Substituted chalcones as therapeutic compounds

Details Substituted chalcones as therapeutic compounds Substituted chalcones as therapeutic compounds

2002-09-26

2004-09-07

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C568S331000, C568S334000, C568S337000, C514S681000, C514S685000, C514S688000

Reexamination Certificate

active

06787672

ABSTRACT:

TECHNICAL FIELD
This invention pertains to substituted chalcones, specifically substituted 1-(4-methoxyphenyl)-3-(3,5-dimethoxyphenyl)prop-1-en-3-ones, which have therapeutic application, for example, as potent antiproliferative agents and antiinflammatory agents. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, for both diagnosis and treatment of, for example, proliferative conditions, such as cancer, and inflammatory conditions.
BACKGROUND
Chalcone, also known as chalkone, benzylideneacetophenone, benzalacetophenone, and phenyl styryl ketone, is 1,3-diphenyl-2-propen-1-one, and has the following structure:
A number of substituted chalcones have been prepared, with one or more substituents on the styryl phenyl group (left), the acyl phenyl group (right), and/or the double bond carbon atoms.
A number of substituted chalcones having a 3,4,5-trimethoxyphenyl group (as the acyl phenyl group) have been reported to have excellent antitumour activity (Hiromitsu, 1996; Ducki et al., 1998; Akihiko, 1986). These compounds have the following general formula:
Surprisingly and unexpectedly, it has now been found that substituted chalcones having a 3,5-dimethoxyphenyl group (as the acyl phenyl group) have highly potent anticancer activity and/or antiinflammatory activity.
One such compound, shown below (Chemical Abstracts Registry Number 169803-62-7), has been reported (Berryman et al., 1995, 1997), but only as an intermediate used in the preparation of 5H-furan-2-one compounds, which are reported to have use as endothelin antagonists. Specifically, the compound shown below was prepared from 3,5-dimethoxyacetophenone and 4-methoxybenzaldehyde (Example 122, page 146, in Berryman et al., 1995), subsequently derivatised (Examples 123 and 124, pages 147 and 148), and then used as a reagent to prepare a number of 5H-furan-2-one compounds (Examples 125-135, pages 148-158).
SUMMARY OF THE INVENTION
One aspect of the present invention pertains to compounds of the formula:
wherein:
X is —H, —OH, —OC(═O)R
3
, —OS(═O)
2
OH, or —OP(═O)(OH)
2
;
Y is —H or a C
1-4
alkyl group;
Z is —H or —OCH
3
;
R
1
is —H, a C
1-4
alkyl group, or C
1-4
fluoroalkyl group;
R
2
is —H, a C
1-4
alkyl group, or C
1-4
fluoroalkyl group; and,
R
3
is —H, a C
1-6
alkyl group, a C
3-20
heterocyclyl group, or
a C
5-20
aryl group;
and pharmaceutically acceptable salts, esters, and protected forms thereof; with the proviso that X, Y, Z, R
1
, and R
2
are not all —H.
In one preferred embodiment, X is —H.
In one preferred embodiment, X is —OH, —OC(═O)R
3
, —OS(═O)
2
OH, or —OP(═O)(OH)
2
.
In one preferred embodiment, X is —OH.
In one preferred embodiment, Y is —H. —CH
3
or —CH
2
CH
3
.
In one preferred embodiment, Y is —H.
In one preferred embodiment, Y is —CH
3
or —CH
2
CH
3
.
In one preferred embodiment, Z is —H.
In one preferred embodiment, Z is —OCH
3
.
In one preferred embodiment, R
1
and R
2
are independently —H, —CH
3
, —CH
2
CH
3
, —CF
3
, —CH
2
CF
3
, or —CF
2
CF
3
.
In one preferred embodiment, both R
1
and R
2
are —H.
In one preferred embodiment, R
3
is —CH
3
. —CH
2
CH
3
, —C(CH
3
)
3
, or -Ph.
Another aspect of the present invention pertains to a composition comprising a compound as described herein (without the proviso) and a pharmaceutically acceptable carrier.
Another aspect of the present invention pertains to a method of treating a proliferative condition in a patient comprising administering to said patient a therapeutically-effective amount of a compound as described herein (without the proviso). In one preferred embodiment, the proliferative condition is cancer.
Another aspect of the present invention pertains to a compound as described herein (without the proviso), for use in a method of treatment of the human or animal body.
Another aspect of the present invention pertains to use of a compound as described herein (without the proviso) for the manufacture of a medicament for use in the treatment of a proliferative condition. In one preferred embodiment, the proliferative condition is cancer.
Another aspect of the present invention pertains to a method of prophylactically treating a proliferative condition in a patient comprising administering to said patient a therapeutically-effective amount of a compound as described herein (without the proviso). In one preferred embodiment, the proliferative condition is cancer.
Another aspect of the present invention pertains to the use of a compound as described herein (without the proviso) for the manufacture of a medicament for use in the prophylactic treatment of a proliferative condition. In one preferred embodiment, the proliferative condition is cancer.
Another aspect of the present invention pertains to a method of treating a inflammatory condition in a patient comprising administering to said patient a therapeutically-effective amount of a compound as described herein (without the proviso). In one preferred embodiment, the inflammatory condition is rheumatoid arthritis, rheumatic fever, osteoarthritis, inflammatory bowel disease, psoriasis, or bronchial asthma.
Another aspect of the present invention pertains to the use of a compound as described herein (without the proviso) for the manufacture of medicament for use in the treatment of an inflammatory condition. In one preferred embodiment, the inflammatory condition is rheumatoid arthritis, rheumatic fever, osteoarthritis, inflammatory bowel disease, psoriasis, or bronchial asthma.
Another aspect of the present invention pertains to a compound as described herein (without the proviso), wherein X is —H, for use in a method of diagnosis of the human or animal body. In one preferred embodiment, the diagnosis is for the presence of tumour cells expressing the CYP1B1 enzyme.
Another aspect of the present invention pertains to the use of a compound as described herein (without the proviso), wherein X is —H, for the presence of tumour cells expressing the CYP1B1 enzyme.
Another aspect of the present invention pertains to a method of diagnosis of a patient for the presence of tumour cells expressing the CYP1B1 enzyme, comprising:
(a) administering to the patient a compound as described herein (without the proviso), wherein X is —H;
(b) determining the amount of the corresponding hydroxylated metabolite, wherein X is —OH, which is subsequently produced; and,
(c) correlating the amount with the presence or absence of the tumour cells in the patient.
As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention.


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