N-disubstituted carbamoyloxy flavones

Details N-disubstituted carbamoyloxy flavones N-disubstituted carbamoyloxy flavones

2001-09-21

2003-08-26

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C549S403000

Reexamination Certificate

active

06610738

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to novel flavones and to processes of making them.
BACKGROUND OF THE INVENTION
Flavonoids, such as flavones, are natural products produced by living organisms. Many of these compounds are natural products that do not appear to have any obvious metabolic or evolutionary function and may be formed by “metabolic accident” or are by-products of the synthetic machinery of the cellular enzymes. Regardless of their utility to the parent organism, their value to man as drugs, herbs, flavorings, poisons, dyes, and the like is undisputed.
The subject flavones comprise oxygenated derivatives of aromatic ring structures. Derivatives of flavone are found throughout the plant kingdom and especially in the higher plants. Although many biologically active flavone derivatives have been found in nature, they also have been produced synthetically. Certain of these compounds are useful as respiratory stimulants (U.S. Pat. No. 3,147,258), as an inhibitor of MAP kinase (Mahboobi, S., Pongratz, H.,
Synthesis of
2′-
Amino
-3
′methoxyflavone
(PD 98059), Synth. Commun., 1999;29:1645), and as an antitumor agent (Akama T., et a.,
Structure
-
activity relationships of the
7-
substituents of
5,4′-
diamino
-6,8,3
′trifluoroflavone, a potent antitumor agent,
J. Med. Chem., Jun. 4, 1998; 41(12):2056-67). An acetylcholine esterase inhibitor compound was described in Rampa A., et al.,
Acetylcholinesterase inhibitors: synthesis and structure
-
activity relationships of omega
-[
N
-
methyl
-
N
-(3-
alkylcarbamoyloxyphenyl
)
methyl] aminoalkoxyheteroaryl derivatives,
J. Med. Chem., Oct. 8, 1998; 41(21):3976-86, in which the flavone structure has a phenyl group bearing an N-methylcarbamoyloxy radical connected with the oxygen atom of the flavone skeleton via a five membered chain:
Flavonoids serve as antioxidants and chemoprotectants against molecular damage from reactive oxygen species (ROS). Their antioxidative activity has been the subject of many studies (e.g., van Acker SA, et al.,
Structural aspects of antioxidant activity of flavonoids,
Free Radic. Biol. Med., 1996;20(3):331-42).
Oxidative stress, manifested by, for example. protein oxidation and lipid peroxidation is one characteristic of the brain of a person suffering from Alzheimer's Disease (AD) (Cf. Varadarajan S, et al.,
Alzheimer's amyloid beta
-
peptide
-
associated free radical oxidative stress and neurotoxicity,
J. Struct. Biol., June 2000; 130(2-3):184-208. The beneficial effect of various antioxidants in the treatment of AD is now widely recognized. Cf. Pratico D, Delanty N.,
Oxidative injury in diseases of the central nervous system: focus on Alzheimer's disease,
Am. J. Med., November 2000; 109(7):577-85; Giacobini E.,
Present and future of Alzheimer therapy,
J. Neural. Transm. Suppl., 2000; 59:231-42; Aisen, P S., et al.,
Anti
-
inflammatory and antioxidant therapies in Alzheimer's disease,
Funct. Neurobio. Aging, 487-492 (Hof and Mobbs edS., Academic Press: San Diego, Calif. 2001). Various compounds incorporating a carbamoyl functionality (e.g., rivastigmine and physostigmine) are useful for the treatment of AD via enhancement of cholinergic transmission through inhibition of acetylcholinesterase (AChE).
The compounds of the present invention were designed as potential therapeutic agents for the treatment of AD by combining both ACHE inhibitory activity and antioxidant activity (by virtue of their carbamoyl and flavonoid pharmacophores).
SUMMARY OF THE INVENTION
The invention relates to compounds of the general Formula I:
wherein each of R
1
, R
2
, R
3
, R
4
and R
5
is a substituent selected from the group consisting of:
hydrogen;
OOCNR
6
(R
7
), in which each of R
6
and R
7
is hydrogen, or a lower alkyl (C
1
-C
4
) and in which each of R
6
and R
7
may be the same or different;
OR
8
, wherein R
8
is hydrogen or a lower alkyl (C
1
-C
4
);
wherein each of R
9
and R
10
is hydrogen or a lower alkyl (C
1
-C
4
);
a halogen atom selected from the group consisting of fluoride, chloride, bromide and iodide;
COOR
11
, wherein R
11
is hydrogen, sodium, potassium, or a lower alkyl (C
1
-C
4
);
CONR
12
R
13
, wherein each of R
12
and R
13
is hydrogen or a lower alkyl (C
1
-C
4
);
NO
2
; and
CN; and
wherein at least one of R
1
, R
2
, R
3
, R
4
and R
5
is OOCNR
6
(R
7
).
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to new flavone derivatives of Formula I above which have at least one N-disubstituted carbamoyloxy unit (OOCNR
6
(R
7
)) coupled directly to one or both aromatic rings of the flavone molecule. Accordingly, the invention embraces compounds of Formulae IA, IB and IC, below. Compounds of Formula IA are characterized by the formula:
wherein R
4
is OOCNR
6
(R
7
), in which each of R
6
and R
7
is hydrogen or a lower alkyl of 1 to 4 carbon atoms and in which each of R
6
and R
7
may be the same or different, and wherein R
4
occurs in the 2′, 3′ or 4′ position; and
wherein each of R
1
, R
2
, R
3
, and R
5
is a substituent selected from the group consisting of:
hydrogen;
OR
8
, wherein R
8
is hydrogen or a lower alkyl of 1 to 4 carbon atoms,
wherein each of R
9
and R
10
is hydrogen or a lower alkyl (C
1
-C
4
);
a halogen atom selected from the group consisting of fluoride, chloride, bromide and iodide;
COOR
11
, wherein R
11
is hydrogen, sodium, potassium, or a lower alkyl (C
1
-C
4
);
CONR
12
R
13
, wherein each of R
12
and R
13
is hydrogen or a lower alkyl (C
1
-C
4
);
NO
2
; and
CN.
Compounds of Formula IB are characterized by the following formula:
wherein R
1
is OOCNR
6
(R
7
), in which each of R
6
and R
7
is hydrogen or a lower alkyl (C
1
-C
4
) and in which each of R
6
and R
7
may be the same or different, and wherein R
1
occurs in the 5, 6, 7, or 8 position; and
wherein each of R
2
, R
3
, R
4
and R
5
is a substituent selected from the group consisting of:
hydrogen;
OR
8
, wherein R
8
is hydrogen or a lower alkyl (C
1
-C
4
);
wherein each of R
9
and R
10
is hydrogen or a lower alkyl (C
1
-C
4
);
a halogen atom selected from the group consisting of fluoride, chloride, bromide and iodide;
COOR
11
, wherein R
11
is hydrogen, sodium, potassium, or a lower alkyl (C
1
-C
4
);
CONR
12
R
13
, wherein each of R
12
and R
13
is hydrogen or a lower alkyl (C
1
-C
4
);
NO
2
; and
CN.
The compounds of Formula IC are characterized by the following formula:
wherein each of R
1
and R
4
is OOCNR
6
(R
7
) and R
1
occurs in the 5, 6, 7, or 8 position and R
4
occurs in the 2′, 3′, or 4′ position, and each of R
6
and R
7
is hydrogen or a lower alkyl (C
1
-C
4
) and in which each of R
6
and R
7
may be the same or different; and
wherein each of R
2
, R
3
, and R
5
is a substituent selected from the group consisting of:
hydrogen;
OR
8
, wherein R
8
is hydrogen or a lower alkyl (C
1
-C
4
);
wherein each of R
9
and R
10
is hydrogen or a lower alkyl (C
1
-C
4
);
a halogen atom selected from the group consisting of fluoride, chloride, bromide and iodide;
COOR
11
, wherein R
11
is hydrogen, sodium, potassium, or a lower alkyl (C
1
-C
4
);
CONR
12
R
13
, wherein each of R
12
and R
13
is hydrogen or a lower alkyl (C
1
-C
4
);
NO
2
; and
CN.
The definitions of each of R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
indicates that each may be an alkyl of 1 to 4 carbon atoms, for example, methyl, ethyl, isopropyl, butyl, isobutyl or t-butyl.
Compounds of the invention are prepared by reacting a hydroxyflavone reactant with dialkylcarbamoyl chloride (R
6
R
7
NCOCl) in the presence of a base such as sodium hydride or potassium carbonate, according to the following reaction scheme:
The reaction is carried out in an organic solvent such as dimethylformamide, acetonitrile or in a mixture of dimethylformamide and acetonitrile. The reaction can be undertaken at room temperature or up to about the boiling or reflux temperature of the solvent. For example, when the solvent contains acetonitrile, the reaction can be carried out at up to about 82° C., as d

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