Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-01
2003-02-18
Aulakh, Charanjit S. (Department: 1627)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S062000, C546S139000, C514S283000, C514S285000
Reexamination Certificate
active
06521757
ABSTRACT:
FIELD OF THE INVENTION
The present invention is generally directed to a method for preparing compounds useful in therapy. More particularly, the present invention provides a method for preparing a class of fused polycyclic alkaloids as well as novel compounds obtained thereby, pharmaceutical compositions containing them and methods of treatment using them.
BACKGROUND OF THE INVENTION
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 polyaromatic framework. Lamellarins C and D have been shown to cause inhibition of cell division in a fertilised sea urchin assay, whereas Lamellarins I, K and L all exhibit comparable and significant cytotoxicity 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. Steglich & coworkers, in
Angew. Chem. Int. Ed. Eng.
1997, 36, 155, have described a biomimetic sequence for the synthesis of Lamellarin G trimethyl ether, however, the process is limited in that it lacks regiochemical control and does not readily lend itself to the specific substitution patterns dictated by the natural products. There is a need, therefore, for a synthetic process which enables the production of the Lamellarins and analogues thereof.
SUMMARY OF THE INVENTION
Throughout this specification, 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 group of integers but not the exclusion of any other integer or group of integers.
In a first aspect, the present invention contemplates a method for the preparation of a compound of general Formula (I):
comprising the step of cyclizing an azomethine ylide of general Formula (II):
wherein,
A is a cyclic group being an optionally substituted aryl group or an aromatic heterocyclic group; or
A is a cyclic group R
A1
R
A2
C—CR
A3
R
A4
wherein 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 and R
A1
and R
A4
are as defined below or together form a bond; or
A is a non-cyclic group R
A1
R
A2
C—CR
A3
R
A4
wherein R
A1
-R
A4
are as defined below and R
A2
and R
A3
may optionally together form a bond;
Z is a carbon or a heteroatom;
n is selected from 0, 1, 2 or 3; and
R
A1-A4
, W, X and Y may be the same or different and each are 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 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; or pharmaceutically acceptable derivatives and salts, racemates, isomers and/or tautomers thereof.
Another aspect of the invention contemplates a compound of Formula (I) prepared by the methods as described herein.
Yet another aspect of the invention relates to novel compounds of general Formula (I)
wherein A, Z, W, X, Y and n are as defined above, provided the compound is not Lamellarin A-N, S-X;
T, U, V or Y 20-sulfate; or D, K, L, M or N-triacetate; G-trimethyl ether; or I-acetate; as herein described.
Still yet another aspect of the present invention relates to a method of treating multidrug resistant tumours comprising the administration of an effective amount of a compound of Formula (I).
A further aspect of the invention provides compositions comprising a compound of Formula (I) together with a pharmaceutically acceptable carrier, excipient or diluent.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The azomethine ylides of general Formula (II) are obtainable from corresponding precursors by methods known to those skilled in the art, for example as described by A. Padwa et al, in
Chem Rev.,
1996, 96, (1), 241 and V. P. Litvinov,
Russian Journal of Organic Chemistry,
Vol. 31 (No. 10), 1995, pp. 1301-1340. A particularly suitable means of generating the azomethine ylide of general Formula (II) is effected by the addition of a base to a compound of Formula (III).
wherein the counter ion L
⊖
is a stable, weakly basic anion.
Suitable anions include those derived from the sulfonates, such as, tosylate, mesylate, triflate, bosylate, besylate, tresylate, nonaflate and nosylate and the halogens, especially chlorine and bromine and iodine. Preferably L
⊖
is bromide or iodide.
In a preferred embodiment, the present invention provides a method for the preparation of a compound of Formula (Ia):
comprising the step of cyclizing an azomethine ylide of general Formula (IIa):
wherein R
1
-R
8
and R
14
are as defined for W, X and Y as described above.
Preferably, the azomethine ylide of Formula (IIa) is generated by the addition of a base to a compound of general Formula (IIIa):
wherein R
1
-R
8
, R
14
, Y, Z, n and L
⊖
are as hereinbefore described.
Suitable bases for generating the azomethine ylide of Formula (II) include those derived from alkali metals such as phenyllithium, butyllithium, KNH
2
and NaNH
2
; metal carbonates such as potassium carbonate, lithium carbonate, sodium carbonate and cesium carbonate; as well as amines. In preference, the base used is a mono-, di- or tri-substituted amine, more preferably an alkylamine. Most preferably the base is triethylamine or diisopropylethylamine.
Cyclization of the azomethine ylide may be effected by any suitable means, such as thermal treatment or treatment with metal salts, preferably Cu(I) salts such as CuI. Preferably cyclization is effected by thermal treatment, such as by heating in optionally boiling solvent. Suitable solvents include tetrahydrofuran, chloroform and 1,2-dichloroethane.
In a further preferred aspect, the cyclization of a compound of Formula (II), is followed by oxidative treatment. Oxidative treatment may be performed by means known to and routinely carried out by those skilled in the art. Particularly suitable means include direct oxidation in air, optionally in the presence of silica gel; treatment with Fremy's salt; treatment with quinones such as chloranil or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), and treatment with metal catalysts such as platinum, palladium and nickel. Preferably the oxidative treatment is effected by DDQ or silica gel in air or Fremy's salt. When L
⊖
of compounds of Formula (III) is iodide, oxidation is promoted.
In a preferred embodiment, a compound of general Formula (I) is prepared by treating a compound of general Formula (III) with triethylamine or diisopropylamine followed by thermally induced cyclization and subsequent oxidative treatment with DDQ or silica gel in air. In a more preferred embodiment a compound of general Formula (Ia) is prepared by treating a compound of general Formula (IIIa) wit
Banwell Martin Gerhardt
Flynn Bernard Luke
Aulakh Charanjit S.
Greenlee Winner and Sullivan P.C.
The Australian National University
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