Chalcones

Details Chalcones Chalcones

2002-02-15

2003-09-16

Owens, Amelia (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S456000, C549S388000, C549S401000

Reexamination Certificate

active

06620842

ABSTRACT:

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.
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 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 leukaemic cells (Br. J. 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 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.
SUMMARY OF THE INVENTION
Thus according to one aspect of the present invention, there is provided a compound of Formula (I):
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, and in particular, compounds 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, paclitaxel and docetaxel.
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
(A) R
2
and R
3
are each independently selected from:
(i) a substituted or unsubstituted, preferably aromatic, 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 being independently selected from the group consisting of:
Cl, Br, F, OH, NO
2
, CF
3
, C
1-4
lower alkyl (in particular CH
3
), SCH
3
, NHCOCH
3
, N(R
6
)(R
8
), OR
10
and OCOR
11
, wherein R
6,
R
8
, R
10
and R
11
are as defined above,
(ii) Cl, (iii) Br, (iv) F, (v) OH, (vi) NO
2
, (vii) a saturated or unsaturated lower Cl 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
, (viii) NHCOCH
3
, (ix) N(R
6
)(R
8
), (x) SR
10
, (xi) OR
10
, and (xii) OCOR
11
, wherein R
6
, R
8
, R
10
and R
11
are as defined above; or
(B) R
2
and R
3
taken together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring having 5 or 6 ring atoms, any heteroatom being selected from N, O or S, said carbocyclic or heterocyclic ring being saturated or unsaturated, and being unsubstituted or substituted with one or more substituents selected from Cl, Br, F, OH, NO
2
, CF
3
, C
1-6
lower alkyl, SCH
3
, NHCOCH
3
, N(R
6
)(R
8
), OR
10
and OCOR
11
, wherein R
6
, R
8
, R
10
and R
11
are as defined above.
Compounds described above, wherein R
2
and R
3
taken together with the carbon atoms to which they are attached form a ring, may be represented by Formula (IA):
wherein the substituents R and Ar are as defined above, and R
2
and R
3
taken together represent Ring Q, said Ring Q being a five- or six-membered, preferably aromatic, carbocyclic or heterocyclic ring, any heteroatom being selected from N, O, or S, said ring being unsaturated or saturated, said carbocyclic ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from: Cl, Br, F, OH, NO
2
, CF
3
, C
1-4
lower alkyl, SCH
3
, NHCOCH
3
, N(R
6
)(R
8
), OR
10
and OCOR
11
, wherein R
8
, R
8
, R
10
and R
11
are as defined for Formula (I).
Compounds of the invention having a structure Formula (IA) represent the xanthone derivatives of the present invention.
The present invention also embraces compounds of Formula (I), wherein R and Ar are as defined for Formula (I) above and wherein R
2
and R
3
are each independently selected from:
(i) a substituted or unsubstituted, preferably aromatic, 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 being independently selected from the group consisting of
Cl, Br, F. OH, NO
2
, CF
3
, C
1-4
, lower alkyl (in particular CH
3
), SCH
3
, NHCOCH
3
, N(R
6
)(R
8
), OR
10
and OCOR
11
, wherein R
6
, R
8
. R
10
and R
11
are as defined above,
(ii) Cl, (iii) Br, (iv) F. (v) OH, (vi) NO
2
, (vii) 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
, (viii) NHCOCH
3
, (ix) N(R
6
)(R
8
), (x) SR
10
, (xi) OR
10
, and (xii) OCOR
11
wherein R
6
, R
8
, R
10
and R
11
are as defined above.
Such compounds include flavone derivatives according to the present invention. One preferred class of compounds according to Formula (I) are those wherein Ar, R and R
3
are as defined in the above paragraph and wherein R
2
represents
a substituted or unsubstituted, preferably aromatic, 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 being independently selected from the group consisting of Cl, Br, F, OH, NO
2
, CF
3
, C
1-4
lower alkyl (in particular CH
3
), SCH
3
, NHCOCH
3
, N(R
6
)(R
8
), OR
10
and OCOR
11
, wherein R
6
, R
8
, R
10
and R
11
are as defined as for Formula (I) above,
represent flavone derivatives according to the present invention.
Preferably for the above described compounds, R
3
is selected from the group consisting of
Cl, Br, F, OH, NO
2
, a saturated or unsaturated lower C
1-6
straight or branched hydrocarbyl group which may be unsubstituted or substit

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