Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-03
2003-01-14
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S292000, C549S293000, C564S161000, C564S164000, C564S192000, C564S193000, C564S197000
Reexamination Certificate
active
06506910
ABSTRACT:
The invention relates to a process for preparing discodermolide and analogues thereof, to novel compounds utilized in the process and to novel compounds prepared by the process.
FIELD OF INVENTION
The present invention relates to the area of synthetic methodology and, more particularly, to a process for preparing discodermolide and analogues thereof.
BACKGROUND OF THE INVENTION
(+)-Discodermolide is a novel polyketide natural product that was isolated from extracts of the marine sponge
Discodernolide dissoluta
by researchers at the Harbor Branch Oceanographic Institution (HBOI) (Gunasekera S P, Gunasekera M, Longley R E, Schulte G K. Discodermolide: a new bioactive polyhydroxylated lactone from the marine sponge
Discodernia dissolute
. [published erratum appears in J. Org. Chem. 1991;56:1346]. J. Org. Chem. 1990;55:4912-15.). Discodermolide lacks obvious structural resemblance to paclitaxel, yet it shares with paclitaxel (the active substance in the drug Taxol) the ability to stabilize microtubules. In mechanism-based assays, discodermolide is more effective than paclitaxel. In fact, of the handful of compounds known to induce polymerization of purified tubulin, discodermolide is the most potent. However, microtubules, a major structural component in cells, are not simple equlibrium polymers of tubulin. They exist as regulated GTP-driven dynamic assemblies of heterodimers of a and P tubulin. Although the dynamics are relatively slow in interphase cells, upon entering mitosis, the rate of growing and shortening increases 20 to 100-fold—the average microtubule turns over half the tubulin subunits every ten seconds. This change in rate allows the cytoskeletal microtubule network to dismantle and a bipolar spindle-shaped array of microtubules to assemble. The spindle attaches to chromosomes and moves them apart. The response to complete suppression of microtubule dynamics in cells is death. However, mitotic cells are more sensitive and the tolerance threshold appears to be cell-type specific. Molecules like paclitaxel that bind with high affinity to microtubules disrupt the dynamics process in tumor cells with lethal results even when the ratio of bound drug to tubulin is very low. Discodermolide binds to tubulin competitively with paclitaxel. Since paclitaxel has proven to be useful in treating some cancers, other compounds of the same mechanistic class may have utility against hyperproliferative disorders.
Future development of discodermolide or structurally related analogues is hindered by the lack of a reliable natural source of the compound or a feasible synthetic route. Naturally occurring discodermolide is scarce and harvesting the producing organism presents logistical problems. Accordingly, there is an ever-growing need for improved syntheses which enable the preparation of commercially acceptable quantities of discodermolide and structurally related analogues.
DESCRIPTION OF THE PRIOR ART
WO 00/04865 discloses the preparation of intermediates for the synthesis of discodermolide and their polyhydroxy dienyl lactone derivatives for pharmaceutical use.
Agnew. Chem., Vol. 39, No. 2, pgs. 377-380 (2000) discloses the total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones.
Org. Lett., Vol. 1, No. 11, pgs. 1823-1826 (1999) discloses the gram-scale synthesis of (+)-discodermolide.
Diss. Abstr. Int., Vol. 60, No. 3, pg. 1087 (1999) discloses the total synthesis of (+)-miyakolide, (−)-discodermolide and (+)-discodermolide.
Tetrahedron Lett., Vol. 40, No. 30, pgs 5449-5453 (1999) discloses the synthesis of C1-C8 and C9-C24 fragments of (−)-discodermolide.
Diss. Abstr. Int., Vol. 59, No. 11, pg. 5854 (1999) discloses a total synthesis of (−)-discodermolide.
J. Org. Chem., Vol. 63, No. 22, pgs. 7885-7892 (1998) discloses the total synthesis of (+)-discodermolide.
WO 98/24429 discloses synthetic techniques and intermediates for polyhydroxy, dienyllactones and mimics thereof.
J. Am. Chem. Soc., Vol. 118, No. 45, pgs. 11054-11080 (1996) discloses the syntheses of discodermolides useful for investigating microtubule binding and stabilization.
J. Am. Chem. Soc., Vol. 117, No. 48, pgs. 12011-12012 (1995) discloses the total synthesis of (−)-discodermolide.
British Patent Application 2,280,677 discloses the total synthesis of discodermolide.
SUMMARY OF THE INVENTION
The present invention relates to a more practical synthesis of discodermolide and analogues thereof. In another embodiment, the instant invention relates to novel compounds useful in the preparation of discodermolide and analogues thereof. In a further embodiment, the instant invention relates to novel compounds which are prepared by the process of the instant invention.
DETAILED DESCRIPTION OF THE INVENTION
The essence of the instant invention is the discovery of a more practical synthesis for discodermolide and analogues thereof. More particularly, it has been discovered that discodermolide and analogues thereof can be prepared by a three-step reaction as follows:
where R
1
is (C
1-6
) alkyl, benzyl or an acid labile hydroxyl protecting group; R
2
is (C
1-6
) alkyl or benzyl; R
3
is hydrogen, (C
1-6
) alkyl, benzyl, C(O)(C
1-12
) alkyl, C(O)Ph, C(O)O(C
1-12
) alkyl, C(O,Ph, C(O)NH(C
1-12
) alkyl, C(O)NHPh or an acid labile hydroxyl protecting group; R
3
″ is an acid labile hydroxyl protecting group; R
4
is hydrogen or methyl; and X is O, NH, NCH
3
, S or CH
2
, with the proviso that when X is O and R
3
is an acid labile hydroxyl protecting group in the compound of formula I, the “—X—R
3
” moiety in the compound of formula V is —OH.
As to the individual steps, Step 1 involves the coupling of a ketone compound of formula I with an aldehyde compound of formula II via an aldol reaction to obtain a &bgr;-hydroxyketone compound of formula III. The coupling is conveniently carried out with between 1 and 20, preferably between 5 and 15, equivalents of the ketone compound of formula I relative to the aldehyde compound of formula II. The coupling is conducted in the presence of: 1) a dialkylboron halide or triflate, preferably a chiral boron chloride or triflate, more preferably &bgr;-chlorodiisopinocamphenylborane; 2) a base, preferably an amine, more preferably triethylamine; and 3) a polar organic solvent, preferably an ether, more preferably diethyl ether, at a temperature of between −100° C. and 20° C., preferably between −78° C. and −20° C., for a period of between 2 and 72 hours, preferably for 16 hours.
Step 2 concerns the reduction of the &bgr;-hydroxyketone compound of formula III and, more particularly, the ketone group common to such compounds, to obtain a 1,3-diol compound of formula IV. The reduction is conducted in the presence of: 1) a ketone reducing agent, preferably a borohydride such as tetramethylammonium triacetoxyborohydride; 2) a polar organic solvent, preferably acetonitrile; and 3) a protic solvent, preferably a carboxylic acid, such as acetic acid, at a temperature of between −78° C. and 20° C., preferably between −40° C. and −10° C., for a period of between 2 and 72 hours, preferably for 16 hours.
As to Step 3, it involves the lactonization and deprotection of the acid labile hydroxyl protecting groups of a compound of formula IV to obtain a compound of formula V. The lactonization and deprotection reaction is conducted in the presence of: 1) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, more preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between −20° C. and 40° C., preferably between 20° C. and 25° C., for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
In another embodiment, the instant invention relates to the novel ketone
Borovian Joseph J.
Novartis AG
Owens Amelia
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