Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1994-05-27
1996-10-01
Kunz, Gary L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 64, 536 182, 536 184, 536 185, 536 174, 536 177, 4241461, 4241551, 4241781, 4241791, 4241831, 556465, A61K 3170, A61K 3944, C07C 5018, C07H 504
Patent
active
055611192
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to glycosylated prodrugs, to a method of preparing them and to their uses, alone or with tumor-specific immunoezymatic conjugates, particularly in the treatment of cancer.
More specifically, the present invention relates to prodrugs comprising modified anthracyclines which can be cleaved, in particular, by the action of said tumor-specific immunoenzymatic conjugates to give cytotoxic substances which are active towards tumoral cells.
2. Discussion of the Background
The combination of a prodrug with enzyme/monoclonal antibody conjugates as therapeutic agents has been described in the literature. In general, the antibodies in question, which are directed against a specific tissue and are covalently bonded to an enzyme capable of cleaving the prodrug, are first injected into an appropriate animal, especially man, after which a prodrug is administered which can be activated by the enzyme. The prodrug is converted to a cytotoxin by the action of the enzyme/antibody conjugate anchored to the specific tissue, the cytotoxin exerting a cytotoxic effect on said tissue.
International patent application WO 81/01145, in the name of UNIVERSITY OF ILLINOIS FOUNDATION, describes prodrugs which can be activated by hydrolytic enzymes, and defines five criteria for the optimum efficacy of a prodrug: (1) there must be sufficient activating enzyme in the region of the tumor for cytotoxic levels of antitumoral agent to be released in the region of the tumor, (2) the prodrug must not be activated in regions other than that of the tumor, (3) the prodrug must be an appropriate substrate for the enzyme associated with the tumor, under physiological conditions, (4) the prodrug must be non-toxic or much less toxic than the activated antitumoral agent, and (5) the activated substance must have a short biological half-life so that the toxic effects are limited to the tumor.
More specifically, said patent application states that antitumoral agents can be made specific for a tumor by the addition of a peptide converting said agent to a prodrug which is pharmacologically inactive, but can be selectively activated only at the site of the tumor by an enzyme present in large amounts in the region of the tumor (plasmin and plasminogen activator in particular). The amino acid sequence of the peptide part of the prodrug is such that it will be cleaved enzymatically from the antitumoral agent part by proteases such as plasmin or plasminogen activator, so as to release the antitumoral agent in its active form in the region of the tumor.
The prodrugs which can be activated by hydrolytic enzymes can have a structure in which the peptide and the antitumoral part are covalently bonded via a self-sacrificing connector whose molecular structure is such that the enzymatic cleavage of the peptide from the self-sacrificing connector will spontaneously cause the cleavage of its bond with the antitumoral part.
However, the prodrugs described in said International patent application can only be used for cancers which cause an increased production of enzymes, and more particularly proteases, at the site of the tumor; now, these activating enzymes capable of cleaving the prodrugs described in said patent application are not found in sufficient amounts in human cancers, so these prodrugs do not afford the desired selective toxicity (K. D. BAGSHAWE, Br. J. Cancer, 1987, 56, 531).
International patent application WO 88/07378, in the name of CANCER RESEARCH CAMPAIGN TECHNOLOGY LTD, describes a therapeutic system containing on the one hand an enzyme/antibody conjugate and on the other hand a prodrug which can be activated by the enzyme. The antibody of the enzyme/antibody conjugate recognizes a tumor-specific antigen and the enzyme is capable of converting the prodrug to a cytotoxic agent.
Said patent application states that it is preferable to use enzymes other than mammalian enzymes, so as to prevent the premature release of cytotoxic agent by endogenous enzymes.
More specificall
REFERENCES:
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Tanino et al. Tetrahedron Letters 1992, 33(10), 1337-40.
Jain et al. Indian J. Chem., Sect. B, 1988, 27B(11), 1019-23.
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Nakatani et al. Agric. Biol. Chem. 1987, 51(10), 2727-32.
Collington et al. Tetrahedron Letters 1985, 26(5), 681-4.
Gray et al. Helv. Chim. Acta 1977, 60(4), 1304-11.
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Bosslet Klaus
Czech J org
Dickneite Gerhard
Florent Jean-Claude
Gaudel Gilbert
Behringwerke A.G.
Fonda Kathleen Kahler
Kunz Gary L.
Laboratoires Hoechst
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