Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-02-07
2004-08-17
Gerstl, Robert (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S150000
Reexamination Certificate
active
06777557
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates generally to the uncoupling of sugar-mediated coupling of proteins, lipids, nucleic acids, and other biomaterials, and any combination thereof, resulting from their reaction with glucose and other reducing sugars. The reaction between glucose and protein amino groups was studied in detail by Maillard in 1912, who 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 the polypeptide chain, and that the proteins are resultantly cross-linked and correspondingly exhibit decreased bioavailability. U.S. Pat. No. 6,007,865 discloses that these reactions occur in vivo at normal glucose levels. U.S. Pat. No. 6,007,865 further terms these reactions as advanced glycosylation (or glycation) end products (AGEs).
Several therapeutic approaches have been attempted based upon intervening in the accumulation of AGEs in vivo. One approach, exemplified in U.S. Pat. No. 4,758,583, concerns the inhibition of the formation of AGEs from their precursors, by the administration of agents such as aminoguanidine and related compounds. By reacting with an early glycosylation product that results from the original reaction between the target protein and glucose, this patent discloses that these agents block the formation of AGEs and further formation of AGEs and cross-links in tissues is inhibited
U.S. Pat. Nos. 5,656,261, 5,853,703, 6,007,865, and 6,121,300, and in P.C.T. Intl. Appl. WO97/42175, disclose agents and methods that reverse (also termed cleave or break) existing AGE cross-links in vitro and in vivo. Specifically, these patents disclose a mechanism of protein crosslinking by sugars, involving formation of a 6-hydroxy-2,3-hexanedione protein-protein cross-linking structure which has an epsilon amino group of one protein attached to the 1 position, and a nucleophilic side chain of another protein attached to the 5 position. Further, these patents disclosed compounds such as 4,5-dimethyl-3-(2-oxo-2-phenylethyl)thiazolium bromide, which were claimed to have broken protein-protein cross-links in a manner consistent with a mechanism involving transient formation of a carbanion by deprotonation of the unsubstituted 2-position of the thiazolium ring, followed by attack of the carbanion at one of the ketone carbonyls of the hypothetical 6-hydroxy-2,3-hexanedione protein-protein cross-linking structure. Subsequent rearrangements known for such thiazolium adducts could lead to cleavage of the bond between the carbonyl carbons, resulting in formation of an aldehyde fragment and a carboxylic acid fragment.
SUMMARY OF THE INVENTION
In one embodiment of the present invention, compositions and methods are disclosed for uncoupling of sugar-mediated coupling of proteins, lipids, nucleic acids, and other biomaterials, and any combination thereof. In another embodiment, sugar-mediated coupling caused by other reactive sugars present in vivo or in foodstuffs, including ribose, galactose and fructose may also be uncoupled by the methods and compositions of the present invention. The compositions and methods comprise the below disclosed compounds.
In another embodiment, the compositions have utility in vivo to reduce the deleterious effects of sugar-mediated coupling processes in an organism, when the organism is exposed to the compound or composition internally, by ingestion, transdermal application, or other means. The compositions comprise the below disclosed compounds
In yet another embodiment, the compositions are useful for the ex-vivo treatment of organs, cells and tissues and external treatment of hair, nails and skin to rejuvenate them by changing deformability and increase the tissue diffusion coefficient. This treatment is accomplished by bathing or perfusing the biological material outside of the body. The compositions comprise the below disclosed compounds.
In still another embodiment, the compositions have utility in treatment of proteinaceous organism-derived materials of commerce comprising fur, leather, feathers, down, silk, wool, gut, or the like, to enhance their softness and suppleness of texture and reduce their stiffness and brittleness, thus increasing the value and functionality of such materials. Such treatment is accomplished by exposing the organism-derived material to the composition or a solution of the composition in water or other suitable vehicle.
In a further embodiment, the present invention relates to the above-identified compositions that comprises one or more compounds of thiazole derivatives where carbon substituents are attached to the 2 position of the thiazolium nucleus and represented by formula (I):
wherein R
1
is a C
1
-C
18
alkyl group, or the group —CH(R
5
)—OH, or the group —CH(R
5
)—OC(═O)—R
6
wherein R
5
is a C
1
-C
18
alkyl group and R
6
is selected from the group consisting of C
1
-C
18
alkyl, phenyl, halosubstituted phenyl, C
1
-C
18
alkoxysubstituted phenyl and naphthyl;
R
2
is selected from the group consisting of hydroxy, phenyl, halosubstituted phenyl, C
1
-C
18
alkoxysubstituted phenyl, a C
5-7
aromatic, unsaturated or saturated heterocyclic ring having one to three heteroatoms selected from the group consisting of N, O and S;
R
3
and R
4
are independently selected from the group consisting of hydrogen, C
1
-C
18
alkyl or hydroxyalkyl, or phenyl, or R
3
and R
4
together are a bridge of 3-6 methylene units, or R
3
and R
4
together with their ring atoms may be an aromatic ring system of 6-10 carbons, optionally substituted with one or more halo, lower alkyl, lower alkoxy, or amino groups; and
X
−
is halide, preferably chloride or bromide, or other pharmaceutically acceptable anion.
Certain compounds of formula (I) may undergo cycloelimination to form lactones or cyclic enol ethers constituting novel thiazolooxazinium derivatives which are also embodiments of this invention.
In a further embodiment the present invention relates to novel compounds of formula:
wherein
R
1
is hydrogen, or —C(═O)—R
6
wherein R
6
is selected from the group consisting of C
1
-C
18
alkyl, C
1
-C
18
alkoxy, phenyl, halosubstituted phenyl, C
1
-C
18
alkoxysubstituted phenyl and naphthyl;
R
1
is hydrogen, phenyl or a C
1-5
alkyl group;
R
3
and R
4
are independently selected from the group consisting of hydrogen, C
1
-C
18
alkyl or hydroxyalkyl, or phenyl, or R
3
and R
4
together are a bridge of 3-6 methylene units, or R
3
and R
4
together with their ring atoms may be an aromatic ring system of 6-10 carbons, optionally substituted with one or more halo, lower alkyl, lower alkoxy, or amino groups; and
X
−
is mesitylene-2-sulfonate or other pharmaceutically acceptable anion.
In another embodiment the present invention relates to the above-identified compositions that comprise one or more compounds of naphthothiazole derivatives of formula (II):
wherein
R
1
is selected from the group consisting of H, C
1-5
lower alkyl, C
1-18
lower alkanoyl, and aroyl;
R
2
is selected from the group consisting of hydrogen and C
1-5
lower alkyl;
R
3
is selected from the group consisting of lower alkyl, C
3
—C
8
cycloalkyl, phenyl, 1-[(aminoiminomethyl)hydrazono]ethyl substituted phenyl, naphthyl, or aminoalkyl of structure:
wherein R
7
and R
8
are independently selected from the group consisting of hydrogen, C
1
-C
6
alkyl, C
1
-C
6
hydroxyalkyl, or R
7
and R
8
taken together with the nitrogen atom form a C
4
-C
7
heterocyclic ring optionally containing one or two additional heteroatoms selected from the group consisting of N, O or sulfur;
R
4
is selected from the group consisting of methyl, lower alkyl, or aminoalkyl of structure
wherein R
9
and R
10
are independently selected from the group consisting of hydrogen, C
1
-C
6
alkyl, C
1
-C
6
hydroxyalkyl, or R
9
and R
10
taken together w
Brines Michael L
Cerami Anthony
Fang Sheng Ding
Ulrich Peter C
Xie Qiao-Wen
Gerstl Robert
Hamble Frederick J.
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