Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-11
2001-06-26
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S465000, C534S703000
Reexamination Certificate
active
06251933
ABSTRACT:
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 IC
50
'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 at the 6-position 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) and KW-2189 (E. Kobayashi et al, Cancer Res., 54, 1994, 2404-2410) which show anticancer activity against a range of human tumours and are in clinical trial. These compounds have the structures A and B respectively:
Further analogues of a similar type are disclosed in WO88/04659 and WO91/16324.
REFERENCES:
patent: 0154445 (1985-09-01), None
patent: 0461603 (1991-12-01), None
patent: 0520435 (1992-12-01), None
patent: WO 88/07378 (1988-10-01), None
Boger et al.;Tetrahedron; (1991) 47 (14/15):2661-2682.
Boger et al.;J. Org. Chem.; (1990) 55:4499-4502.
Boger et al.;J. Am. Chem. Soc.; (1990) 112:8961-8971.
Chemical Abstracts, vol. 126, No. 6, (Feb. 10, 1997), abstract No. 69799.
Chemical Abstracts, vol. 126, No. 6, (Feb. 10, 1997), abstract No. 74710.
Atwell Graham John
Denny William Alexander
Milbank Jared
Tercel Moana
Bozicevic Field & Francis LLP
Higel Floyd D.
Sackey Ebenezer
Sherwood Pamela J.
The Cancer Research Campaign Technology Limited
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