Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-02-18
1999-11-16
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548455, A61K 3140, C07D20914
Patent
active
059859091
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel amino analogues of the general class of cyclopropylindoles and their seco precursors, and is particularly concerned with the use of these compounds as prodrugs for antibody-directed enzyme-prodrug therapy (ADEPT) and gene-directed enzyme-prodrug therapy (GDEPT) for cancer.
BACKGROUND TO THE INVENTION
The use of prodrugs represents a clinically very valuable concept in cancer therapy since, particularly where the prodrug is to be converted to an anti-tumour agent under the influence of an enzyme that is linkable to a monoclonal antibody that will bind to a tumour associated antigen, the combination of such a prodrug with such an enzyme monoclonal/antibody conjugate represents a very powerful clinical agent. This approach to cancer therapy, often referred to as "antibody directed enzyme/prodrug therapy" (ADEPT) is disclosed in WO88/07378.
A further therapeutic approach termed "virus-directed enzyme prodrug therapy" (VDEPT) has been proposed as a method for treating tumour cells in patients using prodrugs. Tumour cells are targeted with a viral vector carrying a gene encoding an enzyme capable of activating a prodrug. The gene may be transcriptionally regulated by tissue specific promoter or enhancer sequences. The viral vector enters tumour cells and expresses the enzyme, in order that a prodrug is converted to an active drug within the tumour cells (Huber et al, Proc. Natl. Acad. Sci. USA (1991) 88, 8039). Alternatively, non-viral methods for the delivery of genes have been used. Such methods include calcium phosphate co-precipitation, microinjection, liposomes, direct DNA uptake, and receptor-mediated DNA transfer. These are reviewed in Morgan & French, Annu. Rev. Biochem., 1993, 62;191. The term "GDEPT" (gene-directed enzyme prodrug therapy) is used to include both viral and non-viral delivery systems.
Cyclopropylindole compounds are a class of highly potent antitumour antibiotics with the natural products CC-1065 (V. L. Reynolds et al, J. Antibiot., 39, 1986, 319-334) and the duocarmycins (D. L. Boger, Pure & Appl. Chem., 66, 1994, 837-844), having IC50's in the low pM range. These compounds bind in the minor groove of DNA and alkylate in a highly sequence selective manner at N-3 of adenine (D. L. Boger et al, Tetrahedron, 47, 1991, 2661-2682). Studies with compounds that model the alkylation subunit have shown that the more stable open chain seco precursors are as potent as the cyclopropylindole compounds. Further, ring closure is not essential for DNA alkylation, and there is some measure of electronic control by the both the 6-substituent (D. L. Boger et al, J. Am. Chem. Soc., 113, 1991, 3980-3983) and the 1-substituent (D. L. Boger and W. Yun, J. Am. Chem. Soc., 116, 1994, 5523-5524)-on the rate of alkylation.
A number of synthetic analogues of the natural products have been prepared in which the oxygen substituent is protected as a carbamate that must be cleaved (by non-specific enzymatic hydrolysis) for activity. These compounds include carzelesin (L. H. Li et al, Cancer Res., 52, 1992, 4904-4913) having the structure A: ##STR1##
A related compound is KW-2189 (E. Kobayashi et al, Cancer Res., 54, 1994, 2404-2410) which has the structure B: ##STR2##
Both carzelesin and KW-2189 show anticancer activity against a range of human tumours and are in clinical trial. Further analogues of a similar type are disclosed in WO88/04659 and WO091/16324.
DISCLOSURE OF THE INVENTION
In one aspect, the present invention relates to the new class of substituted seco indolines, represented by formula (I): ##STR3## wherein:
X is halogen or OSO.sub.2 R, where R represents H or lower straight or branched alkyl (up to five carbon atoms) optionally substituted with from 1 to 4 hydroxyl, acid (COOH) or amino groups which amino groups are optionally substituted by one or two lower alkyl groups;
Y is NH.sub.2, NO.sub.2, NHOH, NHR, NRR, N(O)RR, NROH, SR or SSR, where R is defined as above, but that in the case where Y is SSR, then R can also be another moiety of formula (I) (i.e., a
REFERENCES:
Culver, et al., "In Vivo Gene Transfer With Retroviral Vector-Producer Cells For Treatment Of Experimental Brain Tumors," Science (1992) vol. 256:1550-1552.
Englehardt, et al., "Direct Gene transfer Of Human CFTR Into Human Bronchial Epithelia Of Xenografts With E1-Deleted Adenviruses," Nature Genetics (1993) vol. 4:27-34.
Huber, et al., "Retroviral-Mediated Gene Therapy For The Treatment Of Hepatocellular Carcinoma: An Innovative Approach For Cancer Therapy," Proc. Nat'l. Acad. Sci., USA (1991) vol. 88:8093-8043.
Knox, et al., "Bioactivation Of CB 1954: Reaction Of The Active 4-Hydroxylamino Derivative With Thioesters To Form The Ultimate DNA-DNA Interstrand Crosslinking Species," Biochemical Pharmacology (1991) vol. 42:1691-1697.
Knox, et al., The Bioactive Of 5-(Aziridin-1-yl)-2,4-Dinitrobenzamide (CB1954)-II, A Comparison Of An Escherichia Coli Nitroeductase And Walker DT Diaphorase, Biochemical Pharmacology (1992) vol. 44: 2297-2301.
Mauger, et al., "Self-Immolative Prodrugs: Candidates For Antibody-Directed Enzyme Prodrug therapy In Conjunction With A Nitroductase Enzyme," J. Med. Chem. (1994) vol. 37:3452-3458.
Ram, et al., "In Situ Retroviral-Mediated Gene Transfer For The Treatment Of Brain Tumors In Rats," Cancer Research (1993) vol. 53:83-88.
Denny William Alexander
Tercel Moana
Cancer Research Campaign - Technology Limited
Ramsuer Robert W.
Sherwood Pamela J.
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