Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-12-30
2002-11-05
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S511000
Reexamination Certificate
active
06476242
ABSTRACT:
FIELD OF INVENTION
The present invention relates to 2-debenzoyl-4-deacetyl paclitaxel, 2-debenzoyl-4-deacetyl-2,4-diacyl paclitaxel analogs thereof, and methods for making the same.
BACKGROUND OF THE INVENTION
The natural product paclitaxel (1) (Taxol®) is an effective antitumor drug with demonstrated clinical activity against breast and ovarian cancer, as well as indicated activity against non-small cell lung cancer (24, 25). Studies of use against various other cancers show promising results. Recent studies have elucidated the unique mode of action of paclitaxel, which involves abnormal polymerization of tubulin and disruption of mitosis. Taxol was first isolated and its structure reported by Wani, et al. (26).
Taxol is found in the stem bark of the western yew,
Taxus brevifolia
, as well as in
T. baccata
and
T. cuspidata
. Therefore, there is a limited natural supply of paclitaxel.
Because of the limited availability of paclitaxel and the high demand due to its efficacy against various types of cancer, other derivatives and analogs of paclitaxel have been sought. The relative scarcity of such analogs in relation to their importance as potential anti-cancer agents is due to several factors, including the large size and complexity of paclitaxel compounds, the presence of multiple reactive sites and the presence of many stereospecific sites, making synthesis of even close analogs difficult.
Because it is believed that the tetracyclic taxane nucleus is an important feature in establishing the antineoplastic activity of paclitaxel and analogs thereof, it is desired to alter the ring substituents without disrupting the tetracyclic nucleus in order to develop antineoplastically active derivatives of paclitaxel. The complexity of paclitaxel and its analogs makes it difficult to selectively alter substituents.
The only disclosed preparations of taxol analogs retaining the tetracyclic taxane nucleus are those analogs modified at the C-1, C-2, C-4, C-7 and C-13 positions, and derivatives having a protecting group or a hydroxyl group at the C-10 position (27). However, it has been demonstrated that analogs with improved activity can be prepared by modifications at various functional groups, and several investigators have prepared paclitaxel analogs modified at the 2-position (1-10), at the 4-position (11-15), at the 7-position (16-19), at the 9 and 10 positions (20-21and at the 14-position (22), among others. Baccatin III derivatives (baccatin III is the taxane core of paclitaxel) have also been prepared with substitutions at C-2 and/or C-4 (23).
In particular, analogs at the C-2 position have been prepared by Chaudhary et al. (1,3) using a phase-transfer catalyst to prepare 2-debenzoylpaclitaxel followed by reacylation with a carboxylic acid in the presence of dicyclhexylcarbodiimide (DCC) and pyrollidinopyridine (PP). Similar chemistry has more recently been reported by Georg et al. (2,5,6,13), who used potassium t-butoxide as the base and reacylated in the presence of 1,3-dicyclohexylcarbodiimide (DCC) and N,N-dimethylaminopyridine (DMAP). Nicolaou (4,7) has shown that 2-debenzoylpaclitaxels can be prepared from 10-deacetylbaccatin III by a process involving protection at C-7, oxidation at C-13, selective debenzoylation at C-2, formation of the cyclic 1,2-carbonate derivative, reaction with an aryllithium, reduction at C-13, and finally coupling of the C-13 side chain. A different route to 2-debenzoyl taxoids was developed by Pulicani et al. (8), who were able to prepare 2-debenzoyl docetaxel and certain derivatives by electrochemical reduction of docetaxel followed by reacylation with Butyllithium and an acid chloride. Yet another, albeit restricted, synthesis of certain 2-acyl paclitaxel analogs was achieved by Ojima et al. (9) and Boge et al. (10), who independently hydrogenated baccatin III to its 2-cyclohexylcarbonyl derivative, and then attached the C-13 ester side chain. 2-Debenzoylbaccatin III was prepared by Datta et al. (23) by treatment of 7,13-bis(triethylsilyl)baccatin m with potassium t-butoxide.
4-Deacetylpaclitaxel has been prepared by Neidigh et al. (11) and independently by Georg et al. (12). Neidigh et al. prepared 4-deacetylpaclitaxel by treatment of a protected paclitaxel with base under various conditions, and also by a second method in which a C-13 side chain was attached to a suitably protected 4-deacetylbaccatin III. Georg et al. prepared 4-deacetylpaclitaxel by attachment of the C-13 side chain to a protected deacetylbaccatin III. 4-Deacetylbaccatin III was also prepared by Datta et al. (23) by treatment of 7-(triethylsilyl)baccatin III with potassium t-butoxide. C-4 deacetoxypaclitaxel was prepared by Chordia et al. (15) by preparation of 2-debenzoyl-4-deacetyl paclitaxel by treatment of 2-t-butyldimethylsilyl-7-triethylsilylpaclitaxel with Triton B (an organic-soluble base) followed by formation of the cyclic 1,2-carbonate, formation of a xanthate at C-4, opening of the carbonate with phenyllithium, and deprotection.
Paclitaxels with modified C-4 acyl substituents have been prepared by Chen et al. (14), who protected 7,13-di(triethylsilyl)baccatin III at C-1 with a dimethylsilyl protecting group and then deacylated selectively at C-4 with Red-Al. Subsequent reacylation using acid chloride and lithium hexamethyldisilazide (LHDMS), followed by protecting group manipulations and reacylation at C-13 with the paclitaxel side chain (as its &bgr;-lactam derivative) yielded a range of 4-acylpaclitaxel analogs. A 4-acyl analog of paclitaxel was also prepared by Georg et al. (13), who treated 2′-t-butyldimethylsilyl-7-triethylsilylpaclitaxel with aqueous potassium t-butoxide to give a 2-debenzoyl-4-deacetyl-2′-t-butyldimethylsilyl-7-triethylsilylpaclitaxel. This compound was converted to its cyclic carbonate, acylated at C-4, and treated with phenyllithium to yield a 4-isobutyroylpaclitaxel analog.
In spite of all the work that has been done on the preparation of paclitaxel analog with C-2 and C-4 acyl substituents, no work has been reported to date on the preparation of derivatives with modified substituents at both C-2 and C-4. The preparation of such derivatives is desirable because it is anticipated that such derivatives will have antineoplastic activity, like paclitaxel itself. Further, because previous work has shown that both 2-acyl and 4-acyl analogs independently can have improved activity over paclitaxel, it is thought that some derivatives described herein will also have improved activity. It is further contemplated that the derivatives described herein will be easier to synthesize, will be more abundant, will have greater solubility and/or will have fewer side effects than paclitaxel.
The preparation of analogs of paclitaxel is an important endeavor, especially in view of paclitaxel's clinical activity and limited supply. The preparation of analogs might result in the synthesis of compounds with greater potency than paclitaxel (thus reducing the need for the drug), compounds with superior bioavailability, or compounds which are easier to synthesize than paclitaxel from readily available sources.
SUMMARY OF THE INVENTION
The present application describes paclitaxel analogs which have modified substituents at both the C-2 and C-4 positions, in particular 2-debenzoyl-2-acyl-4-deacetyl4-acyl paclitaxel analogs, as well as pro compounds, and intermediates which can be utilized in preparing these compounds.
The compounds of the present invention have anti-neoplastic activity and may be used to treat patients suffering from cancer, or as intermediates for making compounds which can be used to treat cancer. In a preferred embodiment, the paclitaxel analogs have improved in vivo activities for use as anticancer agents, are more soluble, and/or have fewer side effects than paclitaxel.
Compounds of the present invention include compounds having the general formula:
wherein R
1
is an aryl or substituted aryl; R
2
is an aryl or substituted aryl; R
3
is selected from the group consisting of H, OH, and OC(O)R
a
; R
4
is selected from the gr
Chordia Mahendra Devichand
Jagtap Prakash G.
Kadow John
Kingston David George Ian
Bristol--Myers Squibb Company
Trinh Ba K.
LandOfFree
2-aroyl-4-acyl paclitaxel (Taxol) analogs does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 2-aroyl-4-acyl paclitaxel (Taxol) analogs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 2-aroyl-4-acyl paclitaxel (Taxol) analogs will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2957461