Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-11-26
1999-09-14
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514215, 5142245, 5142295, 514248, 514250, 540578, 544 14, 544 99, 544233, 544245, A61K 31505, C07D26534, C07D23970, C07D27914
Patent
active
059523352
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel fused polycyclic heterocycle derivatives, a process for producing the same and medicinal compositions containing the same as the active ingredient.
BACKGROUND ART
A tricyclic compound amonafide is the most famous fused polycyclic heterocycle antitumor compound having a cyclic imido moiety ##STR2## in its molecule. However, it is reported that amonafide showed a strong bone marrow toxicity and a poor efficacy in clinical tests carried out reported azonafide ione! obtained by converting the aminonaphthalene moiety of amonafide into anthracene to thereby enhance the antitumor activity in preclinical tests (WO9200281).
As fused tetracyclic heterocycle antitumor substances having a uracil structure wherein a nitrogen atom has been introduced into a cyclic imido moiety, there have been known 47, 1035 (1992)! and these compounds showed only a weak antitumor activity in preclinical tests. There has been reported neither pentacyclic nor hexacyclic fused heterocycle antitumor substances of this type.
The present invention aims at providing novel compounds or novel fused pentacyclic and hexacyclic heterocycle derivatives having low toxicity and excellent antitumor activity. The present invention also aims at providing a process for producing these compounds and medicinal compositions containing as the active ingredient these compounds.
DISCLOSURE OF THE INVENTION
To achieve the above-mentioned objects, the present inventors have conducted extensive studies in order to develop excellent antitumor substances. As a result, they have successfully found out that novel fused pentacyclic and hexacyclic heterocycle compounds having a uracil structure in the molecule have excellent antitumor activity and low toxicity, thus completing the present invention.
That is, the present invention relates to a compound represented by the following general formula (I) or pharmacologically acceptable salts thereof: ##STR3## wherein the ring A represents an optionally substituted monocyclic aromatic ring or a dicyclic fused ring in which at least one of the rings is an aromatic ring; the ring B represents pyrrole, 4H-1,4-oxazine, 4H-1,4-thiazine or 4(1H)-pyridone; the ring C represents an optionally substituted, monocyclic or dicyclic fused aromatic ring; and Y represents a group represented by the formula --e--f wherein e represents lower alkylene; and f represents amidino, guanidino or amino, which can be optionally substituted with a lower alkyl which can be optionally hydroxylated or optionally lower-alkylaminated;
provided that the cases where the rings A and C are both optionally substituted monocyclic aromatic rings are excluded.
Further, the present invention relates to a medical composition comprising a fused polycyclic heterocycle as derivative described above in a pharmacologically efficacious dose or pharmacologically acceptable salts thereof and pharmacologically acceptable carriers.
Further, the present invention relates to a method for preventing or treating tumors by administering a fused polycyclic heterocycle derivative as described above in a pharmacologically efficacious dose to a patient.
In the definition of the ring A in the above general formula (I), the term "monocyclic aromatic ring" means an aromatic 5- or 6-membered ring optionally containing at least one oxygen or sulfur atom. The term "dicyclic fused ring in which at least one of the rings is an aromatic ring" means a dicyclic fused ring in which each of the rings is a 5- to 8-membered ring optionally containing at least one nitrogen, oxygen or sulfur atom and at least one of the rings is an aromatic ring. It may have one to three substituents on the rings.
Examples of the ring A include benzene, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, pyrrole, thiazole and the following dicyclic fused rings which may be partly hydrogenated and oxidized at a sulfur atom, if contained therein. These rings may be fused to the ring B at an arbitrary position allowable chemically. ##STR4##
Each of the abo
REFERENCES:
patent: 3962438 (1976-06-01), Berkoff et al.
Antonini et al., Synthesis of (Dialkyamino)alkyl-Disubstituted Pyrimido(5,6,1-de) acridines, a Novel Group of Anticancer Agents Active on a Multidrug Resistant Cell Line, J. Med. Chem., vol. 38, No. 17, pp. 3282-3286, 1995.
Kamata Jun-ichi
Kito Kyosuke
Kotake Yoshihiko
Koyanagi Nozomu
Nagasu Takeshi
Coleman Brenda
Eisai Co. Ltd.
Raymond Richard L.
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