Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-09-24
2003-11-04
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S042000, C514S432000, C514S012200, C514S008100, C514S024000, C536S123100, C536S001110
Reexamination Certificate
active
06642205
ABSTRACT:
TECHNICAL FIELD AND BACKGROUND ART
The present invention relates to reducing side effects of therapeutic agents in a subject without substantial loss in efficacy where the agents would otherwise have significant side effects. This beneficial effect is achieved by coupling a galactose residue to the agent via a spacer.
Directed delivery of an agent to a target site is desirable to minimize side effects in patients and to enhance therapeutic efficacy. Side effects are the hallmark of many chemotherapeutic agents which otherwise are effective in reducing tumor size. For example, anthracycline antibiotics such as Adriamycin (also called 14-hydroxydaunamycin or doxirubicin) are effective anti-tumor agents. (Arcamone, “Doxorubicin: Anti-Cancer Antibiotics”, Medicinal Chemistry Series, (1981) Vol. 17, Academic Press; C. R. Hutchinson, “The Biosynthesis of Tetracycline and Anthracycline Antibiotics,” in Antibiotics IV Biosynthesis, (1981) pp. 1-11, Ed.: J. W. Corcoran, Pub.: Springer-Verlag; R. J. White, “Anthracyclines,” in Biochemistry and Genetic Regulation of Commercially Important Antibiotics, (1983) p. 277-291, Ed.: L. C. Vining, Pub.: Addison Wesley).
In addition to the desired effect of destroying cancer cells, anthracycline antibiotics also damage non-cancer cells resulting in side effects for the patient. These side effects limit the dose and duration of treatment with these agents. Attempts have been made to reduce the side effects of this class of therapeutic agent. In U.S. Pat. No. 5,814,608, the daunosamine moiety of the Adriamycin was substituted with several disaccharide moieties and the modified agent tested using human tumor cell lines showing a marked reduction in cytotoxic potency for the target tumor cells (Arcamone, 1981). These in vitro assays did not however measure side effects which arise in a patient nor indeed did they provide information on cytotoxic effects on non-target cells. An analog of doxorubicin has been made in which a disaccharide replaces the monosaccharide daunosamine of doxorubicin. These compounds actually had increased side effects (Zunino et al., Biochemical Pharmacology (2001) Vol. 61, pp. 933-938; Gonzalez-Paz et al. European Journal of Cancer (2001) Vol. 37, pp. 431-437). It was shown that natural mono-, di- and tri-saccharide derivatives of pyrromycinone possess a progressively increased DNA binding activity with the increase in the length of the oligosaccharide chain. (DuVernay V. H., “Molecular Pharmacology of Anthracycline Antitumor Antibiotics”, in Canver and Chemotherapy, (1981) Vol. III, pp. 233-271, Academic Press, New York.) Although an increase in DNA binding activity was shown, this does not actually mean anti-tumor potency.
Other approaches to reducing side effects have been developed which rely on directing therapeutic agents in the form of pro-drugs to their target site of action. Pro-drugs of Adriamycin were made in which the Adriamycin was linked to spacers at C14, which in turn were linked to ligands, the ligands including monosaccharides. The pro-drugs were then linked to antibodies which directed the pro-drug to target cells. The pro-drugs were hydrolyzed by enzymes which were co-administered with the pro-drugs. The intended result was liberation of the active agent at the target site only. (Leenders et al., Tetrahedron Letters (1995) Vol. 36, pp. 1701-1704; Ghosh et al., Tetrahedron Letters (2000) Vol. 41, pp. 4871-4874; Houba et al., International Journal of Cancer, (2001) Vol. 91, pp. 550-554). In vivo data suggested that pro-drugs were much less toxic compared to the parent agent (Adriamycin) and showed a somewhat higher tumor growth inhibition compared to the parent agent.
SUMMARY OF THE INVENTION
In a first embodiment of the invention there is provided a pharmaceutical compound, that includes a therapeutic agent, a spacer and a galactose, the spacer being covalently linked to the therapeutic agent at a first site on the spacer and covalently linked, at a second site, to at least one galactose by an ether linkage. In examples of the embodiments, the spacer may be polyhydroxylated. The spacer may be an aldose or a ketose, and may further be a triose, tetrose, pentose, hexose or septose. The spacer may be have the chemical composition:
where n=≧0 and <20 and m=≧0 and <20. The presence of the spacer between a therapeutic agent and a galactose causes the galactose to be separated from the therapeutic agent by at least two carbon atoms. The covalent linkage between the spacer and the agent is formed with a reactive group on the therapeutic agent, the reactive group being selected from an amino group, an alkoxy group, a hydroxy group, a carbonyl group, a carboxylic group, a halogen and a thiol group.
In an embodiment of the invention, the therapeutic agent is Adriamycin which is covalently linked to an amide group on the daunosamine via for example an aldose or ketose spacer. In particular embodiments of the invention, the galactose is linked to the spacer by means of a glycosidic linkage. For example, the pharmaceutical compound may include N-[&bgr;-D-galactopyranosyl-(1→4)-&bgr;-O-D-sorbityl]doxorubicin or N-[&agr;-D-galactopyranosyl (1→6)
6&bgr;-O-D-sorbityl]doxorubicin.
In an embodiment of the invention, a pharmaceutical preparation, is provided that includes an effective dose of any of the pharmaceutical compounds described above and a pharmaceutically acceptable excipient.
In another embodiment of the invention, a method is provided for synthesizing a pharmaceutical compound that includes: providing (i) a therapeutic agent; and (ii) a spacer linked to a galactose conjugate; protecting reactive groups on the therapeutic agent other than the reactive site for linking to the spacer; reacting the protected therapeutic agent with the spacer linked to the galactose; and deprotecting the therapeutic agent to form the pharmaceutical compound. For example, the spacer linked to galactose has a formula:
where n=≧0 and ≦20 or
where n=≧0 and ≦20 and m=≧0 and <20.
In another embodiment of the invention, a method is provided for treating a subject suffering from a medical condition, so as to reduce the side effects associated with a therapeutic agent selected for treating the condition, without substantially reducing efficacy, comprising: providing as a conjugate, the therapeutic agent covalently linked to a spacer at a first site and the spacer being covalently linked to galactose at a second site; and administering an effective dose of the conjugate to the subject so that the side effects in the subject are less then they would have been with the unconjugated therapeutic agent.
According to the above, the medical condition may include any of a proliferative condition, high cholesterol, depression, asthma, hypertension and bacterial infections. If the condition is a proliferative condition, it may include cancers such as solid tumors, an invasive tumor such as occurs in brain tumors or circulating cancer cells such as occurs in leukemia. An example of a chemotherapeutic agent is Adriamycin the conjugate corresponding to for example, N-[&bgr;-D-galactopyranosyl-(1→4)-&bgr;-O-D-sorbityl]doxorubicin and N-[&agr;-D-galactopyranosyl-(1→6)-&bgr;-O-D-sorbityl]doxorubicin.
REFERENCES:
patent: 5955100 (1999-09-01), Bosslet et al.
patent: WO 96/19243 (1996-06-01), None
Palomino E: “Carbohydrate Handles as Natural Resources in Drug Delivery”, Advanced Drug Delivery Reviews, Amsterdam, NL. vol. 13, 1994, pp. 311-323, XP000775555 Issn: 0169-409X, p. 317, paragraph 4, p. 320,paragraph 3.
European Search Report.
Klyosov Anatole
Platt David
Bromberg & Sunstein LLP
Dees Jose′ G.
DeWitty Robert M
Pro-Pharmaceuticals, Inc.
LandOfFree
Methods and compositions for reducing side effects in... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods and compositions for reducing side effects in..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods and compositions for reducing side effects in... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3132033