Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-09-14
2001-04-17
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S017900, C536S018100
Reexamination Certificate
active
06218367
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel anti-tumor compounds, methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are novel carbohydrate derivatives of paclitaxel that are more water soluble and have better biological properties compared to paclitaxel.
2. Background
Paclitaxel (Taxol®) is a chemotherapeutic agent that was originally
isolated from the bark of the Pacific yew,
Taxus brevifolia
. It has been shown to have antitumor activity toward a wide variety of cancers including breast, ovarian, melanoma, lung, colon, leukemias and others. Paclitaxel acts by promoting tubulin assembly and by stabilizing the microtubules to prevent their disassociation into free tubulin. Actively dividing cells are thus particularly sensitive to paclitaxel and become arrested at the G2/mitosis cell cycle transition.
Although paclitaxel has promising antitumor activity, it has been difficult to develop for clinical treatments due to its very low solubility in water. Paclitaxel is administered in large volume, low concentration formulations with Cremophor EL which results in many patients developing side effects such as hypersensitivity reactions. Thus, it would be extremely desirable to develop novel paclitaxel derivatives that have increased water solubility while maintaining or surpassing the cytotoxic activity of paclitaxel itself.
See also: Wittman et al., U.S. Pat. No. 5,942,184; Bressi et al., U.S. Pat. No. 5,801,191; Vyas, D. M. et al., “Synthesis and Anti-tumor Evaluation of Water Soluble Taxol Phosphates”, Bio-organic and Medicinal Chemistry Letters, 3, 1357-1360, 1993; Greenwald, R. W. et al., “Drug Delivery Systems: Water soluble Taxol 2′-Poly(ethylene glycol) Ester Pro-drugs-Design and in vitro Effectiveness”, J. Med. Chem. 39, 424-431, 1996; Mathew, A. E. et al., “Synthesis and Evaluation of Some Water Soluble Prodrugs and Derivatives of Taxol with Anti-tumor Activity”, J. Med. Chem., 35, 145-151, 1992; Nicolaou, K. C. et al., “A Water-soluble Prodrug of Taxol with Self-assembling Properties”, Angew. Chem. Int., Ed., 33, 1583-1587, 1994; Souto, A. A. et al., “New Fluorescent Water Soluble Taxol Derivatives”, Angew. Chem. Int., Engl. 34, 2710-2712, 1995; Bissery, M. C. et al., “Experimental Anti-tumor Activity of Taxotere (RP 56976, NSC 628503), a Taxol Analogue”, Cancer Res., 51, 4845-4852, 1991; Deutsch, H. M. et al., “Synthesis of Congeners and Pro-drugs of Taxol with Potent Anti-tumor Activity”, J. Med. Chem., 32, 788-792, 1989.
SUMMARY OF THE INVENTION
The present invention provides novel carbohydrate derivatives of paclitaxel, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more of such compounds. Preferred compounds are more water soluble and have better biological properties compared to paclitaxel. Moreover, preferred compounds of the invention are made from natural non-toxic materials which, when released, will be adsorbed as part of the body components.
The invention thus provides methods for treating an animal bearing susceptible primary or secondary tumors including tumors in the breast, prostate, ovary, central nervous system, brain, colon, lung, skin, etc. or disseminated tumors such as leukemic cells etc. The invention also provides methods which comprise using one or more carbohydrate conjugated paclitaxel derivative to treat susceptible tumors in a mammal, especially a human. The invention further provides pharmaceutical composites that comprise one or more compounds of the invention and a suitable carrier.
The present invention provides compounds having the following general formula:
[paclitaxel]-[link]
1−2
-[sugar].
The link group(s) attached to the paclitaxel and sugar moieties are comprised of dicarboxylic acids, HOOC(CH
2
)
n
COOH, with from 2 to 12 carbon atoms, preferably with from 2 to 6 carbon atoms and most preferably with four carbon atoms. The link group(s) may also comprise amino acids and amino dicarboxylic acids preferably with from 1 to 12 carbon atoms and more preferably with from 1 to 6 carbon atoms. Non-limiting examples include succinic acid, glutamic acid and &ggr;-aminobutyric acid. The link group is attached to the 2′ or 7 hydroxyl group of paclitaxel via an ester conjugation.
The sugar moiety is comprised of mono-, di-, oligo- or poly-saccharides wherein each monosaccharide unit comprises from 3 to 8 carbons, preferably from 3 to 6 carbons, containing polyhydroxy groups or polyhydroxy and amino groups. Non-limiting examples include glycerol, ribose, fructose, glucose, glucosamine, mannose, galactose, maltose, cellobiose, sucrose, starch, amylose, amylopectin, glycogen and cellulose. The hydroxyl and amino groups are present as free or protected groups containing e.g. hydrogens and/or halogens. Preferred protecting groups include acetonide, t-butoxy carbonyl groups, etc. The sugar moiety is preferably conjugated as an ester or an amide.
Each monosaccharide unit of the sugar moiety may be of the L or D configuration and a cyclic monosaccharide unit may contain a 5 or 6 membered ring of the &agr; or &bgr; conformation. Disaccharides may be comprised of two identical or two dissimilar monosaccharide units. Oligosaccharides may be comprised of from 2 to 10 monosaccharides and may be homopolymers, heteropolymers or cyclic polysugars. Polysaccharides may be homoglycans or heteroglycans and may be branched or unbranched polymeric chains. The di-, oligo- and poly-saccharides may be comprised of 1→4, 1→6 or a mixture of 1→4 and 1→6 linkages. The sugar moiety may be attached to the link group through any of the hydroxyl or amino groups of the carbohydrate.
More specifically, the invention provides compounds of the following formula (Formula I) that are useful as anti-tumor treatments:
wherein R and R′ each individually consist of a hydrogen atom or a group containing a sugar molecule, glucose or glucosamine.
The R and R′ substituents are both adjacent to chiral carbons as shown in the above structure (Formula I). Thus, the compound contains two chiral centers and can form 4 diastereomers. The invention includes both racemic mixtures and optically enriched mixtures of Formula I. An optically enriched mixture contains substantially more (e.g., about 60 mole %, 70 mole %, 80 mole %, 90 mole %, 95 mole %, 98 mole % or more) of one enantiomer of Formula I than the other stereoisomers. For use in the therapeutic methods of the invention, preferably a substantially pure optically active mixture is employed, e.g. a mixture containing at least about 92 mole % or 99 mole % or more of one enantiomer of Formula I. Optically enriched mixtures can be obtained by known procedures, e.g., column chromatography using an optically active binding material or by use of optically active reagents or enantiomerically selective reactions.
REFERENCES:
patent: 5489589 (1996-02-01), Whittman et al.
patent: 5677286 (1997-10-01), Srull et al.
patent: 5801191 (1998-09-01), Bressi et al.
Bissery, M.-C. et al. “Experimental antitumor activity of taxotere (RP 56976, NSC 628503), a taxol analogue”, Cancer Res. 51: 4845-4852 (1991).
Boyd, M. R. et al. “Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen”, Drug Dev. Res. 34: 91-109 (1995).
Deutsch, H. M. et al. “Synthesis fo congeners and prodrugs. 3. Water-soluble prodrugs of taxol with potent antitumor activity”, J. Med. Chem. 32: 788-792 (1989).
Greenwald, R. B. et al. “Drug delivery systems: water soluble taxol 2'-poly(ethylene glycol) ester prodrugs—design and in vitro effectiveness”, J. Med. Chem. 39: 424-431 (1996).
Li, C. et al. “Complete regression of well-established tumors using a novel water-soluble poly(L-glutamic acid)-paclitaxel conjugate”, Cancer Res. 58: 2404-2409 (1998).
Mathew, A. W. et al. “Synthesis and evalutation of some water-soluble prodrugs and derivatives of taxol with antitumor activ
Corless Peter F.
Edwards & Angell LLP
O'Day Christine C.
Organomed Corporation
Peselev Elli
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