Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-14
2003-12-16
Lambkin, Deborah C. (Department: 1636)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S020000, C549S021000, C549S022000
Reexamination Certificate
active
06664287
ABSTRACT:
BACKGROUND OF THE INVENTION
&agr;-lipoic acid (thioctic acid, 1,2-dithiacyclopentane-3-valeric acid, 1,2-dithiolane-3-pentanoic acid) is widely distributed in plants and animals in the form of the R-enantiomer; it acts as coenzyme in many enzymatic reactions, constitutes a growth factor for a number of bacteria and protozoa and is used in death-head fungus poisoning. Lipoic acid (1,2-dithiolane-3-pentanoic acid) is a naturally occurring compound. It is a component of mitochondrial multienzyme complexes which dehydrogenates &agr;-keto acids (e.g. pyruvate). In pathological conditions, lipoic acid is applied in the treatment of diabetic polyneuropathy, liver cirrhosis and metal intoxications. Particularly in diabetic polyneuropathy, the antioxidant activity of lipoic acid is considered to contribute to its therapeutic effect.
One aspect of this invention relates to the uses of optical isomers of the novel lipoic acid-related thiazolidinedione and phenyl acetic acid derivatives of the instant invention. In the case of the purely optical isomers of &agr;-lipoic acid (R- and S-form, i.e. R-&agr;-lipoic acid and S-&agr;-lipoic acid), unlike the racemate (Biewenga et al. “An overview of lipoate chemistry.” In: Lipoic Acid in Health and Disease. (Fuchs J, Packer L, Zimmer G, eds.), Marcel Dekker, Inc. 1997, pp 1-32), the R-enantiomer mainly has an anti-inflammatory activity, for example, being stronger by a factor of 10 than that of the racemate (Ulrich et al. U.S. Pat. No. 5,728,735 Mar. 17, 1998), and has been shown to have superior insulin-sensitizing activity and to confer improved cardiac function (Zimmer G et al. J Mol Cell Cardiol. 27:1895-903 (1995)) and ameliorate diabetic peripheral and autonomic neuropathy (Ziegler D, Gries F A. Diabetes. 46 Suppl 2:S62-6 (1997)). In contrast, the S-enantiomer has been shown to be more effective as an anti-nociceptive agent. The anti-nociceptive (analgesic) activity of the S-enantiomer is for example stronger by a factor of 5 to 6 than that of the racemate (Ulrich et al. U.S. Pat. No. 5,728,735 Mar. 17, 1998). Accordingly, the R- and S-enantiomers of the novel lipoic acid-related thiazolidinedione and phenyl acetic acid derivatives are considered to have superior efficacy in the treatment of specific diseases. For example, a particular stereoisomer, e.g. R-(+)-&agr;-lipoic stereoisomeric thiazolidinedione derivative is expected to have superior anti-inflammatory activity whereas the corresponding optical isomers are expected to provide greater efficacy in the treatment of other diseases. In addition, the &agr;-lipoic acid racemate and R and S isomeric forms display anti-inflammatory, anti-nociceptive (analgesic) and cytoprotective properties.
The metabolism of lipoic acid has been studied in Pseudomonas (Furr et al., Arch. Biochem. Biophys. 185:576-583 (1978)) and in rats (Spence et al., Arch. Biochem. Biophys. 174:13-19 (1976); Gal et al., Arch. Biochem. Biophys. 89:253-261 (1960); Harrison et al., Arch. Biochem. Biophys. 160:514-522 (1974)). It has been found that in these species lipoic acid is converted by beta oxidation of its pentanoic acid side chain. Regarding the antioxidant activity of lipoic acid, it has been proposed that reduction of lipoic acid to dihydrolipoic acid is an important step in its therapeutic effect.
Free Radical Formation, Oxidative Stress and Skin Damage
Natural aging of skin and exposure of skin ultraviolet (UV) wavelengths of sunlight can cause sunburn (erythema) and blistering (edema). Exposure to ultraviolet light can also cause the skin to feel dry and taut in moderate doses, and to peel if exposed to higher doses. These short term effects are readily perceptible and triggered by UV-induced formation of free radical, particularly activated oxygen radicals. Other more subtle effects that are not as readily discernable, but also involving free radical formation, such as photo-immunosuppression, cross-linking of deoxyribonucleic acid (DNA), formation of sunburn cells, and loss of Langerhans cells. Moreover, cross-linking of collagen, elastin, laminin and other extracellular matrix proteins, activation of matrix metalloproteinases (MMPs) and inhibition of tissue inhibitors of MMPs (TIMPS) result in the destruction, thinning and dessication of the extracellular matrix leading to the typical appearance of aged skin. The more serious long term effects can occur such as premature aging of the skin, actinic keratosis (a pre-cancerous condition) and frank skin cancer can ultimately develop.
Human skin can be protected from some of these environmental effects. Moisturizers can readily reverse the appearance of dryness regardless of whether it results from low humidity conditions or UV light, and relieve the tautness of the skin caused by UV light and the flaccidity and dryness caused by the aging process. These products either attract moisture from the environment to the skin's surface, or reduce the amount of moisture in the skin that can escape into the environment. These products also add needed moisture to the skin from the formulation itself, and add a layer of emollients on the skin surface to leave it softer and more supple.
Sunscreen products are known to protect the skin from some of the harmful effects of UV exposure. These products contain molecules that absorb the harmful wavelengths of ultraviolet light before they can reach the skin. The absorbed light is converted to heat and rapidly dissipated to the skin and environment, which allows these molecules to revert to a lower energy state, and subsequently absorb another photon of light. In this manner, sunscreen agents can absorb numerous photons of ultraviolet light in a relatively short period of time. By absorbing the harmful wavelengths of light, sunscreen products prevent many of the acute and chronic effects caused by ultraviolet light.
However, sunscreen products are not perfect in their mode of action. There is no single sunscreen agent that is capable of absorbing all of the harmful wavelengths striking the skin. Higher Sun Protection Factor (SPF) formulations address this problem by including a combination of sunscreen agents in the formulation. However, even when using a combination of sunscreen agents, these products do not provide complete protection, particularly from the longer ultraviolet wavelengths. Although these longer wavelengths do not readily elicit many of the acute damaging effects commonly attributed to ultraviolet light exposure, recent research indicates that these wavelengths can create free radicals in the skin. These free radicals may be responsible for the premature aging of the skin commonly linked to ultraviolet light exposure.
According to the free radical theory of premature aging of the skin, ultraviolet light can produce reactive oxygen species (ROS) that damage the skin. ROS are a collection of reactive free radicals produced from the oxygen molecule, and include singlet oxygen, the superoxide radical, hydrogen peroxide, and the hydroxyl radical, as well as the reaction products produced by these free radicals. Due to their reactivity, ROS relatively indiscriminately react with other molecules, and generate a cascade of harmful free radical reactions in the skin.
The skin possesses defense mechanisms against the generation of ROS. These defenses include the presence of enzymes such as superoxide dismutase, catalase, glutathione transferase, glutathione peroxidase and glutathione reductase, as well as antioxidants such as tocopherols, ubiquinone, ubiquinol, ascorbic acid and dehydroascorbic acid. Unfortunately, ultraviolet light entering the skin can easily overwhelm these defense systems, such that the amount of superoxide dismutase and glutathione transferase in the skin declines significantly upon irradiation with solar simulated ultraviolet light. Simultaneous with the loss of these reducing enzymes, there is a dramatic increase in conjugated double bonds formed in the skin from the linoleates present in cell membranes. There is also an increase in thiobarbituric acid reactive substances present in the s
Avery Mitchell Allen
Pershadsingh Harrihar A.
Bethesda Pharmaceuticals, Inc.
Lambkin Deborah C.
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