Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – N-c doai
Patent
1997-07-16
1999-12-21
Geist, Gary
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
N-c doai
514490, 560 21, 560 24, 560 25, 560133, A01N 4710, C07C20506, C07C27150
Patent
active
060050020
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to prodrugs and their use in the treatment of disease, including cancers.
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.
More recently. a similar approach ("GDEPT", Gene-Directed Enzyme Prodrug Therapy) has been proposed where in place of an antibody/enzyme conjugates 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 tumour 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 only in the vicinity of the tumour cells (Huber et al. Proc. Natl. Acad. Sci. USA (1991) 88, 8039). The enzvme may be targeted to particular subcellular locations or expressed at the cell surface.
The present invention provides novel prodrugs which contain protecting groups which are more lipophilic than compounds of the prior art such as those disclosed in WO88/07378. Accordingly, the present invention provides compounds of the formula (I): ##STR2## wherein X and Y are independently chlorine, bromine, iodine, a mesyl group CH.sub.3 SO.sub.3 or a tosyl group OSO.sub.2 phenyl (wherein phenyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from C.sub.1-4 alkyl, halogen, cyano or nitro; or different when n is greater than 1, is fluorine, chlorine, bromine, iodine, hydroxy, mercapto, amino, nitro, C.sub.1-4 alkyl optionally containing one double bond or one triple bond, C.sub.1-4 alkoxy, --CONR.sup.7 R.sup.8 (wherein R.sup.7 and R.sup.8 are as defined below), --NH(C.sub.1-4 -alkyl), --N(C.sub.1-4 alkyl).sub.2 or C.sub.2-5 alkanoyl; or when n is 2 or more and two groups R.sup.1 are on adjacent positions on the phenylene ring, 2 adjacent R.sup.1 groups together represent --CH.dbd.CH-- each optionally substituted with 1, 2, 3 or 4 substituents said substituents each independently selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen, cyano, nitro, C.sub.2-5 alkanoyl and --CONR7R8 (wherein R7 and R8 are as defined below); when m is greater than 1, is fluorine, chlorine, bromine, iodine, hydroxy, mercapto, amino, nitro, C.sub.1-4 alkyl optionally containing one double bond or one triple bond, C.sub.1-4 alkoxy, --CONR.sup.7 R.sup.8 (wherein R.sup.7 and R.sup.8 are as defmed below), --NH(C.sub.1-4 -alkyl), --N(C.sub.1-4 -alkyl).sub.2 and C.sub.2-5 alkanoyl; or when n is 2 or more and two groups R.sup.1 are on adjacent positions on the phenylene ring, 2 adjacent R.sup.1 groups together represent --CH.dbd.CH-- each optionally substituted with 1, 2, 3 or 4 substituents said substituents each independently selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen, cyano, nitro, C.sub.2-5 alkanoyl and --CONR7R8 (wherein R7 and R8 are as defined below); --CH.sub.2 --, --O--, --S--, --(SO)-- or --(SO.sub.2)--(provided that when V has sulphur or oxygen as its second atom, W is other than --COOH) and said group V optionally further carrying one or two substituents Q1 and/or Q2 on carbon; wherein Q.sup.1 and Q.sup.2 each independently represents C.sub.1-4 alkyl or halogen; or, when Q1 and Q2 are bonded to adjacent carbon atoms, Q.sup.1 and Q.sup.2 together may additionally represent a C.sub.3 -C.sub.4 alkylene radical optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C.sub.1-4 alkyl and halogen and cycloalkyl or aryl (as defined in 3 below) group; hydrogen or a C1-6 alkyl, C3-6 cycloalk
REFERENCES:
Anthony B. Mauger et al., "Self-Immolative Prodrugs: Candidates for Antibody-Directed Enzyme Prodrug Therapy in Conjunction with a Nitroreductase Enzyme", Journal of Medical Chemistry, vol. 37, No. 21, pp. 3452-3458 (Oct. 14, 1994).
Niculescu-Duvaz Ion
Springer Caroline Joy
Cancer Research Campaign - Technology Limited
Davis Brian J.
Geist Gary
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