Syntheses of a variety of lamellarin compounds and analogues

Details Syntheses of a variety of lamellarin compounds and analogues Syntheses of a variety of lamellarin compounds and analogues

2001-02-02

2002-10-22

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S056000, C546S081000, C546S084000, C546S113000, C548S418000, C548S427000, C548S430000, C548S432000, C548S532000

Reexamination Certificate

active

06469171

ABSTRACT:

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 Lamellanins 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 a 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 (II).
comprising the step performing an intramolecular cyclization of a compound of Formula (I):
wherein:
R
A1-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 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 R
A1
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 R
A3
, together with the carbon atoms to which they are attached form an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group; or
R
A1
R
A2
C—CR
A3
R
A4
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
)
o
— where U is selected from CH
2
, 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 (II), wherein said intermediate is of Formula (I):
wherein:
R
A1-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 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 R
A1
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 R
A3
, together with the carbon atoms to which they are attached form an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group; or
R
A1
R
A2
C—CR
A3
R
A4
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
)
o
— where U is selected from CH
2
, 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 C
1-20
alkyl or cycloalkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 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, 4,4-dimethylpentyl, 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, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-methyl-octyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2

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