Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-13
2003-08-26
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S367000, C514S394000, C514S399000, C548S152000, C548S202000, C548S205000, C548S309700, C548S336100
Reexamination Certificate
active
06610716
ABSTRACT:
The present invention relates, among other things, to thiazolium and imidazolium compounds and, in an animal, (i) improving the elasticity or reducing wrinkles of a skin, treating (ii) diabetes or treating, inhibiting the (iii) discoloration of teeth, or ameliorating one or more of the following conditions: (iv) adverse sequelae of diabetes, (v) kidney damage, (vi) damage to blood vasculature, (vii) hypertension, (viii) retinopathy, (ix) damage to lens proteins, (x) cataracts, (xi) peripheral neuropathy, (xii) osteoarthritis, or (xiii) damage to cardiovascular tissue due to heart failure, (xiv) improving myocardial elasticity, (xv) preventing damage to tissues in the intraperitoneal cavity caused by contact with elevated levels of reducing sugars, or (xvi) treating or ameliorating other indications described herein.
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 Alc. 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 react with and capture other proteins, which capture is theorized to occur by a crosslinking reaction. This type of reaction 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.
Now, as part of studies on AGE inhibiting or reversing compounds, it has been identified that these compounds inhibit the formation of bioactive agents, such as growth factors and inflammatory mediators, that are associated with a number of indications. These agents include vascular endothelial growth factor (VEGF) and TGF [beta]. As a result, a number of new indications have been identified for treatment with agents that inhibit the formation of, or more preferably break, AGE-mediated cross-links. It is not unreasonable to infer that the effects seen are due to the removal of AGE-related molecules that provide a stimulus for the production or release of these growth factors. Removal of such molecules is believed to proceed in part due to the elimination of AGE-related cross-links that lock the AGE-modified proteins in place. Moreover, such compounds also reduce the expression of collagen in conditions associated with excess collagen production. Regardless of the mechanism, now provided are new methods of treating a number of indications.
SUMMARY OF THE INVENTION
The invention relates, among other things, to a compound of the formula:
wherein:
Y is N or S;
Z is absent when Y is S and, if present, Z is an alkyl group of 1 to 7 carbon atoms (or of 1 to 6 carbon atoms), vinyl, allyl, arylcarbonyl, amino or alkoxycarbonylalkyl, or Z is according to the formula —CH(R
4
)(CN), or Z is —CH
2
C(═O)R
5
, where R
5
is (a) a C
6
-C
10
aryl group, said aryl group optionally substituted by one or more alkyl, alkoxy, halo, dialkylamino, hydroxy, nitro or C
1
-C
2
alkylenedioxy groups or (b) heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur wherein the heterocyclic group can be substituted by one or more substituents selected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl, aryl, and aralkyl group, and the one or more substituents can be substituted by one or more alkyl or alkoxy groups;
R
1
and R
4
are independently hydrogen, alkyl or phenyl optionally substituted with one or more halogen, alkyl, di(lower alkyl)amino or alkoxy groups when Y is N;
R
2
and R
3
are:
1. independently selected from hydrogen, acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, (C
1
-C
3
)alkylenedioxy, allyl, amino, &ohgr;-alkylenesulfonic acid, carbamoyl, carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, hydroxy, (C
2
-C
6
)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid, alkylsulfonyl, alkylsulfinyl, alkylthio, trifluoromethyl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, 4-[C
6
or C
10
]arylpiperidin-1-yl, 4-[C
6
or C
10
]arylpiperazin-1-yl, Ar {wherein, consistent with the rules of aromaticity, Ar is C
6
or C
10
aryl or a 5- or 6-membered heteroaryl ring, wherein 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heteroaryl ring contains from one to three atoms of N or one atom of O or S and zero to two atoms of N, each heteroaryl ring can be fused to a benzene, pyridine, pyrimidine, pyridazine, pyrazine, or (1,2,3)triazine (wherein the ring fusion is at a carbon-carbon double bond of Ar)}, Ar-alkyl, Ar—O, ArSO
2
—, ArSO—, ArS—, ArSO
2
NH—, ArNH, (N—Ar)(N-alkyl)N—, ArC(O)—, ArC(O)NH—, ArNH—C(O)—, and (N—Ar)(N-alkyl)N—C(O)—, or together R
1
and R
2
comprise methylenedioxy [in one embodiment, independently selected from hydrogen, acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, (C
1
-C
3
)alkylenedioxy, allyl, &ohgr;-alkylenesulfonic acid, carbamoyl, carboxy, carboxyalkyl, cycloalkyl, halo, hydroxy, (C
2
-C
6
)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid, alkylsulfonyl, alkylsulfinyl, alkylthio, trifluoromethyl, Ar {wherein, consistent with the rules of aromaticity, Ar is C
6
or C
10
aryl or a 5- or 6-membered heteroaryl ring, wherein 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heteroaryl ring contains from one to three atoms of N or one atom of O or S and zero to two atoms of N, each heteroaryl ring can be fused to a benzene, pyrimidine, pyridazine, pyrazine, or (1,2,3)triazine (wherein the ring fusion is at a carbon—carbon double bond of Ar)}, Ar-alkyl, Ar—O, ArSO
2
—, ArSO—, ArS—, ArSO
2
NH—, ArNH, (N—Ar)(N-alkyl)N—, ArC(O)—, ArC(O)NH—, ArNH—C(O)—, and (N—Ar)(N-alkyl)N—C(O)—]; or
2. together with their ring carbons form
Fang Sheng Ding
Wagle Dilip R.
Alteon Incorporated
Elrifi Ivor R.
Golden Matthew J.
Mintz Levin
Stockton Laura L.
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