Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-12-08
2000-11-14
Seaman, D. Margaret
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514357, 514415, 546344, 546346, 546348, 548509, A61K 31435, A61K 3144, C07D21170, C07D20904
Patent
active
061470821
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a novel class of compounds which have structures related to certain naturally occurring and synthetic chalcones, as well as to methods for the preparation of such compounds and to pharmaceutical uses thereof.
BACKGROUND OF THE INVENTION
The compound 1,3-diphenyl-2-propene-1-one is known by the trivial name "chalcone". Many naturally occurring flavonoids share structural features with chalcone and are referred to by the generic term "chalcones". Also, certain flavonoids, including ones which are also classified as chalcones, have recently been demonstrated to have anticancer activity (Cancer Research, 48, 5754, 1988) and chemopreventive activity in some tumours (J. Nat. Prod., 53, 23, 1990).
In particular, quercetin, an ubiquitous flavonoid found in plants, has been shown to act on the proliferation of human leukemic cells (Br. J. of Haematology, 75, 489, 1990) and on other cell lines (Br. J. Cancer, 62, 94, 942, 1990; Int. J. Cancer, 46, 112, 1990; Gynecologic Oncology, 45, 13, 1992) and to possess a synergic action with common antiblastic drugs.
In addition, some natural or synthetic chalcones, described in our International Patent Publication No. WO 91/17749 and in International Patent Publication No. WO 96/19209 (Baylor College of Medicine) have proved to have a significant antiproliferation activity on a variety of different cell lines.
Although the mechanism of action of the antiproliferation activity of flavonoids and chalcones is still unknown, it is believed to be linked to the interaction of these compounds with type II estrogen receptors.
The action in vivo of these polyphenol substances is certainly much more complicated. All these compounds are generally characterized by an almost complete insolubility in water and, in vivo, by a very poor bioavailability linked to a rapid metabolism of phenols and a marked affinity for lipids and proteins.
SUMMARY OF THE INVENTION
Surprisingly, it has now been found that certain novel chalcones, chalcone derivatives and chalcone analogues, in particular ones in which the phenyl ring in the 3-position is substituted or replaced by rings containing one or more heteroatoms, possess a greater antiproliferation activity both on sensitive cancerous cells and on cells which are resistant to common chemotherapeutic drugs, including the latest generation anti-neoplastic agents, paclitaxel and docetaxel.
DETAILED DESCRIPTION OF THE INVENTION
Thus according to one aspect of the present invention, there are provided compounds of the general formula (A) ##STR1## wherein: Ar represents phenyl, which may be unsubstituted or substituted by one, two or three substituents independently selected from Cl, Br, F, --OMe, NO.sub.2, CF.sub.3, C.sub.1-4 lower alkyl (preferably methyl), --NMe.sub.2, --NEt.sub.2, --SCH.sub.3, --NHCOCH.sub.3 ; 2-thienyl; 2-furyl; 3-pyridyl, 4-pyridyl or 3-indolyl; --CH.dbd.CMe.sub.2, --CMe.dbd.CH.sub.2, --C.tbd.CH; with the proviso that where Ar represents phenyl, R is other than 3-methyl-2-butenyl oxy.
Within this class, preferably Ar is selected from unsubstituted phenyl, 3-pyridyl, 4-pyridyl and 3-indolyl. Particularly preferred are compounds wherein R represents --OCH.sub.2 --CH.dbd.CMe.sub.2, --OCH.sub.2 --CMe.dbd.C.sub.2, or --OCH.sub.2 --C.tbd.CH.
Compounds of formula (A) which contain a basic amino function may be converted to acid addition salts with pharmaceutically acceptable acids such as hydrochloric and phosphoric acids and such salts are included in the present invention.
This invention also includes the use of the compounds of Formula (A) in the treatment and prevention of neoplasms, particularly of the uterus, ovary and breast, and in the treatment and prevention of menopausal disorders and osteoporosis. The invention further includes pharmaceutical compositions comprising one or more of the compounds of Formula (A) and one or more pharmaceutically acceptable excipients.
In vitro results have shown that the compound of the invention have a marked affinity to type II estrog
REFERENCES:
S. Budavari; "The Merck Index, An Encyclopedia of Chemicals, Drugs and Biologicals"; 12.sup.th edition; 1996; p. 1381.
T. Konoshima et al.; "Studies on inihibitors of skin tumor promotion (V). Inhibitory effects of flavonoids of Epstein-Barr virus activation II.", Shoyakugaku Zasshi; ISSN 0037-4377, vol. 43, No. 2, 1989, pp. 135-141.
A. Verma et al.; "Inhibition of 7, 12-Dimethylbenz(a)anthracene-and N-Nitrosomethylureau-induced Rat Mammary Cancer by Dietary Flavonol Quercetin"; Cancer Research, 1988, vol. 48, pp. 5754-5758.
J. Cassady; "Natural Products as a Source of Potential Cancer Chemotherapeutic and Chemopreventive Agents"; Journal of Natural Products, 1990, vol. 53, No. 1, pp. 23-41.
L. M. Larocca et al.; "Type II oestrogen binding sites in acute lumphoid and myeloid leukaemias: growth inhibitory effect of oestrogen and flavonoids"; British Journal of Haematology; 1990; 75; pp. 489-495.
G. Scambia et al.; "Inhibitory effect of quercetin on OVCA 433 cells and presence of type II oestrogen binding sites in primary ovarian tumours and cultured cells"; British Journal Cancer; 1990; 62; pp. 942-946.
J. Eliason et al.; Human Multi-Drug-Resistant Cancer Cells Exhibit A High Degree of Selectively for Steroisomers of Verapamil and Quinidine; International Journal Cancer; 1990; 46, pp. 113-117.
G. Scambia et al.; "Inhibitory Effect of Quercetin on Primary Ovarian and Endometrial Cancers and Synergistic Activity with cis-Diamminedichloroplatinum (II)"; Gynecologic Oncology; 1992; 45; pp. 13-19.
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