Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-06-22
2000-03-07
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546101, C07D47106, C07D22118, A61K 31435
Patent
active
060340924
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to 2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[[2-methylamino)ethyl]amino]indazolo[ 4,3-gh]isoquinolin-6(2H)-one and the pharmaceutically acceptable acid addition salts thereof.
This compound has shown a high antitumor activity.
PRIOR ART
Some 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones have shown antitumor activity in clinical trials. Particularly interesting are ametantrone, 4-bis{[2-(2-hydroxyethylamino)ethyl]amino]anthracene-9,10-dione and mitoxantrone, 5,8-dihydroxy-1,4-bis{[2-(2-hydroxyethylamino)ethyly]amino]anthracene-9,10 -dione. (Zee-Cheng et al., J. Med. Chem., (1978), 21, 291-4; Cheng et al., "Progress in Medicinal Chemistry", Ellis, G. P. and West, G. B., eds.; Elsevier: Amsterdam, 1983; pp. 20, 83 and references cited therein). Mitoxantrone is a broad spectrum oncolytic agent, whose activity is similar to that of the anthracycline antibiotic doxorubicin. Clinical trials have demonstrated that mitoxantrone has particularly promising activity in the treatment of advanced breast cancer, acute leukemia and lymphoma (Legha, Drugs of Today, (1984), 20, 629). The limiting aspect of these medicaments is the cardiotoxicity, particularly with mitoxantrone, and the mielodepressive toxic effect of both of them. In addition, both compounds show cross-resistance towards the cell histotypes developing resistance already against doxorubicin, said resistance being mediated by over-expression of glycoprotein P. Such a resistance, which is named multidrug resistance, involves a number of antitumor antibiotics, among which amsacrine and podophyllotoxin and derivatives, and it is one of the main reasons for therapeutical failures in the treatment of solid tumors with said antibiotics.
In an attempt to overcome these drawbacks, some anthracenediones with the chromophor modified were prepared. For example, EP-A 103,381 claims 2-aminoalkyl-5-aminoalkylamino anthra[1,9-cd]pyrazol-6(2H)-ones (anthrapyrazoles) with antitumor activity. The antitumor activity of said compounds in pre-clinic trials has been reported by H. D. Hollis Showalter et al. (J. Med. Chem., 30, 121-131 (1987)).
However, anthrapyrazoles are not devoid of toxic side-effects, such as severe leukopenia (W.H.O. grade 3 and 4) and neutropenia (W.H.O. grade 4) which turned out to be dose-limiting in clinical trials of phase I and II with anthrapyrazole CI-941 [I. E. Smith et al., J. Clin. Oncol., 9, 2141-2147 (1991)]. Moreover, a marked nephrotoxicity is associated with the treatment with CI-941 in the rat [D. Campling e M. E. C. Robbins, Nephrotoxicity, Peter H. Dekker Bach and., Pag. 345-352 (1991), New York: vedi Chem. Abstracts 116: 294n (1992)] and these authors suggest that the renal damage could be a clinical problem of the anthrapyrazole therapy. Moreover, recent works [Drugs of the Future, 17, 725 (1992); Judson, I. R. et al., Proc. Amer. Assoc. Cancer Res., 32, abstr. 1059 (1991)] show that anthrapyrazole CI-941 induces irreversible cardiotoxicity in man, even though no symptoms of acute cardiac events have ever been reported.
From what stated above, the search for novel active analogues is still highly desirable.
Anthrapyrazole aza-analogues, in which the nitrogen has been introduced at the 8- and 9- positions, are described in PCT/US93/08241 (published on Mar. 31, 1994, WO94/06795). Said compounds have evidenced a high antitumor activity both on in vitro and in vivo models and, contrary to doxorubicin and mitoxantrone, showed no cross-resistance on the LoVo/DX cell line. These data allow to envisage a possible activity in clinic on leukemias and solid tumors sensitive to the treatment with antitumor antibiotics.
Now it has been found that an anthrapyrazole 9-aza-analogous, 2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[[2-(methylamino)ethyl]amino]indazolo [4,3-gh]isoquinolin-6(2H)-one, has a surprising activity which makes it markedly different from the other derivatives of this series. Said compound, in fact, in addition to an higher increase in the average survival time of the treated animals (expressed as % T/C) than
REFERENCES:
patent: 5519029 (1996-05-01), Krapcho et al.
Krapcho Paul
Menta Ernesto
Oliva Ambrogio
Spinelli Silvano
Novuspharma S.p.A.
Rotman Alan L.
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