comhined, dried, filtered and concentrated ira vac~uu to afford a brown
residue
which was dissolved in acetonitrile (20 mL) and cooled to 0° ~'.. A
solution of eerie
arninonium nitrate (2(H7 nag, 0.3fi mmol) in water (6 mI,) was then added and
the
mixture wus allowed to warm to roc?m temperature :end stirred far 2 h, after
which it
was diluted with water. Products were extracted with di.chlorornethane, a,nd
the extract
dried, filtered and concentrated in vcacuo t.o afford 5-h~~omu-3,3-dimethyl-9-
(4-
methylbanzcnesulfonyioxy)-1,?-dihydro-31i-naphtha[2,1-b~pyran-7,10-dione as an
orange-brown solid (193 mg, 970); tn.p. 168-169.5° C (Found: C, 53.6;
H, 3.8.
C2:HI~WrCl6,S requires C, X3.8; H, 3.9 °o). vn,~x 1680x, lf~f$m,
1620th, 1S78w, 1566w,
1382x, 129Us crri j. 1H NMR (300 MHz, C:DC13) $ 1.37 {6H, :;, 2 x CHa). 1.87
(2H, t. J
_ 6.2 Hz. 1-12), 2.50 (3H, s, ArCH~), 3.27 (2H, t, J = 6.~ 1-Iz, Hl), 7.1U ( 1
H, d, J 8.6 =
H~, HS), 7.41 (2H, d, J = 7.7 Hz, H3'), 7.97 (2H, d, J = 7.7 Hz, H2'), R.03
(1H, d, J =
8.6 Hz, Flci). rm'z (BSI+) CMCs~Brl+H), 4~1 (IVI[~''arJ+li).
hxample 11
Cc~r~por«~d 12: ~',9-niehloro-3,3-ciin~ethyl' -r,2-dihydra-3F1-nalrhtho(2,1-
bjpYrc~n-7,IU-
tfiorae
,tap 1
9-Hydroxy-3,3-dimcthyl-1,2-dihydro-:3H-naphtha[2,1-bipyr~n-7,10-thane

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
-40-
O Q
O f OH Q ~, OH
I ,~
a
0
A mixture of 9-hydroxy-3,3-dimethyl-3H-naphtho~2,1-h]pyran-7,10-dione (1.20
g,, 4.6
tnn5p() and platinum(IV) oxide {125 mg) in ethyl acetate (30 mL) was stirred
under
hydrogen far 3.5 h. The dark nllxture was allowed to stir exposed to air for
3t) n,in before
I"~ltration through a plug of Celite~'. Concentration of the filtrate in
vf~crsn gave a yellow
residue wluch was sub,~ect~d to~ flash elromatn~ aphy (ethyl acctatelhexanc
7;3 with l~ii~
glacial acetic acid) followed by recrywtallisation from ethyl acetatc;llmxune
to give 9-
hydroxy-3,3-dimethyl-l,2-dihydro-3H-naphtho[2,1-b~pyran-7,10-dione as yellow
net;dles
1U {948 tng, 79°/u): na.p. 155° C (auhl.), x177° C (dec).
vtn~ 332$, 3148, 31c)$, 1656, 1628,
1566 cm-~, 'H NMR (3C~ MHO, CIaCI;~) ~ 1.38 (bH, s, 2 x C:H3), I.89 (2H, l, J-
_ Ci.S Hz,
H2), 3.'29 (2Ii, t, J = 6.:5 Hz, H3), C~.25 (1H, s, H8); 7.13 (1 H, d, J =
1i:5 Hz, H5), 7.47 (1H,
.;, C7I~), 7.97 (1H, d, .T = b.5 H~, H6). Trr/z (FAB, 31'~1BAI1~2cC)1 () 26I
(M+}I+2,. 11%), 260
(M+Htl, 27%), 259 {M+H, 51).
Step 2
9-Ghlt~re-3,3-dimelhyl-'1,2-dihydra-3H-naphtho~ 2,1-h]pyratl-7,1 ~-dione
O O
a ~.'. aH p ~ ~I
,,., I I ~ I I
2l7 a
9-Efydroxy-3,3-dimcthyl-1,2-dihydro-3N-naphtho[2,1-b]pyran-7,10-dione {1.1 g,
4.3
mmol) was dissolved in dichloromediane (2p niL,) arid thiotiyl chloride (15
mL). The
reaction was stirred at room temperature. for 24 h and the volatiles were
removed ira vucun.

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
- 4'1 -
The residue was dissolved in ethyl acetate (30 mfr), washed with water (30
mL), dried,
filtered and concentrated in vaccco. The residue was purified by flash
chrcamatography
(ethyl acetatelhexanc 5:95} followed by recrystallisation from ethanol to giva
9-chloro-3,3-
dimethyl-1,2-dihydz~o-3H-naphtho(2,1-f~]pyran-7,10-diode as orange noodle;
(633 mg,
53°fu): m.p, 14U-2° C (Found: C, 64.9; H,4.8. C~gHI,C103
requires C, 65.1; H, 4.7%).
~m;i" (lug e) 216, 268, 350 sh, 412 11m (:1.35, 4.25, 3.23, 3.44). Vm,~x 370U-
3300s br,
3070w, 3000w, y 680s, l6fiDa, 1620rn, 1590m, 1580s cm-t. tH NMR (30U MHL,
CDC.1;~)
1.38 (6H, s, 2x CH3), 1.88 (2>-!, t, J = 7,(? 'Hz, H2), 3.29 (21a, t, J = 7.0
HL, H1), 7.12 (11-f,
d, J- 8.5 Ht, H5}, 7.12 (11-1, s, H8), 7.95 (1H, d, ,T- 8.5 Hz, H6}, rnlz
(PAB, 3NEA1280
(M[3761]+H-i-1, 14'~l0), 279 (Mi3~C:l]+H, 4U), 278 (Ml;3~C1]+H+I, 49), 277
(i~i'35C:1]+H,
lUU), 276 (4d), 233 (17).
~itep '3
1S 8,9-Uichloro-3,3-dimethyl -1,2-dihydro-3H-naphtho(2,1-b]pyan-7,10-dione
O
O ~ CI Q J CI
Ci
Q
C:hlarine gas was hubblcd thrc>uglt a scalution of 9-chloro-3,3.dirrtethyl-1,2-
dihydro-3H-
nap)ltho[2,1-b]pyran-7,1U-dicme (633 mg, 2.3 mrttol) in ~lacia! aortic acid
(50 mL)
containing concentrated hydrochloric acid (5 drops) at 70° C for 5 min.
The reaction was
stirred for :55 min at 70° C, cooled to rocam temperature and
concentrated in vacuo. The
re~,'tdue wss purified by flash chrornata~~raphy (tolucne/hexartc 7:3) to.give
8,9- dichJorU-
3,3-dimethyl -1?-dihydro-3H-naphtho[2,1-bJpyran-7,10-dione as ;gin orange
solid (508 mg,
71'0}. A sample of thin material was recrystallised from ethanol to give
orange miero-
crystals: m.p, 158-60° C (Found: C, i7.9; H, 3,7. Ci5HI201203 requires
C;; 57.9; H,
3.910). ~I,m;ix Clog E) '220, 275, 290 sh, 350 sh, 412 nrtl (4.32, 4.19, 4,01,
3.29, 3.38). vmax

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
. 42 _
37t?U- 333(1m br, :~D50m. Z950m, 170Us, 168Um, l6UOm, 158(7s cmv. ~H NMR (30U
MHz,
CDCI;~) F~ 1.38 {6H, s, 7 x GH3), 1.88 (2H, t, J = 7.0 Hz, l-12), 3.2'7 (2H,
t, J = 7.0 Hz, H1),
7.12 (1H, d, ,l = 8.5 Hz, HS), ~3,(~. (1k1, d, J = 8.5 Hz, H6). ndz (FAIL,
3N~.4) 315
(M[~7C;lz]+H, 16%a), 314 (M[37C13~CiJ+H+l, 32}, 3I3 (R~f[3~CI~SC1~+H, 74), 31?
(M(=~sClz~+H+1, 64), 311 (M(3sCl~~+H, 1()U), 310 {42), :i09 (1~).
Example 12
Compound 1'3: Sadi.urn 3,3~rlimethyl-7,x0-d'ioxo-7,10-di3syc~ro-3H-
herrzajfJchro»ten-8-
aCate or' 5~odium 3,3-dimc~hyl'-T,8~diaxa~7,8-dihydra3l'I-ben;,u(~''Jchromen-
r0~-plate
1 t)
O O O
NaOH ' .," ~ l ON~a
O r' pr
,.~ O ~ (J ,.f QNa
Aqueous sodium hydroxide (2.0 M, 3.38 mL, 6.75 mmol) was added drnpwise tc~ a
stirred
1:5 orange suspension of compound 1 (1.73 g, 6.75 rntnoi) in methanol (10 m!-
). The mixture
became homogeneous red. After 30 min valatiles were remuvcd iT~ vck«~n and the
resulting
red residue dissolved W water ( 150 ctrl.), C~ltcred (porosity 4 sint~;r} and
freeze dxied for 4$
h. Compound 13 was obtained as a red solid (1.80 g, 96'0}: tH NlviR (3(?Q MHc,
T3~'DMS(7} ~ 1.38 (bH, s, '~ x CHa), 5.26 (1H, s, H9), 5.82 (!F(, d, J = 10.2
1 f~:, H2), 6.83
2U (1H, d, J = 8.4 H~, H6), 7.64 ( 1 H, d, J = 8.4 H~, H5), 8.14 ( 1 H, d, J =
1U.2 Hz, H 1). n~lz
(k,S~, 30 V) 257 (M-Na+H, 1()O~u); HPLC 1f70%f 4.74 min.
The 1H NMR can also be run in DZO, compound 13 is fully soluble in water at 1U
m« niL
2S H,p'LC' Canddtions

CA 02561896 2006-09-29
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- 43
Perforniccl on Water 2590 Alliance System, using a l~~uters CylB 5 utn
Syrlimetry Column
(Part # WAT04fi98U) and a flaw rate of 0.7 mL.lmin. Column temperature of
3U° C and
measured at a, =254 nNl,
f3yf~'ers:
Buffer A: l0U%n water
Buffer Ii : 100 °b
Buffer ~: 2 °r'c. aqueous formic acid
Uradienl (ldraeur gradient Glcn~e "b")
min ~ min
45% A:50% B:5% C:-~-~ 95% B:5% C--~- 9fi°o 8;59'o C
1 min
5 min
45go A:50% ~;5°!o C '"~ 450~o A:6Q9o '~;5% C
L~;rample 13
CarnporEnd 14: $-HydrQxy-3-methyl-3 phe~~,yl-3H-henzo(fJchrornerae~7,llJ-dune
step 1
3..lVLethyl-3-phenyl-3tA-he~~,o~ fjchromen-8-of
OH OH
HO
HO
A stirred suspension of 2,b-dihydroxy naphthalene (7l ~ rng, 4.47 mmol) in
toluene (2UU
mL) waa heated to rcflux (oil bath temperumre l.fi0° C). After 1 h, the
rnixturc ww
homogeneous and p-toluene sulPhonic acid hydrate (54 mg, U.4c? mmol) was added
(allowed by a. wlution c}L 2-phenyl-but-3-yn-2-of (583 mg, 4.02 mmc51) ilx
toluene (50 mL,)
over 2U min while maintaining rcflu:~. TLC (ethyl acetatt~/he~ane 1:4) after 4
h shcawed

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
-
very faint 2,5-dihydroxy naphthalene. After a further 2 h, the mixture was
cooled to room
temperature and washed with aqueous sodi~rm hydroxide soluticm (10~, 400 m1).
Tle
organic Above was diluted with ethyl Acetate ( 100 mL,), dried (Na~SO~),
filtered and
concentrated ir: vacwc? to afford a black semi-solid (8U4 mg). Thiw was
dissolved in ethyl
acetatelhexaneldiehlorcamothanelmetlanol (1 n~L: 4 mL: 1 mL: 1 mL) and
subjected to
flask chrornatngraphy, eluting with ethyl acetatelhexane 1:4. 3-Methyl-3-
phenyl-3H-
bc.nTO[f~ohlnmen-8-of was obtained as a brown solid (230 mg, 18}: MS (E~Sh)
m/z 287 (M-
1}. HPIfi 99.3 %n/ 7.53 min
~tcp 2
3-Mcthy f-3-phenyl-3 H-benzo( f ]chromene-7, 8-cli one
Co(SALEN)2, 02
~0 0
Co(w~AL,EN)z (23 mg) wa:, added in one portion to a stirred homogenous yellow
solution of
3-methyl-3-phenyl-~H-bcnza~cltxonten-8-oI (217 m~, 0.75 mmol) in acetonitrile
(3 mL).
Oxygen vras bubbled through the mixture and after cJn min the mireure was
filtered
tlirouqh a silica plug, washing the plug with ethyl acetate until no further
colour eluted.
V'olatiles were. removed irt vcrcuu to affcard 3-methyl-'3-phenyl-3H-
benzo[~]chromene-7,8-
dione as an orange solid (228 tng, 100~so}: ~H NMR (300 MHz, ~:DC13} cS x.86
(3H, s,
C:H;~), 6.25 (iFi, d, J = 10.2 Ha;, H2}, 6.43 (1H, d, J= 10.5 Hz, H9), 6.$5
(1H, d, J = 10.2
HG, H1}, b.97 (1f{, d, J= 8.4 Hz, H6), 7.35 (51 f, m, Ari-1), 7.72 (1H, d, .l=
1U.5 Ht, H9),
7.99 ( 1 H, d, J = $.4 Hz, HS) M~ (EST"} rrtlz 30~ (M+1.).

CA 02561896 2006-09-29
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-45-
step 3
8-Hyciroxy-3-methyl-3-phenyl-3H-benzc>[ f]chramene-7,10-dionu
4 N Na~H
a HO
S
Aqueous sodium hydroxide solution (4 M, S mL) was added to stirred orange
suspension
of 3-methyl-3~phenyl-3H benzo[J~chromene-7,8-dione (32 mg, 0.1'1 mmol) iz~
ethanol {5
mL) arid the mixture became IIUIIIO~CIl00t1S hrowm. After 1 h, the mixture was
c:aoled
(icelwater bath) and acidified to pH-~ 2.0 (5.0 M aqueous hydrochloric acid
;solution). The
resulting orange wepcnsion was stirred for LD min in the cooling bath then at
i0 min at
room temperature. The precipitate was cc~ilected by filtration acrd washed
wish water (317
mL) then dried overnight under vacuum tea afford 8-hydroxy-3-methyl-3-phenyl-
3H-
't~nzo~,f]chrc>meno-7,1(>-dinne as an orange solid (27 mg, A2~?o): 'H NMR (300
MHO,
GDCI~) S 1.84 (311, v, CH3), 6.~2 ( 1 H, s, H9), t7.26 ( 1 H, d, ,7 = 10. S
~~T, H2), 7.14 (.I l i, d, J
= 8.7 kl~, H5), 7,2U-7.4.5 (5H, m, ArH), 8.05 (2H, m, H5 and H1). M,8 (FSC)
rn~<, 317 (tvt-
I ). HPLC '1 UO ~~ol 7.12 min.
example 14
Cumpoe~nd ~'S: ~~Hydro~,y-3,~~diphetcyl-aft-hen~u(f]cl~romene-?,ff~dione
Step 1
3,3-Taiphenyl-3H-ben~o[fJchromcit-S-of

CA 02561896 2006-09-29
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-46-
f \
"-. o H
.,. ~". a H
r ,i
HQ
Ha
A stirred ~uapenaion of 2,6-dihydroxy naphthalene (50?. mg, 3.13 mural) in
toluene f2(lU
mL) wav heated to retlux {oil bath temperature 130" C). Aticr 1 li, the.
mixture o~as
hamagenevus and p-toluene sulPhonlc acid hydrate (54 rug, 0.28 n>tnol) was
added
followed by a solution of 1,1-diphcnyi-pxop-2-yn-1-of (583 mg, 2.52 ntmol) in
toluene (40
mL,) over 30 min while n~aintai.nin~ reflex. After 2 d, the mixture was cooled
to room
~emparature and wawhcd with aqueous sodium hydra;cide solution (I0%, 4LlU
mT,). The
uxganic phase was diluted with ethyl acetate (?0t) tnL.}, dried (IVazSO~),
filtered and
1(.) conceittratcd in vucun to afford a black solid. This was dissolved uz
ehlarofai~tn,/hexane (5
mL; 5 r_ttl~) and wbjected to Clash cluomatogr~tphy, eluting with
chloroformlltexanc 1:1
then neat cliloroform. 3,3-biphenyl-3H ben~o[,fjchromen-8-of ryas obtained as
a brown
valid (213 rng, l9~ro): MS (F~f) nt/287 {M-1}. F3PLC BU.:i~7o! 8.89 min
a 5 Step 2
~,3~I7iphcnyl-3FI-henzoG,~]clrromene-7,8-dione
cQ(sat.~N~2, a2
~0 0
zo

CA 02561896 2006-09-29
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- 47 -
Co{SALEN)Z (22 mg) was added in one portion to a stirred hc~mcagenous yellow
solution of
3,3-diphenyl-3H-bcnzo[J)chrome«-$-o! (2,13 mg, 0.61 tnmol) in acetonitrile (3
mL).
Oxygen was laubbled through the mixture ar'<d after 3 h the mixture was
Ciltered through a
silica plug, washing the plug with ethyl acetate until no further colour
eluted. Volatiles
were removed 'vz vacuo to afford brown solid which was dissolved in
dichlcaromathane and
the solution. subjected to flash chromatography, eluting with neat
dichloromethane. 3,3-
Diphenyl-3H-benzo[f'lchromene-7,i1-dime was obtained as an orange solid (3'2
mp, 14'0).
MS {ESI'~ rtt/z 365 (M+1).
1U step 3
8-Hydroxy-3,3-diphenyl-3H-t~en~o[ f ~ chrotnctte-7,'1 U-dione
4 N NaI~H
H (~
Aqueous sodium hydrcaxide solution (4 M, 3 n1L) was added to stirred orange
suspension
of ;i,3-diphenyl-3H-bettzo[J~cluamene-7,8-dicane (22 mg, 0.06 tntnal) in
e.thanvl (3 mL)
and the mixture became homogeneous brown. After 30 min, the mixture was cooled
(iccJwat.er bath) and acidified to pH-- 2.U (5.0 lVl aqueous hydrc~chlot~ic
acid solution). The
resulting orange suspension was stirred for 20 min in the cooling bath then at
1U min at
room temperature. The precipitate was collected by filtration and washed with
water (15
ttiL,). This residua waa dissolved in ethyl acetate (S mL) and filtered though
a silica plug,
eluting the plug with crliyl acetate (150 mL) then ethyl acetatclacctic acid
(3U;1), coLle.cting
3 x 15 ntL fractions. Fractions 1 and 2 were combined ;md concentrated in
vacun to afford
8-hydroxy~'3,3-ciiphenyL-;i7-~-henzo[fJcl>zotnene-7,1U-dione as an grange
solid ('6 mg, Z~.°w).
LH IVMR (300 MHO, CDCl3) 8 6.23 (1H, s, H~). G.45 (11-(, d, J = 10.4 Hz, H2),
7.20 (1H, d,

CA 02561896 2006-09-29
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-48~
J -- 8,4 Hz, H6), 7.40 (10H, III, ArH), 8.00 (1H, d, J = 8.4 Hz, H51. 8.16
(1H, d, J = 10,4
Hz, lily. MS (E~I'~ m/z 381 (M+1). HPLC 86.5°1018.81 min,

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-49-
Antiviral Activity
Test; of antiviral activity were perCornied in 2.2,15 human hepatoma cells
infected with
hepatitis B according to the method of Korba and Gerin, Antiviral Research,
19, 55-70
(199?). Briefly, cells were seeded into} 96 well plates and cell media
containing variaw
concentrations of the compounds was added. Media was changed daily far 9 days
and
fresh media containing compound was added each day. On the 10'~ d:~y, viral
DNA in the
supernatant was measured and the reduction in the amount of virus izi the
supernatant was
calculated compared to cells incubated without drug. Six separate replic;atcs
were
performed for each dmg concentration. 'The cffe.etive concentration for
50°h and 90'0
irtliibition of the replication of the virus was deterntittcd from dose
response curves.
Results fear ;;ome compounds of the invention arc shown in Tahle 1.
Table 1
Teat Compound >H:C50 ~tM EC;90 1M
Compound 1 0.6 3.4
Compound 2 1.1
Antiviral activity was also examined in HepG2 hepatoma cells infected with
HZ~V
eontaiuing mutaticms associated with resistance to larnivudine (3TC). ~l'wo
cell lines
containing an I,1$OM mutation in the HBV DNA polymerar,e, and a double
L180MfM204V mutation were used. Cells were plated out in six well plates and
allowed
to attach overnight, Next day, the culture medium was replaced with either
medium alone
or medium containing the desired concentration of antiviral compound. Media
wsa
chaitgcd for fresh medium with or without. antiviral compound an day 3. cJn
day 5,
supernatant and cell lysates wem analysed CUr lc;vcls of HBV core protein by
non-denuturixy Western blot using an anti-HBV core antihady,
z5
Results for same of the compounds a.re shown in 'fable 2 whore a SU~u
reduction <>r more
in measured level at' the viral core protein compared to contt'ols at a
compound
concentration of groater than 50 Ltmolar is designated +, 50~~'o care
reduction at less than

CA 02561896 2006-09-29
WO 2005/095376 PCT/AU2005/000453
50ymalar is designated ++ end 50°la c~rc redu4tion at Iess than
l0unaolar compound
concentration is designated +++.
Table 2