Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-23
2002-10-01
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S367000
Reexamination Certificate
active
06458819
ABSTRACT:
The present invention relates, among other things, to thiazole compounds and, in an animal, (i) improving the elasticity or reducing wrinkles of the skin, treating (ii) diabetes or treating or preventing (iii) adverse sequelae of diabetes, (iv) kidney damage, (v) damage to blood vasculature, (vi) hypertension, (vii) retinopathy, (viii) damage to lens proteins, (ix) cataracts, (x) peripheral neuropathy, or (xi) osteoarthritis.
The reaction between glucose and proteins has been known for some time. Maillard in 1912, observed that glucose or other reducing sugars react with amino acids to form adducts that undergo a series of dehydrations and rearrangements to form stable brown pigments. Further studies have suggested that stored and heat treated foods undergo nonenzymatic browning as a result of the reaction between glucose and polypeptides, resulting in cross-links and decreased bioavailability.
This reaction between reducing sugars and food proteins was found to have its parallel in vivo. Nonenzymatic reaction between glucose and the free amino groups on proteins to form a stable, 1-deoxyketosyl adduct, known as the Amadori product, has been shown to occur with hemoglobin, where a reaction of the amino terminal of the beta-chain of hemoglobin with glucose forms the adduct known as hemoglobin A1c. Like reactions have been found to occur with a variety of other body proteins, such as lens crystallins, collagen and nerve proteins. See Bucala et al., “Advanced Glycosylation; Chemistry, Biology, and Implications for Diabetes and Aging” in Advances in Pharmacology, Vol. 23, pp. 1-34, Academic Press (1992).
Brown pigments with spectral and fluorescent properties similar to those of late-stage Maillard products have also been observed in vivo in association with several long-lived proteins, such as lens proteins and collagen from aged individuals. An age-related linear increase in pigment has been observed in human dura collagen between the ages of 20 to 90 years. Interestingly, the aging of collagen can be mimicked in vitro by cross-linking induced by glucose. Glucose-induced collagen products capture of other proteins, which capture is theorized to occur by a crosslinking reaction, and is believed to account for the observed accumulation of albumin and antibodies in kidney basement membrane. These reaction products with glucose are typically referred to as “advanced glycosylation endproducts” or AGEs.
Reagents have been identified that inhibit the formation of advanced glycosylation endproducts. These are believed to operate by reacting with an early glycosylation product. Some such reagents are believed to operate by breaking at least certain sugar-derived crosslinks. One of the agents identified as an inhibitor was aminoguanidine, and further testing has borne out its efficacy.
While the success that has been achieved with aminoguanidine and other compounds is promising, a need continues to exist to identify and develop additional inhibitors that broaden the availability and perhaps the scope of this potential activity and its diagnostic and therapeutic utility.
SUMMARY OF THE INVENTION
In accordance with the present invention, a method and compositions are disclosed for, among other things, in an animal, (i) improving the elasticity or reducing wrinkles of the skin, treating (ii) diabetes or treating or preventing (iii) adverse sequelae of diabetes, (iv) kidney damage, (v) damage to blood vasculature, (vi) hypertension, (vii) retinopathy, (viii) damage to lens proteins, (ix) cataracts, (x) peripheral neuropathy, or (xi) osteoarthritis. Without being bound by theory, these effects are believed to be related to the inhibition of formation of advanced glycosylation of proteins (protein aging) and to breaking the cross-links that form between advanced glycosylation (glycation) endproducts (AGEs) or between AGEs and other proteins. The invention further relates to preventing or reversing advanced glycosylation endproducts and cross-linking caused by other reactive sugars present in vivo or in foodstuffs, including ribose, galactose and fructose.
In particular, the compositions comprise agents for inhibiting the formation of and reversing the pre-formed advanced glycosylation (glycation) endproducts and breaking the subsequent cross-links. While not wishing to be bound by any theory, it is believed that the breaking of the pre-formed advanced glycosylation (glycation) endproducts and cross-links is a result of the cleavage of alpha-dicarbonyl-based protein crosslinks present in the advanced glycosylation endproducts.
Certain of the agents useful in the present invention are members of the class of compounds known as thiazoles.
The compounds, and their compositions, utilized in this invention are believed to react with an early glycosylation product thereby preventing the same from later forming the advanced glycosylation end products that lead to cross-links, and thereby, to molecular or protein aging and other adverse molecular consequences. Additionally, they react with already formed advanced glycosylation end products to reduce the amount of such products.
The ability to inhibit the formation of advanced glycosylation endproducts, and to reverse the already formed advanced glycosylation products in the body carries with it significant implications in all applications where advanced glycation and concomitant molecular crosslinking is a serious detriment. Thus, in the area of food technology, for instance, the retardation of food spoilage would confer an obvious economic and social benefit by making certain foods of marginal stability less perishable and therefore more available for consumers. Spoilage would be reduced, as would the expense of inspection, removal, and replacement, and the extended availability of the foods could aid in stabilizing their price in the marketplace. Similarly, in other industrial applications where the perishability of proteins is a problem, the admixture of the agents of the present invention in compositions containing such proteins would facilitate the extended useful life of the same. Presently used food preservatives and discoloration preventatives such as sulfur dioxide, known to cause toxicity including allergy and asthma in animals, can be replaced with compounds such as those described herein.
The present method has particular therapeutic application as the Maillard process acutely affects several of the significant protein masses in the body, among them collagen, elastin, lens proteins, and the kidney glomerular basement membranes. These proteins deteriorate both with age (hence the application of the term “protein aging”) and as a consequence of diabetes. Accordingly, the ability to either retard or substantially inhibit the formation of advanced glycosylation endproducts, and to reduce the amount of cross-links formed between advanced glycosylation endproducts and other proteins in the body carries the promise for treatment of the complications of diabetes and aging for instance, and thereby improving the quality and, perhaps, duration of animal and human life.
The present agents are also useful in the area of personal appearance and hygiene, as they prevent, and reverse, the staining of teeth by cationic anti-microbial agents with anti-plaque properties, such as chlorhexidine.
DETAILED DESCRIPTION
Provided is, among other things, a method of, in an animal, (i) improving the elasticity or reducing wrinkles of the skin, treating (ii) diabetes or treating or preventing (iii) adverse sequelae of diabetes, (iv) kidney damage, (v) damage to blood vasculature, (vi) hypertension, (vii) retinopathy, (viii) damage to lens proteins, (ix) cataracts, (x) peripheral neuropathy, or (xi) osteoarthritis, the method comprising administering an amount effective therefor of one or more compounds of the following formula:
wherein
R
1
and R
2
are independently hydrogen, hydroxy(lower) alkyl, lower acyloxy(lower)alkyl, or lower alkyl, or R
1
and R
2
together with their ring carbons form an aromatic fused ring;
Ar is an aryl group;
X is a pharmaceutically acce
Egan Jack
Vasan Sarah
Wagle Dilip
Alteon Inc.
Dechert
Jarvis William R. A.
Kim Vickie
LandOfFree
Thiazolium compounds and treatments of disorders associated... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Thiazolium compounds and treatments of disorders associated..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Thiazolium compounds and treatments of disorders associated... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2989634