Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-01-05
1999-08-10
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 64, A61K 31435, C07D49512
Patent
active
059359692
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the invention
This invention is directed to positions 2 and 5.
These compounds have been shown to have antitumor activity.
2. Background which show antitumor activity in clinical trials. Of particular interest has been ametantrone, mitoxantrone, "Progress in Medicinal Chemistry", Ellis, G. P. and West, G. B., eds.; Elsevier: Amsterdam, 1983, vol. 20, pp. 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 have demonstrated a diminished cardiotoxicity in comparison to doxorubicin, some clinical cardiotoxicity has been observed also with Stuart Harris et al., Lancet, 219, (1984) and references cited therein!.
Ametantrone has been reported to be, in animals, about 10-fold less potent and cardiotoxic than mitoxantrone. Because a delayed toxicity is observed only with mitoxantrone after administration of the two drugs by the i.p. route to non-tumor bearing rats at equieffective antitumor dosages, it is suggested that the presence of the 5,8-dihydroxy substitution in Cancer Chemother. Pharmacol., 6, 161 (1981)!.
In addition, both mitoxantrone and ametantrone have a remarkable myelodepressive toxicity and both compounds show cross-resistance to cell histotypes developing resistance against doxorubicin mediated by overexpression of glycoprotein P. Such a resistance, which is named multidrug resistance (MDR), involves a number of antitumor antibiotics, among which amsacrine and podophyllotoxinic In addition, both mitoxantrone and ametantrone have a remarkable myelodepressive toxicity and both derivatives, and it is one of the main reasons for therapeutic failures in the treatment of solid tumors with said antibiotics.
In an attempt to overcome the above mentioned drawbacks some chromophore modified anthracenediones have been prepared. For example, E. P. Patent Application 103.381 discloses 2-aminoalkyl-5-aminoalkylamino substituted have antitumor activity. The antitumor activity of said compounds in a number of preclinical models has been reported by H. D. Hollis Showalter not devoid of toxic side effects, with severe leukopenia (W.H.O. grade 3 and 4) and neutropenia (W.H.O. grade 4) being dose limiting in phase I and al., J. Clin. Oncol., 9, 2141-2147 (1991)!. Moreover a marked and M. E. C. Robbins, Nephrotoxicity, Peter H. Dekker Bach editor, pp. 345-352 (1991), New York; see Chemical Abstract 116: 294n (1992)! and these authors suggest that renal injury may be a clinical problem with 17, 725 (1992); Judson, I. R. et al., Proc. Amer. Assoc. Cancer Res., 32, abstr. 1059 (1991)! indicate that the anthrapyrazole CI-941 induces irreversible cardiotoxicity in humans, although no symptoms of cardiac failure or acute cardiac events have been reported.
Furthermore, WO94/06795 (31.03.94) describes aza-anthrapyrazole derivatives which are endowed with antitumor activity.
In the attempt to reduce the radical formation "in vivo" by eliminating the Hollis Showalter et al., J. Med. Chem., 31, 1527-1539 (1988)!. In these compounds a carbonyl group at C-6 position has been replaced by a sulphur atom. A compound of this series, CI-958, has been chosen for development toward clinical trials.
However, the search for newer active analogues is still highly desirable. We have now discovered that the introduction of one nitrogen atom in the positions 7, 8, 9 or 10 of the above mentioned benzothiopyranoindazoles positions 2 and 5, which have showed a marked antitumor activity.
BRIEF SUMMARY OF THE INVENTION
The compounds of the invention have the general formula (I): ##STR2## wherein: one of X, Y, Z or T is nitrogen (.dbd.N--) and the others are a .dbd.CH-- group; D is selected from the group consisting of nitro or --NH--A, wherein A is on its turn selected in the group consisting of hydrogen, --CO--CH.sub.2 --NR.sub.2 R.sub.3, C.sub.1
REFERENCES:
patent: 4604390 (1986-08-01), Elslager et al.
patent: 5519029 (1996-05-01), Krapcho et al.
Aulakh Charanjit S.
Rotman Alan L.
University of Vermont
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