Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-05-04
2002-04-16
Killos, Paul J. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S552000, C514S886000, C514S914000, C552S208000, C560S008000, C560S129000
Reexamination Certificate
active
06372785
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field Of The Invention
This invention relates to novel anthracene compounds useful in the treatment of allergic, inflammatory, and tumor conditions, and to therapeutic compositions containing such compounds. The invention provides therapeutic compositions effective at low doses with low irritancy. The agents of the invention form a distinct class, lacking the anthrone or anthraquinone nucleus.
2. Description Of The Prior Art
Anthracenone derivatives display potent and selective antitumor activity against inter alia GBM and KB cell lines, telomerase inhibition and antioxidant activity, and their mechanism of action, though yet to be defined, may be novel.
The discovery of the antitumor activity of 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones such as ametantrone (1) and mitoxantrone (2) (see
FIG. 1
) (Zee-Cheng, R. K. V. et al.,
J. Med. Chem,
21, 291-294, (1978); Zee-Cheng, R. K. V. et al.,
J. Pharm. Sci.,
71, 708-709, (1982); Murdock, K. C. et al.,
J. Med. Chem.,
22, 1024-1030 (1979)) has led to numerous physicochemical and pharmacological studies on the tumoricidal mechanisms of these chemotypes. Krapcho, A. P. et al.,
J. Med. Chem.,
34, 2373-2380, (1991); Morier-Teissier, E. et al.,
J. Med. Chem.,
36, 2084-2090, (1993).
1,8-Dihydroxy-9(10H)-anthracenone (anthralin; dithranol) (3) (see
FIG. 1
) is recognized as a potent antipsoriatic agent, and has been in clinical use, especially in European countries, for more than half a century. Unna published the first part of his fundamental monograph on the structure-activity relationships of 1,8-dihydroxy-9(10H)-anthracenone and related hydroxyanthrones in 1916. Unna P. G.
Dermatol. Wochenschr.,
62, 175-183 (1916). 1-Hydroxy-9-anthrone (4) has been shown by Krebs and Schaltegger (Krebs, A.; Schaltegger, H.
Hautarzt,
20, 204-209, (1969)) to comprise the “minimal basic structure for antipsoriatic activity”.
The mechanism of the antitumor activity of the anthracene-9,10-diones such as ametantrone (1) and mitoxantrone (2) is probably multimodal in nature. However, a number of studies have indicated that an intercalative interaction with DNA may be a major cellular event. Denny, W. A.
Anti
-
Cancer Drug Design,
4, 241-263 (1989). Mitoxantrone, an anthracene-9,10-dione, has gained an important position in the clinical management of leukemia and lymphomas as well as in combination therapy of advanced breast and ovarian cancers. Faulds, D. et al.,
Drugs,
41, 400-449 (1991). Although mitoxantrone is endowed with an improved tolerance prolife when compared with doxorubicin and other anthracyclines, significant toxic side effects, notably those associated with myelosuppression and cardiotoxicity, remain. Benekli, M. et al.,
Ann. Intern. Med.,
126, 409 (1997).
Mitoxantrone (2) also shows a cross-resistance to cell histotypes developing resistance against doxorubicin mediated by overexpression of glycoprotein. P. Bailly, J. D. et al.,
Leukemia,
11, 1523-1532 (1997). Several studies suggest that intercalation into DNA is a major cellular event and this intercalative interaction may serve as an anchor for the drug at specific base pair sites, which is then followed by the critical cell-killing events. The biochemical basis for the cardiotoxicity exhibited by mitoxantrone is not fully understood. It is generally believed that the in vivo reduction of the quinone moiety is probably more related to the cardiotoxic side effects of mitoxantrone than to its mechanism of cytotoxicity. Krapcho, A. P., et al.,
J. Med. Chem.,
41, 5429-5444 (1998).
Antitumor quinones represent one of the largest classes of clinically approved anticancer agents in the U.S.A., second only to the chloroethyl alkylating agents. Antitumor quinones have been selected from the large number of naturally occurring quinones (Moore, H. W. et al.,
Drugs Expl. Clin. Res.,
12, 475-494, (1986)) and from synthetic quinones (Bruce, J. M. ed.,
Benzoquinones and Related Compounds,
Vol. 3, Part 4, 1-306, (1974)). The planar tricyclic system is known to intercalate into DNA base pairs and interfere in the transcription and replication processes of the cell. Johnson, R. K. et al., Cancer Treat. Rep., 63, 425-439, (1979); Lown, J. W. et al., Biochemisty, 24, 4028-4035, (1985). The DNA binding affinity (quantified as a binding affinity constant) and the dissociation rate constant for the DNA-ligand complex have been evaluated. Drug-DNA binding constants for ametantrone (1), mitoxantrone (2) and related congeners with calf thymus DNA show a large sensitivity to the position and number of the OH substitutions and the nature of the charged side chain. Denny, W. A.
Anti
-
Cancer Drug Design,
4, 241-263 (1989).
Anthraquinone-based compounds currently occupy a prominent position in cancer chemotherapy, with the naturally occurring aminoglycoside anthracycline doxorubicin and the aminoanthraquinone mitoxantrone both being in clinical use. These and other experimental anthraquinone derivatives are believed to act at the duplex DNA level, probably through the stabilization of a ternary complex with DNA topoisomerase II. Zunino, F. et al.,
Anti
-
Cancer Drug Des.,
5, 307-317 (1990).
There is increasing evidence that intercalation into DNA represents an attractive target for the rational design of new anticancer agents in view of its central role in the control of cellular proliferation. Normal human cells undergo a finite number of cell divisions and ultimately enter a nondividing state called replicative senescence. During successive rounds of cell division, this end-replication problem results in telomere shortening and ultimately senescence. As such, the loss of telomeric repeats after each round of cell division has been likened to a “biological clock” limiting the proliferative life span of normal somatic cells. Harley, C. B. et al.,
Nature,
345, 458-460 (1990). Consequently, telomerase has been proposed as a potentially highly selective target for the development of a novel class of antiproliferative agents.
Additional references disclose 1,4- and 2,6-disubstituted or regioisomeric amidoanthracene-9,10-dione derivatives as inhibitors of human telomerase include Philip J. Perry et al.
J. Med. Chem.
41, 3253-3260 (1998) and Philip J. Perry et al.
J. Med. Chem.
41, 4873-4884 (1998). However, in order for a therapeutic treatment to be effective, both the inflammatory and hyperproliferative aspects of the condition must be addressed without an increase in toxicity or the lack of patient tolerance observed with existing therapeutic agents.
Substantial evidence suggests that free radicals and active oxygen species play a key role in both the therapeutic activity and side effects of anthracenone derivatives. The generation of free radicals from quinones occurs by addition of an electron to the quinone to form semi-quinone free radicals which then transfer an electron to molecular oxygen to afford superoxide radical anion. The resulting radical anions ultimately lead to hydroxyl radicals which can damage cardiac tissue. Despite the attempts to rationalize the cardiotoxicity of anthracene-9,10-dione antitumor agents, few compounds have been shown to possess both good antitumor activity and little or no cardiotoxicity. Consequently there appears to be no way to predict which compounds will be cardiotoxic and which compounds will not. One is thus confronted with the major problem of designing molecules with high efficacy and no toxicity. Krapcho, A. P. et al.,
J. Med. Chem.,
41, 5429-5444 (1998).
As noted above, cancer is typically characterized by hyperproliferative component. There is thus a continuing need for effective compounds that address these aspects of cancer disease.
The present invention differs from the prior art in the absence of the anthrone or anthraquinone structures. This modification is not suggested by the prior art which teaches the significance of the quinone structure in the antitumor activity of these agents through free radical generation.
The invention satisfies the need for effective therapeutic agents f
Chao Fei-Fei
Keith Chan, President GloboAsia, LLC
Killos Paul J.
Reyes Hector M
Venable Baetjer Howard & Civiletti LLP
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