Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-15
2004-07-27
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S283100, C514S337000
Reexamination Certificate
active
06767916
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a novel class of compounds which have a structures related to naturally and synthetically occurring chalcones, as well as to methods for preparation of such compounds and to pharmaceutical uses thereof.
TECHNICAL FIELD
The compound 1,3-diphenyl-2-propene-1-one is known by the trivial name chalcone. Many naturally occurring flavanoids share structural features with chalcone and are referred to by the generic term “chalcones”. Also certain flavanoids, including ones which are 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; Gynaecologic 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 9117749 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 antiproliferative 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 characterised 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.
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 1-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, pacitaxel and docetaxel.
SUMMARY OF THE INVENTION
Thus according to one aspect of the present invention, there is provided a compound of Formula (I):
or a pharmaceutically acceptable salt or solvate thereof wherein:
Ar represents:
a substituted or unsubstituted, (preferably aromatic), carbocyclic or heterocyclic group, said carbocyclic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents on the Ar group being independently selected from the group consisting of:
(a) Cl, (b) Br, (c) F, (d) OH, (e) NO
2
, (f) CF
3
, (g) C
1-4
lower alkyl (in particular CH
3
), (h) SCH
3
, (i) NHCOCH
3
, (j) N(R
6
)(R
8
) wherein R
6
and R
8
are the same or different and each represents H or lower C
1-4
alkyl, (k) OR
10
wherein R
10
represents a saturated or unsaturated lower C
1-6
straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from:
Cl, Br, F, OMe, NO
2
and CF
3
,
and (I) —OCOR
11
, wherein R
11
represents a saturated or unsaturated lower C
1-6
straight or branched hydrocarbyl group or a phenyl group;
R represents
OH, OR
10
or OCOR
11
, wherein R
10
and R
11
are as defined above; and R
1
represents H or a lower C
1-6
straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl, Br, F, OMe, NO
2
and CF
3
.
REFERENCES:
patent: 5525625 (1996-06-01), Bridges et al.
patent: 5808137 (1998-09-01), Bombardelli et al.
patent: 2387956 (1978-11-01), None
patent: WO 91/17749 (1991-11-01), None
Thaker et al, Synthesis of 2′-(3″-pyridyl)-y-pyranocoumarins and 3′-hydroxy-2′-(3″-pyridyl)-y-pyranocoumarins.*
CA 95:203793, Thakar et al. 1981.*
CA 92:58620, Fr. 2387956, 1980.*
Verma, A.K. et al,. “Inhibition of 7, 12-Dimethylbenz(&agr;)anthracene- andN-Nitrosomethylurea-induced Rat Mammary Cancer by Dietary Flavonol Quercetin,” Cancer Research 48, pp. 5754-5758, 1988.
Baird, W. et al., “Natural Products as a Source of Potential Cancer Chemotherapeutic and Chemopreventive Agents,” Journal of Natural Products, 53;1, pp. 23-41, 1990.
Larocca, L.M. et al., “Type II Oestrogen Binding Sites in Acute Lymphoid and Myeloid Leukaemias: Growth Inhibitory Effect of Oestrogen and Flavonoids,” British Journal of Hermatology, 75, pp. 489-495, 1990.
Scambia, G. 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,” Br. J. Cancer, 62, pp. 942-946, 1990.
Gogusev, J. et al., “Genotype Markers and Proto-Oncogene Analysis in the CD30-Positive “Malignant Histiocytosis,” Del Cell Line With t(5;6)(q35;21),” Int. J. Cancer, 46, pp. 106-112, 1990.
Scambia, G. et al., “Inhibitory Effect of Quercetin on Primary Ovarian and Endometrial Cancers and Synergistic Activity withcis-Diamminedichloroplatinum(II),” Gynecologic Oncology, 45, pp. 13-19, 1992.
Skehan, P. et al., “New Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening,” Journal of the National Cancer Institute, 82:13, pp. 1107-1112, 1990.
Sharan, P. et al., “Synthesis of some 7-Hydroxy-4-methylcoumarin-8-yl Chalcones and related Iso-oxazoles as Potential Fungicides,” J. Indian Chem. Soc., 66, pp. 393-394, 1989.
Nair, M.S. et al., “Synthesis of Some Functionalized Oxapolyquinanes,” Indian Journal of Chemistry, 27B, pp. 701-706, 1988.
Sangwan, N.K. et al., “Synthesis and Biological Properties of Substituted 2H-1-Benzopyran-2-ones and 2H, 10H-Benzo [1,2-b:3,4-b']dipyran-2, 10-diones,” Journal f. prakt. Chemie., 330:1, pp. 137-141, 1988.
Bombardelli Ezio
Valenti Piero
Chang Ceila
Indena S.p.A.
Jones Day
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