AU755919B2 - Syntheses of a variety of lamellarin compounds and analogues - Google Patents

Description

WO 99/67250 PCT/A 109/nnfI6 1- Syntheses of a variety of Lamellarin compounds and analagoues TECHNICAL FIELD The present invention is generally directed to intermediates useful in the preparation of compounds useful in therapy. More specifically, the present invention relates to intermediates useful in the preparation of a class of fused polycyclic alkaloids. The invention also relates to methods for the preparation of the fused polycyclic alkaloids and their analogues and derivatives.

BACKGROUND ART Naturally occurring molecules which exhibit potentially beneficial pharmacological properties are isolable from a range of environments, such as marine, plant and microbial sources. One example of such molecules is the general class of compounds known as the Lamellarins.

These polyaromatic alkaloids are isolated from marine sources and comprise a fused framework. Lamellarins C and D have been shown to cause inhibition of cell division in fertilised sea urchin assay, whereas Lamellarins I, K and L all exhibit comparable and significant cytoxicity against P388 and A549 cell lines in culture. Recently, Lamellarin N has been shown to exhibit activity in lung cancer cell lines by acting as a Type IV microtubule poison. Furthermore, these compounds have also been shown to possess cytotoxic activity on multidrug resistant cells as well as efficacy as non-toxic modulators of the multidrug resistant phenotype and, therefore, afford an attractive potential source of chemotherapeutic agents.

However, the potential clinical usefulness of the Lamellarins is severely limited by the modest quantities produced naturally as well as the difficulties involved in their isolation.

There has accordingly, been significant activity directed towards the development of a synthetic route to this class of molecules, and approaches to these molecules have included SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AU99/00516 -2a sequential double cyclization of a 1,3,4-triaryl-2,5-dicarboxysubstituted pyrrole ring (Steglich et al, Angew., Chem. Int. Ed. Eng. 1997, 36, 155), and N-ylide-mediated pyrrole ring formation to install the pyrrole and lactone portions of the molecule (Banwell et al, Chem. Commun., 1997, 2259) Ishibashi et al, Tetrahedron, 1997, 53, 5951).

The present invention now provides an alternative method via a synthetic intermediate, which allows for the incorporation of a range of substitution patterns and potentially permits access to a variety of Lamellarin compounds and analogues containing the fused polycyclic-pyrrole core.

DISCLOSURE OF THE INVENTION Accordingly, in a first aspect the invention relates to a method for the preparation of a compound of Formula RA 2 RA 1RA Y

RA

4 /Z (II) X N S00

W

comprising the step performing an intramolecular cyclization of a compound of Formula RA2 SRA RA 3 V RA4 x N z wherein: W 0 RAI-A4 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/Ar o99/01 6 -3alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano; or

R

A2 and R A3 may optionally together form a bond and RAl and R A4 are as defined above or together with the carbon atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic group; or

R

A2 and RA, together with the carbon atoms to which they are attached form an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group; or

RAIRAC-CRA

3

RA

4 forms an optionally substituted aryl group or aromatic heterocyclic group; Y is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano; W and X are as defined for Y, or together with the nitrogen and carbon atoms to which they are attached, form a saturated or unsaturated nitrogen containing heterocyclic group which may be optionally substituted or optionally fused to a saturated or unsaturated carbocyclic group, aryl group or heterocyclic group; V represents a halogen or hydrogen atom; Z is -(CH 2 )n-U-(CH 2 where U is selected from CH2, NH or a heteroatom, and n and o are independently selected from 0, 1, 2 or 3.

In a second aspect, the present invention provides an intermediate compound useful in the preparation of compounds of Formula wherein said intermediate is of Formula v SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AU99/00516 -4- RA2 Y\ RA3 A

RA

4 X N W O (I) wherein: RAi-A 4 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano; or

R

A2 and RA 3 may optionally together form a bond and RAl and RA 4 are as defined above or together with the carbon atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic group; or

R

A2 and RA 3 together with the carbon atoms to which they are attached form an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group; or RAIRA2C-CRA 3

RA

4 forms an optionally substituted aryl group or aromatic heterocyclic group; Y is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyi, acyioxy, mercapto, optionally substituted aikyithio, halogen, nitro, sulfate, phosphate and cyano; W and X are as defined for Y, or together with the nitrogen and carbon atoms to which they are attached, form a saturated or unsaturated nitrogen containing heterocyclic group which may be optionally substituted or optionally fused to a saturated or unsaturated carbocyclic group, aryl group or heterocyclic group; SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AU99/00516 V represents a halogen or hydrogen atom; Z is -(CH 2 )n-U-(CH 2 where U is selected from CH2, NH or a heteroatom, and n and o are independently selected from 0, 1, 2 or 3.

Yet a further aspect of the present invention relates to compounds of Formula (II) as defined above, prepared by the methods described herein.

As used herein the term "alkyl", denotes straight chain, branched or cyclic fully saturated hydrocarbon residues. Unless the number of carbon atoms is specified the term preferably refers to CI- 20 alkyl or cycloalkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, secamyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2,-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methoxyhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethyl-pentyl, 1,2,3,trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 6- or 7-methyl-octyl, 1-, 4- or 5-ethylheptyl, 2- or 3-propyihexyl, decyl, 7- and 8methylnonyl, 5- or 6-ethyloctyl, 3- or 4-propylheptyl, undecyl, 2- S3-, 8- or 9-methyldecyl, 6- or 7-ethylnonyl, 4or 5-propylocytl, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 7-, or 0- e 7 or 8-e tdecy, 2, 5- or 6-propylnonyl, 3- or 4-butyloctyl, 1-2-pentylheptyl and the like. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.

As used herein the term "alkenyl" denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon-carbon double bond including SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AU99/00516 -6ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined. Unless the number of carbon atoms is specified the term preferably refers to

C

1 2 0 alkenyl. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, isobutenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1-4,pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7cyclooctatetraenyl.

As used herein the term "alkynyl" denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon-carbon triple bond including ethynically mono-, di- or poly- unsaturated alkyl or cycloalkyl groups as previously defined. Unless the number of carbon atoms is specified the term preferably refers to C 1 20 alkynyl. Examples include ethynyl, 1-propynyl, 2-propynyl, and butynyl isomers, and pentynyl isomers.

The terms "alkoxy, "alkenoxy and "alkynoxy respectively denote alkyl, alkenyl and alkynyl groups as hereinbefore defined when linked by oxygen.

The term "halogen" denotes fluorine, chlorine, bromine or iodine.

The term "aryl" denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbon ring systems. Examples of aryl include phenyl, biphenyl, terphenyl, quaterphenyi, naphthyi, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, idenyl, azulenyl, chrysenyl.

The term "heterocyclic" denotes mono- or polycarbocyclic groups, including aryl, wherein at least one carbon atom is replaced by a heteroatom, preferably selected from nitrogen, sulphur and oxygen. Where the mono- or polycarbocyclic group which has at SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AU99/00516 WO 99/67250PCT/AU99/00f51 6 -7least one carbon atom replaced by a heteroatom is an aryl group, this is referred to as a aromatic heterocyclic group.

Suitable heterocyclic groups include N-containing heterocyclic groups, such as, unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl or piperazinyl; condensed saturated or unsaturated heterocyclic groups containing 1 to 5 nitrogen atoms, such as, indolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoindolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, purinyl, quinazolinyl, quinoxalinyl, phenanthradinyl, phenathrolinyl, phthalazinyl, naphthyridinyl, cinnolinyl, pteridinyl, perimidinyl or tetrazolopyridazinyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 3 oxygen atoms, such as tetrahydrofuranyl, tetrahydropyranyl, tetrahydrodioxinyl, unsaturated 3 to 6-membered hetermonocyclic group containing an oxygen atom, such as, pyranyl, dioxinyl or furyl; condensed saturated or unsaturated heterocyclic groups containing 1 to 3 oxygen atoms, such as benzofuranyl, chromenyl or xanthenyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms, such as, thienyl or dithiolyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, oxazolyl, oxazolinyl, isoxazolyl, furazanyl or oxadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms andl 1 to 3 nitrogen atoms, such as, morpholinyl; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolyl, thiazolinyl or thiadiazoyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AU99/00516 -8to 3 nitrogen atoms, such as, thiazolidinyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolyl.

The term "acyl" refers to a carboxylic acid residue wherein the OH is replaced with a residue, for example, as defined for W, X, and Y and specifically may denote carbamoyl, aliphatic acyl group or acyl group containing an aromatic ring, which is referred to as aromatic acyl or a heterocyclic ring, which is referred to as heterocyclic acyl, preferably

C

1 2 0 acyl. Examples of suitable acyl include carbamoyl; straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl and heptyloxycarbonyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; ailcylsulfonyl such as methylsulfonyl and ethylsulfonyl; alkoxysulfonyl such as methoxysulfonyl and ethoxysulfonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl phenylacetyl, phenyipropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenyihexanoyl) and naphthylalkanoyl naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl]; aralkenoyl such as phenylalkenoyl phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g.

naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aralkoxycarbonyl such as phenylalkoxycarbonyl benzyloxycarbonyl); aryloxycarbonyl such as phenoxycarbonyl and napthyioxycarbonyi; aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; aryithiocarbamoyl such as phenyithiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and napthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienyipropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AU99/00516 -9heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolylglyoxyloyl and thienylglyoxyloyl.

The term "acyloxy" refers to acyl, as herein before defined, when linked by oxygen.

In this specification "optionally substituted" is taken to mean that a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy mercapto, alkylthio, benzylthio, acylthio, cyano, nitro sulfate and phosphate groups. The term "optionally protected" is taken to mean that a group such as a hydroxy group may or may not be protected by a protecting group. Suitable protecting groups are known and examples thereof are described in Protective Groups in Organic Synthesis, by T.W. Greene, (1981), John Wiley Son.

As used herein, "heteroatom" refers to any atom other than a carbon atom which may be a member of a cyclic organic compound. Examples of suitable heteroatoms include nitrogen, oxygen, sulfur, phosphorous, boron, silicon, arsenic, sellenium and telluruim, especially nitrogen, oxygen and sulfur.

In preferred embodiments of compounds of Formulae and U, as defined in Z, is selected from one of CH 2 NH, oxygen or sulfur. More preferably U is NH or oxygen.

Most preferably, U is oxygen. In another preferred embodiment of Z, n o 1, 2, 3 or 4. Suitable examples of Z include -O-CH 2

-CH

2

-O-CH

2

-(CH

2 3

-CH

2

NH-CH

2 or -CH 2

-O-CH

2 In another preferred embodiment, n and o are both zero.

SUBSTITUTE SHEET (Rule 26) (RO/AU) wA 00/471so Dd'rTi/A Tnn/AIC1 In another preferred form, V is hydrogen, iodine or bromine.

In other embodiments of Formulae and when W and X, together with the nitrogen and carbon atoms to which they are attached, form a saturated or unsaturated heterocyclic group, the group is preferably optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted dihydroquinolinyl, optionally substituted dihydroisoquinolinyl, optionally substituted pyridyl or dihydro or tetrahydro congeners thereof, or optionally substituted phenanthridine. Preferably, W and X together with the nitrogen and carbon atoms to which they are attached, form an optionally substituted isoquinolinyl or optionally substituted dihydroisoquinolinyl group of general Formula

R

3 I I I (i)

R

2

R'

wherein R 1

R

4 and R 1 4 are as defined for Y above, and represents an optional double bond.

Preferably R 1

R

4 of Formula are hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester, wherein the ester is preferably methyl, ethyl, propyl or butyl ester; optionally substituted amino,; carboxamido, wherein the nitrogen atom thereof is optionally substituted by one or two alkyl groups independently selected from methyl, ethyl, propyi or butyl; or sulfate. Most preferably they are hydrogen, hydroxy, methoxy, ethoxy, iso-propoxy, methyl, ethyl, propyl, acetoxy or sulfate. Preferably R 14 is hydrogen or hydroxy.

In yet other embodiments of Compounds of Formulae and when RARA2C-

CRA

3

RA

4 form an aryl group or an aromatic heterocyclic group, it may be an optionally substituted benzene or naphthalene ring or an optionally substituted aromatic heterocyclic SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/A I i99/nnl 16 -11group such as pyridine, furan, pyrrole or thiophene and benzene-fused analogues thereof, for example, quinoline, indole, benzofuran and benzothiophene. Attachment of the bicyclic heterocyclic group may be via the benzene or heterocyclic ring. Preferably RA1RA2C-CRA 3

RA

4 forms an optionally substituted benzene group. Preferably the substituents are hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester, wherein the ester is preferably methyl, ethyl, propyl or butyl ester; optionally substituted amino,; carboxamido, wherein the nitrogen atom thereof is optionally substituted by one or two alkyl groups independently selected from methyl, ethyl, propyl or butyl; or sulfate. Most preferably they are hydrogen, hydroxy, methoxy, ethoxy, iso-propoxy, methyl, ethyl, propyl, acetoxy or sulfate.

In another embodiment RAl A 4 are preferably independently selected from hydrogen, optionally substituted alkyl, optionally protected hydroxy, optionally substituted alkoxy, optionally substituted phenyl or acyloxy. In one preferred embodiment, at least one of RAl or RA 3 may be hydrogen. In another embodiment, both R A 1 and R A 3 are hydrogen.

In yet a further emodiment, three or four of RA _A 4 are hydrogen.

In another embodiment, when R A2 and RA 3 together form a bond so as to form a group RA1C=CRA 4 RAl and RA 4 each may be independently selected from hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester, wherein the ester is preferably methyl, ethyl, propyl or butyl ester; optionally substituted amin or; carboxamido, wherein the nitrogen atom thereof is optionally substituted by one or two alkyl groups independently selected from methyl, ethyl, propyl or butyl. In especially preferred forms, one or both of RAl and RA 4 are hydrogen.

L.)

When R A and RA 3 together with the carbons to which they are attached, form a carbocyclic or heterocyclic group as defined above, preferably they form a 3 to 8membered cyclic group, preferably 5 to 6-membered cyclic group. Preferably they form a cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, tetrahydrofuran, dihydrofuran, pyrrolidine, pyrroline, pyran, dihydrophyran, tetrahydropyran or piperidene group. Preferably, RAl and RA 4 are hydrogen.

SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AI I99/nl516 -12- In still yet a further embodiment, Y is preferably an optionally substituted phenyl group of Formula (ii):

R"

Rl°. .R 12 (ii) R9) R13 Wherein R 9

R

1 3 are as defined for R 1

R

4 and R 1 4 as described above.

More preferably, R 9

R

13 are hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester, wherein the ester is preferably methyl, ethyl, propyl or butyl ester; optionally substituted amino,; carboxamido, wherein the nitrogen atom thereof is optionally substituted by one or two alkyl groups independently selected from methyl, ethyl, propyl or butyl; or sulfate. Most preferably,

R

9

R

13 are selcted from hydrogen, hydroxy, methoxy, ethoxy, iso-propoxy, methyl, ethyl, n-propyl, isopropyl, acetoxy or sulphate.

Another preferred embodiment of Formula is a compound of Formula (Ia) where X is hydrogen and W is a group of the formula (iii); ,(CH2)m V\ (iii) RB4 RB1 DB3 D B 2 wherein V is hydrogen or halogen; RB -B 4 are correspondingly defined as for RAl-A 4 herein above; and m is selected from 1, 2, 3 or 4.

v SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AU99/00516 -13- Thus, in a preferred embodiment, the present invention relates to a method for the preparation of a compound of Formula (IIa):

RA

RA A 2

RA

3 RY R A4

RB

4 z (Ha)

R

6 100

RB

2 (CH2)m

R

B 1 comprising the step of performing two intramolecular cyclizations on a compound of Formula (Ia): RA2 Y. R> RA

RA

4 I(Ia)

(CH

2 )m O

R

B4

R

B 1

RB

3

RB

2 wherein: RA1-A4 Y, Z are as defined above;

RB-

B4 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano; or

RB

2 and RB 3 may optionally together form a bond and R A 1 and RA 4 are as defined above or together with the carbon atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic group; or

RB

2 and RB 3 together with the carbon atoms to which they are attached form an SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AU99/00516 -14optionally substituted saturated or unsaturated carbocyclic or heterocyclic group; or

RBIRB

2

C-CRB

3

RB

4 form an optionally substituted aryl group or aromatic heterocyclic group; and m is selected from 1, 2, 3 or 4.

Another preferred embodiment of the invention provides an intermediate compound of Formula (Ia) RAl Y K. RA 3 SR A4

Z

N

(Ia) S (CH 2 )m

R

B4

R

e

B

RB

3

RB

2 wherein: RAl-A 4

RBI-B

4 V, Y, Z and m are as defined above and optionally, one or more

(CH

2 groups of (CH 2 )m defined in formula (iii) may be optionally substituted by a group

R

1 4 as defined above.

In a preferred embodiment m is 1 or 2. Even more preferably m is 2.

In yet other embodiments of Compounds of Formulae (Ia) and when RB'RB 2

C-

CRB3R B4 form an aryl group or an aromatic heterocyclic group, it may be an optionally substituted benzene or naphthalene ring or an optionally substituted aromatic heterocyclic group such as pyridine, furan, pyrrole or thiophene and benzene-fused analogues thereof, for example, quinoline, indole, benzofuran and benzothiophene. Attachment of the bicyclic heterocyclic group may be via the benzene or heterocyclic ring. Preferably

RBIRB

2

C-CRB

3

RB

4 forms an optionally substituted benzene group. Where RB'RB 2

C-

CRB3RB 4 forms a benzene group (containing the substituent V) cyclization can afford a group of formula as described herein above. Preferably the substituents are hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester, wherein the ester is preferably methyl, ethyl, propyl or butyl ester; SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/A Io99/lnn6 optionally substituted amino,; carboxamido, wherein the nitrogen atom thereof is optionally substituted by one or two alkyl groups independently selected from methyl, ethyl, propyl or butyl; or sulfate. Most preferably they are hydrogen, hydroxy, methoxy, ethoxy, iso-propoxy, methyl, ethyl, propyl, acetoxy or sulfate.

In another embodiment RB 1 -B4 are preferably independently selected from hydrogen, optionally substituted alkyl, optionally protected hydroxy, optionally substituted alkoxy, optionally substituted phenyl or acyloxy. In one preferred embodiment, at least one of R' or RB 3 may be hydrogen. In another embodiment, both RBI and RB 3 are hydrogen.

In yet a further emodiment, three or four of RB 1 B4 are hydrogen.

In another embodiment, when RB 2 and RB 3 together form a bond so as to form a group

RB'C=CR

B4

RB

1 and RB 4 each may be independently selected from hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester, wherein the ester is preferably methyl, ethyl, propyl or butyl ester; optionally substituted amin or; carboxamido, wherein the nitrogen atom thereof is optionally substituted by one or two alkyl groups independently selected from methyl, ethyl, propyl or butyl. In especially preferred forms, one or both of RAl and RA 4 are hydrogen.

When RB 2 and RB 3 together with the carbons to which they are attached, form a carbocyclic or heterocyclic group as defined above, preferably they form a 3 to 8membered cyclic group, preferably 5 to 6-membered cyclic group. Preferably they form a cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, tetrahydrofuran, dihydrofuran, pyrrolidine, pyrroline, pyran, dihydrophyran, tetrahydropyran or piperidene group. Preferably, R B and RB4 are hydrogen.

SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AU99/00516 -16- Especially preferred compounds of Formula have the structure of Formula (Ib) below: R" R12

/R

6

R

1 o R R1R53 R 7

R

9

~R

R

4 (Ib)

R

3 N 0 R 14

R'

where R' R 1 4 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyan. Preferred R'

R

14 are selected from hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester, wherein the ester is preferably methyl, ethyl, propyl or butyl ester; optionally substituted amino, such as mono or dialkyl amino; carboxamido, wherein the nitrogen atom thereof is optionally substituted by one or two alkyl groups independently selected from methyl, ethyl, propyl or butyl; or sulfate.

More preferably R' R 13 are selected from hydrogen; hydroxy; optionally substituted alkyl, such as methyl, ethyl or propyl; optionally substituted alkyloxy such as methoxy, ethoxy, n-propoxy, iso-propoxy; acyloxy such as acetoxy; or sulfate and R14 is preferably hudrogen or hydroxy. V is as defined above, preferably hydrogen, iodine or bromine.

T

SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AU99/00516 -17- Thus a further preferred form of the invention provides a method of preparing a fused polycyclic pyrrole-containing compound of Formula (lib): (IIb) comprising the step of performing two cyclizations on a compound of Formula (Ib).

The intramolecular cyclizations of compounds of Formula preferably of Formula (la) or to form the polycyclic fused compounds of Formula preferably of Formula (Ia) or (IIb) can be carried out by any suitable means known to those skilled in the art.

Suitable methods are described below, however, any other method which will effect the desired cyclization also forms part of the present invention. It will be understood that the groupsV, W, X, Y, Z, R

A

-A

4

R

B B4 and R 1 14 are such that they do not interfere with the cyclization process.

Where V represents a hydrogen atom, an oxidative intramolecular cyclization process, such as those described by Black et al, Tetrahedron Lett., 1989, 30, 5807 and Kita et al, Chem. Commum, 1996, 1481, may be used to effect the cyclization.

SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AU99/00516 -18- Alternatively, when V is a halogen atom, the intramolecular cyclization may proceed via the generation of a suitable radical in an analogous manner to those described by Antonio et al, Can. J. Chem., 1994, 72, 15 and Moody et al, Tetrahedron Lett., 1995, 36, 9501.

Yet another method for intramolecularly cyclizing a compound of Formula when V is halogen, involves a Pd[0]-mediated cyclization. The intramolecular Pd[0]-catalyzed olefination of an organic halide (intramolecular Heck Reaction) is known to those skilled in the art and can be carried out by any suitable combination of reagents which will provide palladium in the zero state Suitable combinations of reagents for effecting Pd[0]-catalysed cyclization are described, for example, in Burwood et al, Tetrahedron Lett., 1995, 36, 9053; Desarbe et al, Heterocycles, 1995, 41, 1987; Harayoma et al, Chem. Pharm. Bull., 1997, 45, 1723; and Grigg et al, Tetrahedron, 1995, 50, 359.

Thus, in one embodiment of the invention, Pd[0]-catalysed cyclization of Formula may be effected by generating Pd[0] in situ by a combination of a Pd[I] reagent and a "ligand", and further providing a base for regeneration of the Pd[0] catalyst.

Suitable examples of a Pd[II]/Pd[0] reagent include, but are not limited to: Pd(OAc) 2 PdC1 2

(CH

3 CN)2, PdCl 2 (PPh 3 2 Pd(C 6

H

5

CN)

2 C1 2 Pd(dibenzylideneacetone) 3 Suitable examples of "ligand" providing reagents include, but are not limited to: PPh 3 P(o-tolyl) 3 1,3-bis[diphenylphosphino]propane and 1,3-bis[diphenylphosphino]ethane.

Suitable bases for regenerating Pd[0] from Pd[II], which is formed during the Pd[0]catalysed cyclization, include, but are not limited to; alkylamines, such as triethylamine and diisopropylethylamine; acetates, such as sodium acetate and potassium acetate; carbonates such as potassium carbonate, sodium carbonate, silver carbonate; and hydroxides such as sodium and potassium hydroxide.

SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PfT/A iTo/nncif -19- When a compound of Formula (Ia) or (Ib) is treated to effect a double cyclization, to form compounds of Formula (la) or the cyclizations may be effected by the radical, oxidative or Pd-mediated cyclization procedures as described above, and each cyclization may be effected in the same, similar or different manner.

Thus, in one embodiment, the two cyclizations may be performed sequentially, in any order, and may optionally employ different reagents and conditions, for example as described above. Optionally, after one cyclization, is performed, the mono-cyclized product may be isolated before being treated under suitable sonditions to perform the second intramolecular cyclization. In another form, the "double cyclization" may be effected in "one-pot", preferably under a single set of reaction conditions..

In a more preferred form, a compound of Formula preferably is made to undergo a "double cyclization" to form a compound of Formula preferably (lib), under Pd[0]-catalysed conditions.

In an even more preferred form, both cyclizations are effected in "one-pot" under a single set of reaction conditions.

The compounds of Formula (la) and (Ib) may be prepared, starting from a pyrrole core, by standard procedures known to the skilled addressee for effecting substitution of the carbon atoms of the pyrrole core, for example by electrophilic aromatic substitution or halogenating the pyrrole nucleus and effecting a substitution by Stille, Suzuki, or Negishi cross-coupling reactions with stannane, boronic acid or zinc compounds such as arylstannanes, aryl boronic acid and aryl zinc compounds. Substitution of the N-atom can be effected by standard procedures.

One suitable approach, although by no means limiting, is depicted below in Scheme 1 which is considered to be illustrative of suitable methods for substituting the pyrrole nucleus.

J.

SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/A ToQQ/nn~1 It will be understood that by use of the appropriate reagents in steps used to introduce the 4- substitution pattern of the pyrrole core, for example, the phenyl containing reagents used in steps, and wherein the phenyl moiety is further substituted as hereinbefore described, a range of substitution patterns and substituents may be introduced to form the intermediates amenable to the cyclization processes and the formation of the corresponding cyclized compounds.

SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PrT/A11jGQ/nnC1f -21-

(C)

N N N H H H CC1 3 H CCI 3 H O 1,(d) 0 0 H 0 Brr (h)

OH

Br N' J 0 Scheme 1 Scheme 1: Reagents and conditions: C13CCOCI (1 mole equiv.), Et2O, 35 0 C, lh 12 (1 mole equiv.), AgO2CCF3 (1 mole equiv.), CHCI3, 18'C, Ilh K2C03 [9M in HM0), DMR0,I R 8 0 32 h (rif (r(VI I~ e-uV) ijj ~L) CH2Cl2, 18 0 C, 2 h; (ii) o-bromophenol (1 mole equiv.), DMAP CH42CI2, 18 0 1 h K2C03 (1.14 mole equiv.), Bu4NCI 1 mole equiv.), DMF, 80'C, 2 h PhZnC1 (1.3 mole equiv.), PdCI2(PPh3)2 (0.05 mole equiv.), THF/DMF, 18 0 C, 1 h Pd(OAc)2 (0.5 mole equiv.), PPh13 (I equiv.), NaOAc (4 equiv.), DMF, 130 0 C, 6 h TsCI (2.4 mole equiv.), KOH (2.4 mole equiv.), Et2O, 0618 0 C, 2 h SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AIO/flk1A -22- Where the optional double bond is present, as in the compounds of Formula (II) which contain moiety of Formula such as compounds of Formula (IIb), this may be introduced either by dehydrogenation of the cyclized product, or alternatively, by incorporation of the corresponding double bond into a precursor thereof. Suitable methods therefor will be known to the skilled addressee (see for example, Advanced Organic Chemistry, Reactions, Mechanisms, and Structure by Jerry March, Third Edition, Wiley Interscience). One such suitable method comprises treating the cyclized compound of Formula with DDQ (2,3-Dichloro-5,6-dicyano-l,4-benzoqionone).

For example, Lamellarin T diisopropylether (Compound 37 in Table 2) can be converted into Lamellarin W diisopropylether (Compound 11 in Table 1) by treatment with DDQ in dry chloroform at 60-65C (see Example 11 in W098/50365) WO 97/01336 the entire contents of which are taken to be incorporated herein by reference) describes Lamellarin class compounds as having inhibitory and/or cytotoxic activity against multidrug resistant-type tumours.

Accordingly, yet another aspect of the present invention contemplates a method of treatment comprising the administration of a treatment effective amount of a compound of general Formula as prepared by the methods described herein, as an active ingredient, to an animal, including a human, in need thereof.

As used herein, the term "effective amount" relates to an amount of compound which, when administered according to a desired dosing regimen, provides the desired therapeutic activity. The dose will depend on the age, weight and condition of the subject and it is within the skill of the attending physician to determine suitable doasages. Dosing may occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods. Suitable dosages lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage. Preferably, the dosage is in the range of 1 yg to 1 g per kg of body weight per dosage. More preferably, the dosage is in the range of 1 mg to 1 g per dosage per kg of body weight. Suitably, dosages are in the range of about I mg to 500 mg per kg of body weight, such as between 1 mg and 250 mg \f SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AU99/00516 -23or 1 mg and 100 mg.

In a preferred embodiment, the method of treatment relates to treating multidrug resistant tumors.

In another embodiment, the method of treatment contemplates improving the antitumor chemotherapeutic effect of multidrug resistant affected drugs.

In another preferred embodiment, the method of treatment is a method for inducing apoptosis. More preferably, the method of treatment is a method of inducing apoptosis on a multidrug resistant cell In another embodiment, the method of treatment contemplates modulating immunological functions.

The active ingredient may be administered in a single dose or a series of doses. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a composition, preferably as a pharmaceutical composition.

Yet another aspect of the invention contemplates compositions comprising a compound of general Formula as prepared according to the present invention, together with a pharmaceutically acceptable carrier, excipient or diluent.

The carrier must be pharmaceutically "acceptable" in the sense of being compatible with the other ingredients of the composition and not injurious to the subject. Compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parental (including subcutaneous, intramuscular, intravenous and intradermal) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared SUBSTITUTE SHEET (Rule 26) (RO/AU) W o/o//;"70n T ^ir rA rt/ nr« 24- rT. IAUYVuaiC by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.

Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g inert diluent, preservative disintegrant sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Compositions for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter.

SUBSTITUTE SHEET (Rule 26) (RO/AU) WO q0/i7250f D"Tr/AU in1 U IU Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bactericides and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Preferred unit dosage compositions are those containing a daily dose or unit, daily subdose, as herein above described, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the active ingredients particularly mentioned above, the compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine. Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring.

Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl SUBSTITUTE SHEET (Rule 26) (RO/AU) WO' o/6-720 T I A f«^ -26- rL IAUYlUIJ paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

The present invention also provides the use of a compound of general Formula as prepared according to the present invention, in the manufacture of a medicament for treatment of an animal or human in need thereof.

Another aspect of the invention contemplates an agent for the treatment of an animal or human in need thereof comprising a compound of general Formula as prepared according to the present invention.

In a first embodiment, the agent is for treating multidrug resistant tumors.

In another embodiment the agent is for inducing apoptosis on a multi-drug resistant cell.

In yet another embodiment, the agent is for improving the anti-tumour chemotherapeutic effect of multidrug resistant affected drugs.

A further embodiment is an agent for modulating immunological functions.

Suitable, although by no means limited, examples of compounds which may be prepared via the intermediates of the present invention are depicted below in Tables 1 and 2: SUBSTITUTE SHEET (Rule 26) (RO/AU) Table 1 Compound R 1

W

2 R R4 R' R7 R R" 0

R

1 R 12 19 R 13 1H H H H H H H H H H 2(Laniellarin B) OMe OMe OMe H OMe OH H OMe OH H 3(Lamellariin D) H OH OMe H OMe OH H OMe OH H 4(Laniellari D- H OAc OMe H OMe OAc H OMe OAc H triacetate) OH- OMe 1 0 H OMe OH H ome OH H 6(Lamellarini Mtriacetate) OAc IOMe IOMe I H OMe I OAc H OMe OAc Compound R 1 1 W R R4 R 6 R7 R 8 R'O R"1 R 12 7(Lamellarin. N) H OH OMe H OMe OH H OH OMe H H QAc OMe H OMe QAc H QAc OMe H 8(Laniellarin Ntriacetate)____ 9(Lamellariri W) OMe OMe OMe H OMe OH H OH OMe H 1O(Lamellarin X) OH OMe OMe H OMe OH H OH OMe H 11 OMe OMe OMe H OMe ,O'Pr H O'Pr OMe H Table 2.

0 Compound R 1

R

2 le R R' R 7

R

8

R

10 R" R 12 R 1 4 12 (Lamellarin A) OMe OMe OMe H OMe OH H OMe OH H OH 13 (Lamellarin C)1 OMe OMe OMe H OMe OH H OMe OH H H 14 (Lamellarin E) OH OMe OMe H OMe OH H OH OMe H H F) OH OMe OMe H OMe OH H OMe OMe H H (LamellarinG)I H OH OMe H OH OMe H OH OMe H H 17 (LamellarinHK) H OH OH HFOH OH H OH OH H jH Compound Ri 2 R R4 R 6 R~ 7R8 R 10 R"1 R' 2 R 1 4 OMe OMe OMe H OMe OH H OMe OMe H H 18 (Lamellarin I) 19 (Lamellarin I- OMe OMe OMe H OMe OAc H OMe OMe H H acetate) (Lamnellarin J) H OH OMe H OMe OH H OMe OMe H H 21 (Lamellarin K) OH OMe OMe H OMe OH H OMe OH H H 22 (Lamellarin OAc OMe OMe H OMe OAc H OMe OAc H H triacetate) 23 (Lamnellarin Li) H OH OMe H OMe OH H OH O0 e H H 24 (Lamellarin H OAc OMe H OMe OAc H OAc OMe H H triacetate)III (Lamellarin S) H OH OMe H OH OH H OH OH H H 26 (Lamellarin T) OMe -OMe OMe H OMe IOH H OH OMe H H Compound R 1 12 R R R 6 R7 R" 1110 R" R2 R 14 27 (Lamellarin OMe OMe OMe H OMe 0503 H OMe OH H H Na 28 H OMe OMe H H H H H H H H 29 (Lainellarin U) H OMe OMe H OMe OH H OH OMe H H (Lamnellarin H OMe OMe H OMe 0503 H OH OMe H H __Na 31 (Larnellarin V) OMe OMe OMe H OMe OH H OH OMe H OH 32 (Lamellarin OMe OMe OMe H OMe 0S0 3 H OH OMe H OH Na 33 (Lamellarin H OMe OH H OMe 0S0 3 H OH OMe H H Na 34 H OMe OMe H OMe O'Pr H OMe O'Pr H H H OMe OMe H OMe OH H OMe OH H H Compound R 1 R 2

R

3

R

4 R' R 7

R

8

R

10

R

12 R 1 4 Rs R 9 R1 36 O'Pr OMe OMe H OMe O'Pr H OMe O'Pr H H 37 OMe OMe, OMe H OMe O'Pr H O'Pr OMe H H- 38 H OMe OMe H OMe Q'Pr H O'Pr OMe H H 39 (Lamellarin T OMe OMe OMe H OMe OAc H GAc OMe H H diacetate)__ wO 9/67250 Tnr PIy A irh mn r W-33- A YYMuv iO The invention will now be described with reference to the following Examples. However, it is to be understood that these do not supercede the generality of the preceding description.

EXAMPLES

Example 1 2- (Trichloroacetyl)pyrrole 2-(Trichloroacetyl)pyrrole was prepared from pyrrole (12.5 g, 186 mmol) and trichloroacetyl chloride (36.5 g, 200 mmol) according to the method of Bailey et al, Org.Synth., 1971, 100.

In this manner the title compound (31.3 g, 80%) was obtained as a cream solid, m.p. 73-74 *C (lit. m.p. 73-75 OC). 'H n.m.r. d 9.30, broad s, 1H; 7.39, m, 1H; 7.17, m, 1H; 6.40, dt, J 3.9 and 2.4 Hz, 1H. (see also J. Org. Chem., 1972, 37, 3618; 1993, 58, 7245).

4-Iodo-2-(trichloroacetyl)pyrrole The title compound was prepared from 2-(trichloroacetyl)pyrrole according to the method of B6langer, Tetrahedron Lett., 1979, 2505. Thus, iodine (12.0 g, 47.2 mmol) was added portionwise (approximately 1 g per portion) over 0.17 h to a magnetically stirred mixture of silver trifluoroacetate (11.0 g, 49.8 mmol) and 2 -(trichloroacetyl)pyrrole (10.0 g, 47.1 mmol) in dry chloroform (70 ml) maintained at 0 *C (ice-bath). After addition was complete the reaction mixture was allowed to warm to 18 *C and stirred at this temperature for a further 2 h. The resultant suspension was filtered through a sintered glass funnel (No. 3 porosity) and the filtrate washed with Na 2

S

2 05 (1 x 80 ml of 5% w/v aqueous solution) and water (2 x 80 ml) then dried (MgSO 4 filtered and concentrated under reduced pressure. The solid residue thus obtained was treated with hexane/ether (50 ml of a 4:1 v/v mixture) and the resulting suspension stirred at 18 *C for 5 h then the solid was filtered off to give the title compound (13.1 g, 82%) as a cream solid, m.p. 129-130 OC (lit. m.p. 128-130 OC). 1 H n.m.r. d 9.45, broad s, 1H; 7.44, dd, J2.6 and 1.3 Hz, 1H; 7.19, dd, J2.6 and 1.3 Hz, 1H.

SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 -34- PCT/AU99/00516 4-Iodopyrrole-2-carboxylic acid

K

2 C0 3 (100 ml of a 2 M aqueous solution) was added to a solution of 4-iodo-2- (trichloroacetyl)pyrrole (8.5 g, 2.5 mmol) in dmso (30 ml) and the resulting mixture stirred at 18 *C for 3 h then diluted with H 2 0 (200 ml). The solution thus obtained was washed with ethyl acetate (2 x 100 ml) then acidified, by dropwise addition of HCl (2 M aqueous solution), to pH 3. The resulting slurry was extracted with ethyl acetate (3 x 100 ml) and the combined organic fractions were dried (MgSO), filtered and concentrated under reduced pressure to give the title compound (5.51 g, 92%) as a white solid, m.p. 200 *C (Found: M 236.9285. CsH 4 INO2 requires M 236.9287). nm (KBr) 3287, 3129, 3035, 1703, 1544, 1430, 1300, 1212, 1122 cm H n.m.r. [300 MHz, 3:1 (CD 3

)SO/CDCI

3 d 11.98, broad s, 1H; 6.98, t, J 1.5 Hz, 1H; 6.76, broadened s, 1H (resonance due to N-H not observed). 13 C n.m.r. [75.5 MHz, 3:1

(CD

3 2 SO/CDCI d 159.0 126.0 123.3 118.8 59.0 Mass spectrum m/z 237 (100%) 219 (87) H 2 2-Bromophenyl 4 -lodopyrrole-2-carboxylate Oxalyl chloride (203 mL, 2.32 mmol) was added to a magnetically stirred suspension of 4iodopyrrole-2-carboxylic acid (500 mg, 2.11 mmol) in dry CH 2

C

2 (15.0 ml) containing dmf (1 drop). After stirring the resulting solution at 18 *C for 2 h it was added to a magnetically stirred solution of o-bromophenol (363 mg, 2.11 mmol), triethylamine (660 ml, 4.73 mmol) and 4-(N,N-dimethylamino)pyridine (dmap, several crystals) in CH 2 Cl 2 (10 ml). After 1 h the reaction mixture was concentrated onto silica gel (5 g) and the residue subjected to flash chromatography (silica gel, 3:1 hexane/ether elution). Concentration of the appropriate fractions (Rf 0.2) then gave the title compound (761 mg, 92%) as a white crystalline solid, m.p. 126-127 OC (Found: C, 33.9; H, 1.7; Br, 20.4; I, 32.4; N, 4.0. C, 11 HBrINO 2 requires C, 33.7; H, 1.8; Br, 20.4; I, 32.4; N, nm (KBr) 3383, 2969, 1709, 1580, 1541, 1472, 1444, 1377, 1312, 1218, 1169, 1133, 1043 cm- 1 1H n.m.r. d 9.57, broad s, 1H; 7.65, dd, J 8.1 and Hz, 1H; 7.37, td, J 8.1 and 1.5 Hz, 1H; 7.27, m, 2H; 7.18, td, J 8.1 and 1.5 Hz, 1H; 7.08, m, 1H. 13 C n.m.r. d 158.0 148.3 134.0 129.8 129.1 128.1 (CH), 124.4 124.3 123.6 116.9 62.9 Mass spectrum m/z 393 391 (22) 220 (100) C6H 4 SUBSTITUTE SHEET (Rule 26) (RO/AU) 71 7 ff£ C I~ VVJ 7UU 35- PCT/AU99/00516 2-(2-Bromophenyl)ethyl 4 -Methylbenzenesulfonate (13) A magnetically stirred solution of 2-bromophenethyl alcohol (5.00 g, 24.9 mmol, ex ALDRICH) and 4-methylbenzenesulfonyl chloride (11.20 g, 59.7 mmol) in diethyl ether (50 ml) was cooled to 0 OC (ice-bath) then treated with powdered KOH (3.2 g, 2.4 mole equiv.). The reaction mixture thus obtained was allowed to warm to 18 stirred at this temperature for h then diluted with water (100 ml). The separated organic phase was washed with water (1 x 100 ml) then dried (MgSO), filtered and concentrated under reduced pressure to give a white solid.

Since this material contained residual 4 -methylbenzenesulfonyl chloride it was dissolved in pyridine (75 ml) and the resulting solution stirred at 18 °C for 0.16 h then diluted with water (500 ml) and extracted with diethyl ether (1 x 500 ml). The separated organic phase was washed with HC1 (1 x 250 ml of a 5 M aqueous solution) then sodium hydrogen carbonate (1 x 250 ml of a 0.5 M aqueous solution) before being dried (MgSO 4 filtered and concentrated under reduced pressure to give the title compound (8.66 g, 98%) as white crystalline masses, m.p.

39-39.5 OC (Found: C, 50.9; H, 4.2; Br, 22.6; S, 8.8. C 15

H

15 BrO 3 S requires C, 50.7; H, 4.3; Br, 22.5; S, n, (KBr) 1356, 1177, 1021, 980, 962, 895, 812, 769, 752, 665, 557 cm 1H n.m.r. d 7.68, d, J 8.3 Hz, 2H; 7.45, d, J 7.7 Hz, 1H; 7.27, d, J 8.3 Hz, 2H; 7.17, m, 2H; 7.07, m, 1H; 4.25, t, J 7.0 Hz, 2H; 3.09, t, J 7.0 Hz, 2H; 2.43, s, 3H. 13 C n.m.r. d 144.5 135.3 132.7 132.8 131.3 129.7 128.5 127.6 127.4 124.2 68.6 (CH 2 35.5 (CH2), 21.5 (CH 3 Mass spectrum m/z 356 354 184 (98) 182 (100) [M -H 3

CC

6

H

4

SO

3 171 (49) 169 155 103 91 (80) (C 7 2-Bromophenyl 1-[2 "-Bromophenyl)ethyl-4-iodopyrrole-2-carboxylate Compound (13) (700 mg, 1.97 mmol), tetraethyl ammonium chloride (30 mg, 0.18 mmol) and K 2 C0 3 (278 mg, 2.0 mmol) were added to a solution of compound (11) (700 mg, 1.79 mmol) in dry dmf (30 ml) and the resultant slurry stirred at 80 *C for 2 h. The cooled reaction mixture was diluted with ethyl acetate (150 ml) and washed with water (3 x 150 ml). The separated organic phase was then dried (MgSO 4 filtered and concentrated under reduced SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 -36- PCT/AU99/00516 pressure. The solid residue thus obtained was subjected to flash chromatography (silica gel, 4:1 hexane/ether elution) and concentration of the appropriate fractions (Rf 0.5, 3:1 hexane/ether elution) gave the title compound (14) (920 mg, 89%) as a white crystalline solid, m.p. 122-123 *C (Found: C, 39.5; H, 2.1; Br, 27.6; I, 22.1; N, 2.3. CI 9 H4Br 2

INO

2 requires C, 39.7; H, Br, 27.8; I, 22.1; N, na (KBr) 2949, 1716, 1517, 1468, 1438, 1411, 1374, 1326, 1232, 1216, 1191, 1055, 1028 cm 'H n.m.r. d 7.65, dd, J 7.8 and 1.8 Hz, 1H; 7.55, dd, J 7.8 and 1.8 Hz, 1H; 7.37, m, 2H; 7.28-7.04, m, 5H; 6.70, d, J 2.1 Hz, 1H; 4.55, t, J 7.5 Hz, 2H; 3.20, t, J 7.5 Hz, 2H. 3 C n.m.r. d 157.0 147.8 136.9 134.5 133.3 132.7 131.2 128.6 128.4 127.6 127.3 126.7 (CH), 124.4 124.0 122.0 116.6 59.6 49.0 (CH 2 38.0 Mass spectrum m/z 577 575 573 496 (10) 494 (11) 404 (98) 402 (100)

C

6

H

4 2-Bromophenyl "-Bromophenyl)ethyl]-4-phenylpyrrole-2-carboxylate (4) Phenylzinc chloride [prepared by the addition of anhydrous zinc chloride (540 mg, 3.96 mmol) to a solution of phenyllithium (2.0 ml of a 1.8 M solution in cyclohexane/ether, 3.6 mmol) in thf (4.0 ml)] was added dropwise, over 2 min., to a magnetically stirred solution of compound (14) (1.75 g, 3.04 mmol) and Pd(PPh 3 2

C

2 (106 mg, 0.152 mmol) in dmf (15 ml).

Stirring was continued at 18 °C for 1 h then the reaction mixture was transferred to a separatory funnel, diluted with ethyl acetate (100 ml) and washed with NH 4 CI (100 ml of a saturated aqueous solution) then H20 (2 x 100 ml). The separated organic phase was dried (MgSQ filtered and concentrated under reduced pressure to give light-yellow oil which was subjected to flash chromatography (silica, 2:1 hexane/CH 2 Cl 2 elution). Concentration of the appropriate fractions (Rf 0.5) gave the title compound (1.52 g, 95%) as a microcrystalline solid, m.p. 92 *C (Found: C, 57.1; H, 3.4; Br, 30.7; N, 2.5. C 2 5

HI

9 Br 2

NO

2 requires C, 57.2; H, 3.7; Br, 30.4; N, n, (KBr) 2958, 2930, 1718, 1603, 1580, 1562, 1472, 1397, 1215, 1196, 1066, 1024 cm- 1 1H n.m.r. d 7.70, dd, J 8.0 and 1.5 Hz, 1H; 7.60-7.00, m, 14H; 4.63, t, J 6.9 Hz, 2H; 3.32, t, J 6.9 Hz, 2H. 3 C n.m.r. (75.5 MHz, CDCI 3 d 158.4 148.3 137.5 134.2 133.5 132.9 131.5 128.9 128.6(3) 128.6(1) 127.8 127.4 127.3 126.5 125.4 124.8 124.6 SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 or-, ,llVll 124.4 120.9 117.5 (CHI), 116.9 49.3 (CH 2 38.2 (CH 2 Mass spectrum m/z 527 525 523 446 (12) 444 (11) -BriT 354 (100) 352 (96)

C

6

H

4 BrO-)].

14-Phenyl-8, 9-di/zydro-6H-[llbenzopyrano[4', 3':4,5SJpyrrolo[2 1-alisoqinolin-6-one Pd(OAc) 2 (32 mng, 0. 143 mmol) was added to a magnetically stirred solution of compound (148 mg, 0.282 mmol), NaOAc (92.7 mg, 1.13 nimol) and PPh 3 (74.0 mg, 0.282 mmol) in dnif (2 ml) contained in a Schienk tube. The resulting mixture was evacuated (1.0 mmHg) and back-filled with N 2 (gas) three times (to remove dissolved oxygen) then heated under nitrogen at 135 *C for 6 h. The cooled reaction mixture was diluted with ether (25 niL) and washed with brine (2 x 20 ml) then water (20 nil) before being dried (MgSO 4 filtered and concentrated onto silica (2 The residue was subjected to flash chromatography (silica, 1:2, 1:1 then 2:1

CH

2

CI

2 /hexane elution) and the appropriate fractions (Rf 0.3, 2:1 CH 2 Cl 2 /hexane elution) were concentrated under reduced pressure to give the title compound (16 mg, 16%) as a creamcoloured microcrystals, m.p. 259-260 C (Found: 363.1257.

C

25

H

7 N0 2 requires

M+-

363.1259). (KBr) 2925, 2853, 1708, 1449, 1420, 1396, 1339, 1281, 1241, 1198, 1151, 11 33, 1106, 1085, 1047 cnf'. 'H n.m.r. d 7.58-7.55, mn, 2H; 7.51-7.50, m, 2H; 7.40, dd, J and 0.9 Hz, 1H; 7.32-7.18, mn, 4H; 7. 10, dd, J 7.8 and 1.2 Hz, 1H; 7.01-6.97, mn, 3H; 4.88, t, J 6.9 Hz, 2H; 3.21, t, J 6.9 Hz, 2H. 1 3 C n.m.r. d 155.3 151.2 135.6 135.3 133.8 130.7 129.4 (CII), 128.3 (CHI), 128.1 (CII), 127.5 127.4 (CHI), 126.9 (CHI), 125.7 123.7 123.3 118.2 117.5 117.1 (CHI), 42.3 (CII), 29.3 (CH2) (three peaks obscured or overlapping). Mass spectrum m/z 363 (100%) 2 '-Bromophenyl S. 6-Dihydro-1 -phenylpyrrolo[2, 1-alisoquinoline-3-carboxylate (16) and Brono{2 6 "-dihydro-1 "-phenylpyrrolo[2 ",11"-aisoquinoline-3 "-carboxy)phenyl)bis (triphenylphosphine)palladium (1 7) Pd(OAc) 2 (197 mg, 0.88'mmol) was added to a solution of compound (230 mg, 0.438 mmol), NaQAc (80 mg, 0.975 nimol) and PPh 3 (460 mg, 1.75 nimol) in dmf (20 ml). The SUTBSTIUTE SHEET (Rule 26) (ROIAU) WO 99/67250 PrT/A I Qo/nnC1i 38solution was evacuated (1.0 mmHg) and back-filled with N 2 (gas) three times to remove dissolved oxygen and then heated under nitrogen at 110 °C for 19 h. The cooled reaction mixture was diluted with ethyl acetate (25 ml) then washed with brine (2 x 20 ml) and water (1 x 20 ml). The separated organic phase was then dried (MgSO 4 filtered and concentrated under reduced pressure onto silica (2 Subjection of the resulting material to flash chromatography (silica, 1:2 then 1:1 CH 2 Cl 2 /hexane followed by 4:1 CH 2 C 2 /ethyl acetate elution) gave two fractions, A and B.

Concentration of fraction A (Rf0.6, 2:1 CH 2

C

2 /hexane elution) afforded compound (16) (34 mg, 17%) as off-white crystalline masses, m.p. 130-131 *C (Found: M 443.0529.

1 79BrNO 2 requires M 443.0521). n, (KBr) 2950, 1710, 1471, 1439, 1418, 1240, 1212, 1176, 1046 cm i 1 H n.m.r. d 7.57, dd, J 8.1 and 1.5 Hz, 1H; 7.45-7.05, m, 12H; 6.95, br t, J 8.1 Hz, 1H; 4.57, t, J 6.3 Hz, 2H; 3.05, t, J 6.3 Hz, 2H. 13 C n.m.r. d 158.5 148.1 136.1 133.4 133.3 132.9 129.1 128.6 128.4 (CH), 128.1 127.9 127.7 127.1 126.9 126.7 125.5 124.2 123.5 121.3 119.4 116.7 42.4 (CH 2 29.5 (CH 2 Mass spectrum m/z 445 443 272 (100) C 6

H

4 BrO-)].

Concentration of fraction B (Rf 0.1, CH 2 Cl 2 elution) afforded compound (17) (40 mg, as off-white crystalline masses, m. p. 159-162 n, (KBr) 3052, 2923, 1705, 1481, 1435, 1416, 1238, 1172, 1095, 1058, 1024 cm 1 7. 1H n.m.r. d 7.65-7.40, m, 18H; 7.30-7.05, m, 22H; 6.58, m, 1H; 6.52, t, J 6.6 Hz, 1H; 6.39, m, 1H; 6.07, q, J 6.6 Hz, 1H; 4.73, m, 2H; 3.05, m, 2H. 13C n.m.r. d 159.2 151.8 138.3 136.5 134.8 133.2 131.8 131.5 131.0 129.9 129.8 129.5 129.0 128.7 127.8 127.5 127.2 127.0 125.7 125.0 123.2 123.0 121.9 121.1 120.5 42.2 29.7 Mass spectrum m/z 365 (6) -Pd(PPh 3) 2Br 277 272 (32) C 6 H 4 0Pd(PPh 3) 2 BrI 262 (100) (Ph 3

P

1-Phenylpyrrolo[2,1-a]isoquinoline (18) and "-Bromophenyl)ethyl]-4-phenylpyrrole (19) A solution of the dibromide (13 mg, 25 mmol), trans-di(m-acetato)-bis[o-(di-otolylphosphino)benzyl]dipalladium(II) Chem., Eur., 1997, 3, 1357, (2.5 mg, 2.5 mmol) and SUBSTITUTE SHEET (Rule 26) (RO/AU) P:\OPER\MJC45907-99 sp.ci.doc-27Ai902 -39anhydrous sodium acetate 6.2 mg, 75 mmol) in degassed N,N-dimethylacetamide (0.25 ml) was heated, under nitrogen, at 140 °C for 72 h. The cooled reaction mixture was then diluted with diethyl ether (5 ml) and the resulting solution washed with brine/water (3 x ml of a 1:1 v/v mixture). The organic phase was then dried (MgS04), filtered and concentrated under reduced pressure to give a light-yellow oil. Subjection of this material to flash chromatography (silica, 3:7 then 7:3 CH 2 Cl 2 /hexane elution) gave, after concentration of the appropriate fractions (Rf 0.7, 3:7 CH 2 Cl 2 /hexane elution), a 1:3 mixture of compounds (18) and (19) (4 mg, 52% combined yield) as a light-yellow and unstable oil. (KBr) 1705, 41.2, 1555, 1500, 1471, 1441, 1359, 1202, 1071, 1027, 751, 694, 655 cm 1 'H n.m.r. d [compound 7.60-6.95, complex m, 9H; 6.92, t, J 2.0 H, S: 1H, H-2; 6.63, t, J1.6 Hz, 1H, H-5; 6.43, broadened t, J2.3 Hz, 1H, H-4; 4.14, t, J7.7 Hz, 2H; 3.22, t, J 7.7 Hz, 2H; [compound 7.60-6.95, complex m, 9H; 6.73, d, J 2.7 Hz, 1H, H-3; 6.23, d, J2.7 Hz, 1H, H-2; 4.08, t, J7.7 Hz, 2H; 3.10, t, J7.7 Hz, 2H. G.c./m.s.

[compound (Rt 4.52 min.) 245 (100) 167 149 120 [compound 5.85 min.) 327 (12) 325 (12) 246 (100) The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variants and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more S of said steps or features.

Claims (42)

1. A method for the preparation of a compound of Formula (II) A1 R A 2 R A3 RY RA 4 z X N I 0 w (II) 5 comprising the step of performing an intramolecular cyclization of a compound of Formula SA1 /R A2 R R A 3 V RA4 z x oN W O optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, 1 optionally substituted alylthi, halogen, nit, sulfate, nhosphate and cyano; or RA2 and RA3 may optionally together form a bond and RA and RA 4 are as defined above or together with the carbon atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic group; or RA2 and RA 3 together with the carbon atoms to which they are attached form an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group; or RAIRA2C-CRA3RA 4 forms an optionally substituted aryl group or aromatic heterocyclic group; WO 99/67250 PCT/AU99/00516 -41- Y is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano; W and X are as defined for Y, or together with the nitrogen and carbon atoms to which they are attached, form a saturated or unsaturated nitrogen containing heterocyclic group which may be optionally substituted or optionally fused to a saturated or unsaturated carbocyclic group, aryl group or heterocyclic group; V represents a halogen or hydrogen atom; Z is -(CH 2 )n-U-(CH 2 o where U is selected from CH2, NH or a heteroatom, and n and o are independently selected from 0, 1, 2 or 3.

2. A method according to claim 1 wherein W and X together with the nitrogen and carbon atoms to which they are attached, form a saturated or unsaturated nitrogen containing heterocyclic group which may be optionally substituted or optionally fused to a saturated or unsaturated carbocyclic group, aryl group or heterocyclic group.

3. A method according to claim 2 wherein W and X, together with the nitrogen and carbon atoms to which they are attached, form a group selected from an optionally substituted quinolinyl group, optionally substituted isoquinolinyl group, optionally substituted dihydroquinolinyl group, optionally substituted dihydroisoquinolinyl group, optionally substituted pyridyl group or dihydro or tetrahydro congeners thereof, or optionally substituted phenanthridine.

4. A method according to claim 3 wherein W and X together with the nitrogen and SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AU99/00516 -42- carbon atoms to which they are attached, form an optionally substituted isoquinolinyl or optionally substituted dihydroisoquinolinyl group of general Formula R 4 R3 (i) R2 R14 R 1 wherein R 1 R 4 and R 1 4 are as defined for Y in claim 1, and represents an optional double bond.

A method according to claim 4 wherein R L R 4 are independently selected from the group consisting of hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester; optionally substituted amino; carboxamido; or sulfate; and R 1 4 is hydrogen or hydroxy.

6. A method for the preparation of a compound of Formula (Ia): RA2 RA1 RA 3 RA 4 RB 4 N R 9 3 I t RB 2 (CH2)m (Ha) RB 1 comprising the step of performing two intramolecular cyclizations on a compound of Formula (Ia): SUBSTITUTE SHEET (Rule 26) (RO/AU) P:OPERW4JCU 5907-99 spi.doc-27A)9/2 -43- S RA/ R A So B3 R 2 RB4 RB 1 RB RB 2 (Ia) wherein: R A A 4 V, Y, Z are as defined in claim 1; RB-B4 are each independently selected from hydrogen, optionally substituted alkyl, 5 optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano; or RB 2 and RB 3 may optionally together form a bond and RAl and RA 4 are as defined above or together with the carbon atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic group; or RB 2 and R B 3 together with the carbon atoms to which they are attached form an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group; or RBIRB 2 C-CRB 3 RB 4 form an optionally substituted aryl group or aromatic heterocyclic group; and m is selected from 1, 2, 3 or 4.

7. A method according to claim 6 wherein m is 1 or 2.

8. A method according to claim 1 or claim 6 wherein RARA 2 C-CRA3RA 4 forms an aryl group or an aromatic heterocyclic group, said group selected from: an optionally substituted benzene or naphthalene ring or an optionally substituted pyridine, optionally RA/ substituted furan, optionally substituted pyrrole or optionally substituted thiophene and benzene-fused analogues thereof. WO 99/67250 PrT/A I -44-

9. A method according to claim 8 wherein RAIRA2C-CRA 3 RA 4 forms an optionally substituted benzene group.

A method according to claim 9 wherein the substituents are selected from: hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester; optionally substituted amino; carboxamido; or sulfate.

11. A method according to claim 1 or 6 wherein Y is an optionally substituted phenyl group of Formula (ii): R11 R R 12 Wherein R 9 R 13 are as defined for R 1 R 4 in claim 4.

12. A method according to claim 11 wherein R 9 R 13 are independently selected from hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester; optionally substituted amino; carboxamido; or sulfate.

13. A method according to claim 10 wherein R 9 R 13 are independently selected from hydrogen, hydroxy, methoxy, ethoxy, iso-propoxy, methyl, ethyl, n-propyl, isopropyl, acetoxy or sulphate.

14. A method of preparing a fused polycyclic pyrrole-containing compound of Formula (lib): SUBSTITUTE SHEET (Rule 26) (RO/AU) WO 99/67250 PCT/AU99/00516 (IIb) comprising the step of performing two intramolecular cyclizations on a compound of Formula (Ib): R1" R 12 R 6 R 1 R 13 R 5 R 7 R 4 (Ib) 1,, R2/ R14 R 1 wherein V is halogen or hydrogen and R 1 R 14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, SUBSTITUTE SHEET (Rule 26) (RO/AU) P:\OPER\MJC\45907-99 spcci.doc-27M9)2 -46 carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano; and optionally dehydrogenating the cyclized product to form a compound of Formula (Ib) wherein the optional double bond is present.

A method according to claim 14 wherein R' R 14 are independently selected from: hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester; optionally substituted amino; carboxamido; or sulfate. *o

16. A method according to claim 14 wherein R R 3 are independently selected from hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; or sulfate and R 14 is hydrogen or hydroxy. 15

17. A method according to any one of claims 14 to 16 wherein V is bromine, iodine or hydrogen.

18. A method according to claim 1 or 6 wherein U, as defined in Z, is selected from one of CH 2 NH or oxygen.

19. A method according to claim 18 wherein U is oxygen.

A method according to claim 18 or 19 wherein n o 0, 1, 2, 3 or 4.

21. A method according to claim 20 wherein n o 0.

22. A method according to claim 1 or 6 or 14 wherein each V is independently hydrogen, bromine or iodine.

23. A method according to claim 1 wherein V is hydrogen, and the cyclization occurs under oxidative conditions. P:\OPER\MJC4I5907.-99 speci.doc-27M9A112 -47-

24. A method according to claim 1 wherein V is a halogen atom and the cyclization occurs via the generation of a radical of Formula

25. A method according to claim 1 wherein V is a halogen atom and the cyclization occurs via a Pd[0]-catalyzed process.

26. A method according to claim 6 or claim 14 wherein both V are halogen and the two cyclizations are performed in one pot. 0

27. A method according to any one of claims 24 to 26 wherein V is bromine or iodine.

28. A method according to claim 27 wherein the one pot double cyclization is Pd[0]- catalyzed. **CC C C* C. C C C C C.* C. C CCC. C CC.. C C C

29. A method according to claim 6 wherein m is 2.

30. A compound of Formula RA 3 wherein: R A -A4 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally 2 substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, P:\OPER\MJC\45907-99 spci.doc-27A)9A2 -48- optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano; or R A2 and RA may optionally together from a bond and R Al and RA 4 are as defined above or together with the carbon atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic group; or R A2 and RA, together with the carbon atoms to which they are attached form an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group; or RAIRAC-CRRA 4 forms an optionally substituted aryl group or aromatic heterocyclic group; Y is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted hererocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano; W and X together with the nitrogen and carbon atoms to which they are attached, form a saturated or unsaturated nitrogen containing heterocyclic group which may be optionally substituted or optionally fused to a saturated or unsaturated carbocyclic group, aryl group or heterocyclic group; V represents a halogen or hydrogen atom. Z is -(CH 2 )n-U-(CH 2 where U is selected from CH2, NH or a heteroatom, and n and o are independently selected from 0, 1, 2 or 3. P:\OPERUMJC45907-99 speci.doc-27D9/2 -49-

31. A compound of Formula (Ia): /V N I o V (CH 2 )m RB4 BR RB3 R B 2 oo 0 9 eeee *ee e ee eeee eeee ee eeee eeee ee wherein RAI-A 4 RBI-B 4 V, Y, Z and m are as defined in claim 6.

32. A compound according to claim 30 or 31 wherein RA-R C-CRA3RA 4 forms an optionally substituted benzene group.

33. A compound of Formula (Ib): K (Ib) wherein RAI-A 1 4 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano; and P:\OPER\MJC\45907-99 speci.doc-27I9Ai2 V is halogen or hydrogen.

34. A compound according to claim 33 wherein R' R 1 4 are independently selected from: hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester; optionally substituted amino; carboxamido; or sulfate.

35. A compound according to claim 33 wherein R' R 1 3 are independently selected 10 from hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; or sulfate and R' 4 is hydrogen or hydroxy.

36. A compound according to any one of claims 32 to 34 wherein V is bromine, iodine or hydrogen.

37. A method for the treatment of multidrug resistant tumours comprising the administration of a treatment effective amount of a compound of Formula (IIa) or (IIb), according to any one of claims 1, 6 or 14 as prepared by the methods described herein, to an animal, including a human, in need thereof.

38. Use of a compound of Formula (IIa), (IIb), according to any one of claims 1, 6 or 14 as prepared by the methods described herein, in the manufacture of a medicament for the treatment of multidrug resistant tumour.

39. An agent for treating multidrug resistant tumours comprising a compound of Formula (IIa), or (IIb), according to any one of claims 1, 6 or 14 as prepared by the methods described herein.

A composition for treating multidrug resistant tumours comprising a compound of Formula (IIa), or (lib), according to any one of claims 1, 6 or 14 as prepared by the methods described herein, together with a pharmaceutically acceptable P:\OPER\MJC45)7-99 speci.doc-27/09A)2 -51 carrier, diluent or excipient.

41. A method according to claim 1 substantially as hereinbefore described.

42. A compound according to claim 30 substantially as hereinbefore described. DATED this 2 7 th day of September 2002 10 THE AUSTRALIAN NATIONAL UNIVERSITY By DAVIES COLLISON CAVE Patent Attorneys for the Applicant *o g*