Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-02-08
2002-02-12
Russell, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S212010, C514S315000, C514S423000, C514S561000, C514S614000, C514S626000, C514S665000, C548S532000, C548S537000, C558S252000, C560S170000, C564S151000, C564S198000, C562S567000
Reexamination Certificate
active
06346547
ABSTRACT:
BACKGROUND OF THE INVENTION
A common phenomenon associated with disease etiology is the overproduction of an undesired metabolic byproduct. Although mammalian life requires molecular oxygen (O
2
), the normal metabolic pathway for oxygen clearance involves a one-electron reduction to superoxide (O
2
−
). Even though natural processes exist to render this superoxide harmless, they are often out of balance, leading to several serious diseases initiated by chronic buildup of the effects of reactive oxygen.
Natural antioxidants are available through consumption of a nutritious diet, by consumption of specific nutritional supplements and prescription pharmaceutical preparations. A factor governing the effectiveness of this lifestyle and therapy is their abundance and absorption after oral ingestion, limiting their local concentration in circulation. Overall, the number and variety of antioxidant compositions is rather large.
However, while some antioxidant compositions are capable of reducing physiological oxidation within the human body, most compounds do not possess the requisite low-toxicity, high-bioavailability, and/or versatility that a desirable dietary supplement should possess. Generally, anti-oxidant compositions function as substrates which are more easily oxidized than the substances which would otherwise be attacked (i.e., the body's cells). In effect, an antioxidant composition provides for the preferential oxidation of itself as opposed to cells. Unfortunately, some antioxidant compositions used to treat certain diseases and ailments are unable to provide the desired low degree of toxicity, high bioavailability and/or the versatility to treat a wide variety of diseases.
Some substances, which are generally referred to as free-radical scavengers, have the ability to reduce oxidation by being more easily oxidized themselves, however, many are too toxic for ingestion. Other compounds which are both anti-oxidants and non-toxic suffer from an inability to reach certain portions of the body due to their solubility properties. For example, vitamin E is generally lipid-soluble yet not very water-soluble. Analogs of vitamin E which are water-soluble have been prepared. However, in some instances, these analogs are either toxic or less effective than the vitamin itself.
The preparation of therapeutic antioxidant agents and the development of treatments using antioxidant therapeutic agents continues to be an area of interest in preventing and/or treating various antioxidant responsive diseases. Such diseases include a wide variety of antioxidant responsive diseases such as the use of antioxidants in the treatment of central nervous system neurodegenerative disorders such as Parkinson's, Alzheimer's and Creutzfeldt-Jakob's diseases.
Antioxidants have been used for treating other conditions of peripheral tissues, such as acute respiratory distress syndrome, amyotrophic lateral sclerosis, atherosclerotic cardiovascular disease and multiple organ disfunction. Correlative pathways between oxidative stress and various neurodegenerative pathologies have also been found. For example, evidence has been accumulated which connects oxidative stress with pathogenesis of Parkinson', Alzheimer's, Creutzfeldt-Jakob's diseases and other human neurodegenerative disorders. See U.S. Pat. No. 5,874,468. These studies were initiated since auto-oxidation of levodopa and dopamine are known to produce oxygen free radicals and, peroxides, quinones and semiquninones.
In addition to these diseases, antioxidants have been used for treatment of oxidant injury, particularly in reperfusion injury which has been observed to occur upon reperfusion following ischemia caused, for example, by blood clots, organic repair and transplant surgery. A number of causes and mechanisms have been suggested for the damage that occurs to tissue after ischemia and reperfusion. While it is likely that a variety of causes and mechanisms contribute to the damage, a popular current theory that is supported by experimental evidence involves the generation of free radicals upon reperfusion. See U.S. Pat. No. 5,080,886, incorporated herein by reference, wherein the current consensus on the role of free radicals in reperfusion injury in the heart is discussed in the various articles cited therein.
While the positive effects of antioxidants for treatment of the above noted and other antioxidant responsive diseases is known, there continues to be a need in the art for therapeutic antioxidant agents for use in pharmaceutical antioxidant compositions which possess low toxicity, high bioavailability and which are able to treat a wide variety of diseases and/or ailments.
BRIEF SUMMARY OF THE INVENTION
The present invention includes amino acid-based compounds of the general formula (I):
A—N(Z)—CH(R
1
)C(O)—Q (I)
wherein A is represented by the formula:
XO—[C(R
2
)
2
]
n
—
wherein n is an integer of from 1 to about 3, X is selected from the group consisting of a hydrogen atom, an acyl group and a halogenated acyl group and each R
2
is independently selected from the group consisting of a hydrogen atom, an alkyl group having from 1 to about 3 carbon atoms and a hydroxyalkyl group having from 1 to about 3 carbon atoms, and CH
2
OX; Z is selected from the group consisting of a hydrogen atom, an alkyl group of from 1 to about 3 carbon atoms, and A; R
1
is selected from an amino acid side chain group or an amino acid side chain group which forms with R
2
a single heterocyclic ring structure having a total of from 5 to 7 atoms in the ring; and Q is a substituent selected from the group consisting of —N(R
2
)
2
, —NR
2
N(R
2
)
2
, —SR
2
, an alkoxy, a halogenated alkoxy, an O-acyl and an O-halogenated acyl.
The present invention also includes amino acid-based compounds of the general formula (I)
A—N(Z)—CH(R
1
)C(O)—Q (I)
wherein A is represented by the formula:
XO—[C(R
2
)
2
]
n
—
wherein n is an integer of from 1 to about 3, X is selected from the group consisting of a hydrogen atom, an acyl group and a halogenated acyl group and each R
2
is independently selected from the group consisting of a hydrogen atom, an alkyl group having from 1 to about 3 carbon atoms and a hydroxyalkyl group having from 1 to about 3 carbon atoms, and CH
2
OX; Z is selected from the group consisting of a hydrogen atom, an alkyl group of from 1 to about 3 atoms, and A; R
1
is an amino acid side chain group which forms with R
2
a single heterocyclic ring structure having a total of from 5 to 7 atoms in the ring; and Q is a substituent selected from the group consisting of a hydroxyl, —N(R
2
)
2
, NR
2
N(R
2
)
2
, —SR
2
, an alkoxy, a halogenated alkoxy, an O-acyl and an O-halogenated acyl.
In one embodiment, the invention includes amino-acid based compounds in accordance with formula (I) above in which Z is a hydrogen atom, R
1
is a hydrogen atom and A is —C(CH
2
OH)
3
, wherein Q is is a substituent selected from the group consisting of —N(R
2
)
2
, —NR
2
N(R
2
)
2
, —SR
2
, an alkoxy, a halogenated alkoxy, an O-acyl and an O-halogenated acyl.
Additionally, the present invention includes low-toxicity, highly-bioavailable, pharmaceutical antioxidant compositions for administration to mammals, said pharmaceutical antioxidant compositions comprising an amino acid-based compound of the general formula (I)
A—N(Z)—CH(R
1
)C(O)—Q (I)
wherein A is represented by the formula:
XO—[C(R
2
)
2
]
n
—
wherein n is an integer of from 1 to about 3, X is selected from the group consisting of a hydrogen atom, an acyl group and a halogenated acyl group and each R
2
is independently selected from the group consisting of a hydrogen atom, an alkyl group having from 1 to about 3 carbon atoms and a hydroxyalkyl group having from 1 to about 3 carbon atoms, and CH
2
OX; Z is selected from the group consisting of a hydrogen atom, an alkyl group of from 1 to about 3 carbon atoms and A; R
1
is selected from an amino acid side chain group and an amino acid side chain group in which forms wit
Checkpoint, Genetics, Inc.
Gollin Michael A.
Haddaway Keith G.
Russell Jeffrey E.
Venable
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