Derivatives of benzylidene cyclohexanone, benzylidene...

Details Derivatives of benzylidene cyclohexanone, benzylidene... Derivatives of benzylidene cyclohexanone, benzylidene...

2002-02-27

2004-08-17

Barts, Samuel (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ketone doai

C514S680000, C514S681000, C514S684000, C568S326000, C568S327000, C568S330000

Reexamination Certificate

active

06777447

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to benzylidene derivatives, and more particularly to benzylidene cyclohexanone, benzylidene cyclopentanone, and benzylidene acetone, and derivatives thereof. The invention also relates to the biological activities of the aforementioned compounds in vivo and in vitro, pharmaceutical compositions thereof, and therapeutic methods of administration of same in animals.
BACKGROUND OF THE INVENTION
Curcumin (structure shown below) has a dual effect in oxygen radical reactions; i.e., it can act as a scavenger of hydroxyl radicals or catalyze the formation of hydroxyl radicals depending on the conditions. Curcumin inhibits in vitro lipid peroxide formations by liver homogenates of edemic mice. The inflammatory response induced experimentally in animals appears to be correlated with disturbances of the regulation of cellular oxidative processes, as is evident from the anti-inflammatory action of well-known antioxidants. There is evidence of a parallel between edema formation in mice induced by carragenan and the in vitro production of lipid peroxides in liver cells.
Thus, curcumin has been widely used medicinally as an anti-inflammatory, anti-bacterial, antioxidant, anti-hepatotoxic, hypochlolesterolanemia, anti-cyclooxygenase, anti-cancer, and radical scavenger agent. However, it has been reported that curcumin is not stable in an alkali (pH>6.5) solution.
Toxicological studies indicate that curcumin is non-toxic at high doses. In contrast, certain pyrazolone compounds are much more toxic. For example, the use of aminophyrin as an anti-inflammatory was reported to be unsafe, because it could produce nitrosamine, a carcinogen. Dipyron, another pyrazolone derivative, is also known to give rise to adverse side effects such as agranulocytosis and allergic reaction. Similar side effects have been observed in still other by pyrazolone derivatives (phenazone, oxyphenylbutazone, phenylbutazone, etc.). The pharmacological and toxicological profile of phenylbutazone and its derivatives is illustrated below (
J. Phar. Pharmacol
, 1955, 7, 1002).
TABLE 1

Structure of pyrazolone derivatives
Acute toxicity (rat),
Anti-inflammation
LD 50 g/kg
activity
Sub-
Intra-
Substituent
(3 × 50 mg/kg)
Oral
cutaneous
peritoneal
R = n-buthyl
+++
0.73
0.23
0.23
X = Y = phenyl
(Phenylbutazone)
R = allyl/propyl
+++
∞
X = Y = phenyl
R = n-butyl
+++
Toxicity
X = Y =
decrease
p-CH
3
—C
6
H
4
R = n-butyl
+
∞
∞
∞
X = Y =
p-COOH-C
6
H
4
R = n-butyl
+
−
−
−
X = H, Y = phenyl
R = n-butyl
X = Y = (3-OH,
4-carboxy)-phenyl
Cyclopentanone
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery that modification of the substituents on the aromatic rings of curcumin can affect that biological activity of curcumin. In particular, substitution on the aromatic rings of curcumin with electron donating and withdrawing groups increases anti-inflammatory activity.
Also, as noted above, curcumin is unstable at a pH above 6.5. It was postulated that the instability of curcumin at pH above 6.5 may be caused by the active methylene group. Accordingly, the present invention is also based, at least in part, on the discovery that modifying curcumin by deleting the active methylene and adjacent carbonyl group yields 1,4-pentadien-3-ones that are stable at pH above 6.5 and still possess advantageous biological, e.g., antioxidative, properties.
Therefore, in one aspect, the invention is a method for treating a responsive state in a subject. The method includes administering to a subject an effective amount of a compound of formula I such that said responsive state is treated, wherein said compound of formula I is:
wherein
n is an integer from 0 to 3, and R
1
and R
2
are each independently selected from the group consisting of methyl, ethyl, isopropyl, tertiary butyl, hydroxy, chloro, trifluoromethyl, methoxy, and dimethylamine; and R
3
is selected from the group consisting of methyl, ethyl, isopropyl, tertiary butyl, hydroxy, chloro, trifluoromethyl, methoxy, hydrogen, and dimethylamine; and pharmaceutically acceptable salts thereof.
In another aspect, the invention is directed to pharmaceutical compositions comprising an effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
In yet another aspect, the invention is directed to certain compounds of formula I, including 2,5-bis(4-hydroxy-3,5-dimethyl benzylidene)cyclopentanone, 2,5-bis(4-hydroxy-3,5-dimethoxy benzylidene)cyclopentanone, and pharmaceutically acceptable salts thereof


REFERENCES:
patent: 5691320 (1997-11-01), von Borstel et al.
patent: 6462075 (2002-10-01), Bowen et al.
patent: 6541672 (2003-04-01), Sardjiman et al.

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