Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-12-12
1997-04-22
Trinh, Ba K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549510, 549511, A61K 31335, C07D30514
Patent
active
056229860
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to compounds having anti-microtubule activity. In particular, the invention relates to taxoid-based derivatives which demonstrate prolonged anti-neoplastic activity and/or improved water-solubility.
BACKGROUND OF THE INVENTION
Taxol, or paclitaxel as it is sometimes called, has been investigated as an anti-cancer agent. Taxol is a plant product derived in minute quantities from the needles and bark of the western pacific yew, Taxus brevifolia. In chemotherapy, taxol is known as an anti-microtubule agent and is thought to inhibit cell mitosis through the enhancement of the rate of microtubular assembly and prevention of microtubular depolymerization. Numerous studies indicate that the agent has activity against several malignancies. To date, its use has been severely limited by, among other things, its short supply, poor water solubility and immunogenicity.
The pacific yew is a rare, slow-growing tree which is not typically cultivated. In addition, the anti-neoplastic portions of the tree are very minute. Extraction of these portions is complicated and costly. One solution to the problem of short supply has been suggested in U.S. Pat. No. 5,019,504 which discloses an artificial media for producing certain desirable alkaloids. Alternatively, synthetic derivations such as taxotere and taxol intermediates have also been reported. See, for example, U.S. Pat. No. 5,015,744.
Hypersensitivity reactions from taxol administration are known. See, for example, J. Clin. Oncol. 8:1263-1268 (1990). Indeed, since taxoids are usually extracted from a natural plant source, some hypersensitivity is expected. Moreover, certain non-aqueous vehicles which have been used to overcome the water solubility problems of taxol have also been implicated in causing hypersensitivity reactions.
Although taxoids hold promise as therapeutic agents, there is a need to provide taxoid-based derivatives which are more water soluble and/or are more active against a wider range of virulent neoplasms than taxol.
SUMMARY OF THE INVENTION
The present invention is generally directed to 2'- and/or 7- substituted taxoid-based compositions, methods of their preparation and use in mammals. The inventive compositions include a taxoid substituted in at least one of the 2'- and 7- positions with a moiety of Formula (I): ##STR1## wherein:
n=zero or a positive integer, preferably one;
X=oxygen or NL, where L is selected from the group consisting of hydrogen, C.sub.1-8 alkyls, aryls and aralkyls; and
R.sub.1 =a group which enhances the water solubility and/or therapeutic activity of the composition when compared to the unmodified taxoid. R.sub.1 represents moieties capable of forming polymeric esters, simple or polymeric carbonates. Such moieties can include functionalized, substantially nonantigenic polymers, substituted or unsubstituted C.sub.1-12 alkyls. R.sub.1 preferably includes an alkyl-terminated polyalkylene oxide such as monomethoxy polyethylene glycol, (mPEG). These aspects provide compositions such as taxoid-7-carbonates, 2'- taxoid-PEG-esters and/or simple taxoid-7-carbonates in combination with 2'-PEG esters. Another particularly preferred aspect of the invention is where (n) is one and R.sub.1 includes a polyethylene glycol.
The invention thus includes the following types of taxoid-based compositions:
i) 7-carbonates; 2'-carbonates;
ii) 7-polymeric esters; 2'-polymeric esters;
iii) 2'-polymeric ester-7-carbonates;
iv) 2',7-disubstituted polymeric esters; 2',7-disubstituted carbonates; and
v) combinations thereof.
In those aspects of the invention where the taxoid is disubstituted, it is to be understood that the moieties included in the 2' and 7 position need not be the same; bis-substituted taxoids, however, are within the scope of the invention.
Methods of making and using the compositions described herein are also provided.
DETAILED DESCRIPTION OF THE INVENTION
A. INTRODUCTION
The taxoid-based compositions of the present invention contain substituents in the 2' and/or 7 positions of the
REFERENCES:
patent: 4101380 (1978-07-01), Rubinstein et al.
patent: 4179337 (1979-12-01), Davis et al.
patent: 4275000 (1981-06-01), Ross
patent: 4534899 (1985-08-01), Sears
patent: 4582805 (1986-04-01), Bozzelli et al.
patent: 4680338 (1987-07-01), Sundoro
patent: 4814470 (1989-03-01), Colin et al.
patent: 4847325 (1989-07-01), Shadle et al.
patent: 4904582 (1990-02-01), Tullis
patent: 4942184 (1990-07-01), Haugwitz et al.
patent: 4943579 (1990-07-01), Vishnuvajjala et al.
patent: 4960790 (1990-10-01), Stella et al.
patent: 5004758 (1991-04-01), Boehm et al.
patent: 5015744 (1991-05-01), Holton
patent: 5019504 (1991-05-01), Christen et al.
patent: 5059699 (1991-10-01), Kingston et al.
patent: 5091176 (1992-02-01), Braatz et al.
patent: 5122614 (1992-06-01), Zalipsky
patent: 5136060 (1992-08-01), Holton
patent: 5157049 (1992-10-01), Haugwitz et al.
patent: 5227400 (1993-07-01), Holton et al.
patent: 5229526 (1993-07-01), Holton
patent: 5272171 (1993-12-01), Ueda et al.
patent: 5278324 (1994-01-01), Kingston et al.
patent: 5342947 (1994-08-01), Lackey et al.
patent: 5352805 (1994-10-01), Kingston et al.
patent: 5362831 (1994-11-01), Mongelli et al.
Mathew et al, "J. Med. Chem.," vol. 35, No. 1, pp. 145-151, 1992.
Nathan et al, "Polymer Preprints", vol. 31, pp. 213-214. 1990.
Zalipsky et al, "Eur. Polym. J.", vol. 19, No. 12, pp. 1177-1183, 1983.
Weiner et al, "J. Med. Chem.", vol. 16, No. 5, pp. 573-574, 1973.
Cecchi et al, "J. Med. Chem.", vol. 24, No. 5, pp. 622-625, 1981.
Angew, Chem. Int. Ed. Engl, (1994), 33, No. 1516, K.C. Nicolaou, et al.
Bioorganic & Medicinal Chemistry Letters, vol. 4, No. 20, pp. 2465-2470, (1984), Richard B. Greenwald, et al.
Proc. Int. Symp. Control. Release Bioact. Mater., 21 (1994) #1381, Yuichi Ohya, et al.
Cancer Treatment Reviews (1990), 17, 127-131, Terrence W. Doyle, et al.
Bioorganic & Medicinal Chemistry Letters, vol. 4, No. 18, pp. 2223-2228 (1994) Shu-Hui Chen, et al.
Journal of Pharmaceutical Sciences, vol. 83, No. 4, Apr. 1994, Tetsuiji Yamaoka, et al.
Clinical Pharmacy, vol. 8, Apr. 1989, pp. 274-293, Ronald A. Fleming, et al.
Oncology, Dec. 1992, pp. 17-23, Michael J. Hawkins, et al.
Biotechnology and Applied Biochemistry 9, 258-268 (1987).
Journal of Controlled Release, 10 (1989) 145-154.
Polymer Bulletin 18, 487-493 (1987).
Ouchi et al, Drug Design & Discovery, vol. 9, pp. 93-105, (1992).
Nicolaou, Nature, vol. 364, pp. 464-466, 29 Jul. 1993.
Commercon et al, Tetrahedron Letters, vol. 33, No. 36, pp. 5158-5188 (1992).
Magre et al, J. Org. Chem., vol. 51, pp. 797-802 (1986).
Gueritte-Voegelein et al, J. Med. Chem., 34, pp. 992-998 (1991).
Bolikal Durgadas
Greenwald Richard B.
Enzon Inc.
Mercanti Michael N.
Trinh Ba K.
LandOfFree
2'-and/or 7-substituted taxanes 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'-and/or 7-substituted taxanes, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 2'-and/or 7-substituted taxanes will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-342128