Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclohexadiene having atoms double bonded directly at the 1-...
Reexamination Certificate
2000-11-03
2002-02-12
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclohexadiene having atoms double bonded directly at the 1-...
C552S293000, C514S529000
Reexamination Certificate
active
06346633
ABSTRACT:
The invention relates to cytotoxic anti-tumour agents. More particularly the invention relates to novel (1,4-benzoquinonyl)alkanoic acid derivatives which bear a substituent comprising a cytotoxic nitrogen mustard moiety. The invention also relates to processes for the preparation of said (1,4-benzoquinonyl)alkanoic acid derivatives, to pharmaceutical compositions containing them and to their use in the production of an anti-tumour effect in a warm-blooded animal such as man.
Many of the current treatments for cell proliferation diseases such as cancer and psoriasis utilise cytotoxic agents which inhibit DNA synthesis or cell division. Such compounds tend to lack specificity and can be toxic to cells generally as neoplastic cells are usually only slightly different from normal cells. The toxic effect of the cytotoxic agent on rapidly dividing tumour cells can be beneficial but normal cells in which continual cell division occurs such as bone marrow cells and gut epithelial cells can also be adversely affected.
There are particular difficulties in obtaining an effective treatment of solid tumours using either chemotherapy with cytotoxic agents or radiotherapy as, within the inner hypoxic regions of the tumour mass where the network of blood capillaries is deficient, cell division is slow or absent. Such hypoxic regions exist in most major classes of solid tumours, for example in bladder, breast, cervical, colorectal, head and neck, lung, ovarian, pancreatic, prostate and stomach tumours. In particular it has been shown by analysis of clinical samples that a significant proportion of most head and neck, breast and cervical tumours, for example between 10% and 30% of the tumour mass, is severely hypoxic with an oxygen tension below 5 mm Hg (0.0066 bar).
It has been recognised that the presence of such hypoxic regions within solid tumours could present an opportunity to allow a more selective cytotoxic drug therapy based on either a prodrug or double-prodrug approach. For example, a prodrug approach is disclosed by B. D. Palmer et al.,
J. Med. Chem
. 1992, 35, 3214-3222, and in International Patent Application WO 93/11099 concerning a nitro-substituted anilino-mustard compound which may be capable of reduction to a more potent amino-substituted anilino-mustard. A problem with this approach was that those additional substituents which were necessary to allow rapid enzymatic reduction of the nitro group tended to diminish the cytotoxic potency of the resultant amino-substituted compound. The double-prodrug approach was taken up to address this problem. For example, it is disclosed by G. J. Atwell et al.,
J. Med. Chem
., 1994, 37, 371-380, and B. M. Sykes et al.,
J. Chem. Soc. Perkin Transact. II
, 1995, 337-342, that certain N-{4-[bis(2chloroethyl)amino]phenyl}-2-nitrophenylacetamide derivatives could be reduced to the corresponding 2-aminophenylacetamide derivatives which could cyclise to release the anilino mustard 4-[bis(2-chloroethyl)amino]aniline. An alternative double-prodrug approach involves the interconversion in biological systems of quinone and hydroquinone moieties. For example, it is disclosed by L. A. Carpino et al.,
J. Org. Chem
., 1989, 54, 3303-3310, that certain (1,4-benzoquinonyl)alkanoic acid derivatives could provide a feasible approach for the delivery of a cytotoxic agent. Model compounds which were prepared included N,N-di-(2-chloroethyl)-3-(2-methoxy-3,5-dimethyl-1,4-benzoquinonyl)-3-methylbutyramide and N,N-di-(2-chloroethyl)-3-(2,3-dimethoxy-5-methyl-1,4-benzoquinonyl)-3-methylbutyramide which were designed to release the simple mustard bis(2-chloroethyl)amine. It is further known from
Proceedings of the American Association for Cancer Research
, 1997, 38, 433-434 (Abstract No. 2894) that the cytotoxic mustard drug melphalan can be linked to a (1,4-benzoquinonyl)alkanoic acid. It was noted that the fastest in vitro bio-reductive activation of certain prodrugs was of the order of 25% per hour i.e. a t
½
of approximately 2.5 hours and this was linked to reduction potentials in the range −480 to −520 mV. In contrast a slower in vitro bio-reductive activation of other prodrugs of the order of 10% per hour i.e. a t
½
of approximately 6 hours was linked to a reduction potential of the order of −730 mV.
It is an object of the present invention to provide double-prodrug quinone compounds which on reduction to the hydroquinone rapidly break down to release the cytotoxic agent.
The present invention provides an anti-tumour agent of the formula I
wherein R
1
is hydrogen, (1-4C)alkyl, (1-4C)alkenyl, (1-4C)alkynyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, pyrrolidin-1-yl(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl, N,N-di-[(1-4C)alkyl]carbanoyl-(1-4C)galkyl, amino, (1-4C)alkylamino, (3-4C)alkenylamino, (3-4C)alkynylamino, di-[(1-4C)alkyl]amino, di-[(3-4C)alkenyl]amino, di-[(3-4C)alklenyl]amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, hydroxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di-[(1-4C)alkyllamino-(2-4C)alkylamino, pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino, morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino, (2-4C)alkanoylamino, (2-4C)alkanoylamino-(2-4C)alkylamino, carboxy-(1-4C)alkylamino, (1-4C)alkoxycarbonyl-(1-4C)alkylamino, carbamoyl-(1-4C)alkylamino, N-(1-4C)alkylcarbamoyl-(1-4C)alkylamino, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkylamino, hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy or 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy;
R
2
is hydrogen, (1-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, pyrrolidin-1-yl]-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl, 4-(2-4C)alkylpiperazin-1-yl-(1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkyl, amino, (1-4C)alkylamino, (3-4C)alkenylamino, (3-4C)alkynylamino, di-[(1-4C)alkyl]amino, di-[(1-4C)alkenyl]amino, di-[(3-4C)alkynyl]amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, hydroxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di-[(1-4C)alkyl]amino-(2-4C)alkylamino, pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino, morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino, (2-4C)alkanoylamino, (2-4C)alkanoylamino-(2-4C)alkylamino, carboxy-(1-4C)alkylamino, (1-4C)alkoxycarbonyl-(1-4C)alkylamino, carbamoyl-(1-4C)alkylamino, N-(1-4C)alkylcarbainoyl-(1-4C)alkylamino, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkylamino, hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy or 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy;
R
3
is hydrogen, (1-4C)alkyl, (1-4C)alkenyl, (3-4C)alkynyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)
AstraZeneca AB
Chaudhry Mahreen
Killos Paul J.
Winthrop LLP Pillsbury
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