US 6,440,749 B1Granted

Method of treating certain indications associated with hyperglycemia

AssigneesAlteon Inc., The Picower Institute for Medical Research

InventorsAnthony Cerami, Peter C. Ulrich, Dilip R. Wagle, San-Bao Hwang, Sara Vasan, John J. Egan

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Abstract

The present invention relates to compositions and methods for inhibiting and reversing nonenzymatic cross-linking (protein aging). Accordingly, compositions are disclosed which comprise an agent capable of inhibiting the formation of advanced glycosylation endproducts of target proteins, and which additionally reverse pre-formed crosslinks in the advanced glycosylation endproducts by cleaving alpha-dicarbonyl-based protein crosslinks present in the advanced glycosylation endproducts. Certain agents useful are thiazolium salts. The method comprises contacting the target protein with the composition. Both industrial and therapeutic applications for the invention are envisioned, as food spoilage and animal protein aging can be treated. A immunoassay for detection of the reversal of the nonenzymatic crosslinking is also disclosed.

Claims55

Dependent claims

A method of, in an animal, treating (i) diabetes or treating or ameliorating (ii) adverse sequelae of diabetes, (iii) kidney damage, (iv) damage to blood vasculature or atherosclerosis, (v) hypertension, (vi) retinopathy, (vii) peripheral neuropathy, (viii) cataracts, (ix) osteoarthritis, (x) Alzheimer's disease or (xi) damage to a tissue caused by contact with elevated levels of reducing sugars or (xii) improving the elasticity or reducing wrinkles of the skin of an animal or (xiii) increasing RBC deformability in an animal, the method comprising administering an amount effective therefor of one or more compounds of the following formula:

wherein
R1 and R2 are independently selected from the group consisting of hydrogen, hydroxy(lower)alkyl, (lower)acyloxy(lower)alkyl, lower alkyl, lower alkenyl, C6-C10 aryl (wherein aryl is optionally substituted with up to two groups which are halo, hydroxy, lower alkoxy, alkylenedioxy or di(lower)alkylamino groups) or R1 and R2 together with their ring carbons may be a C6-C10 aromatic fused ring, optionally substituted with one or more amino, halo or alkyenedioxy groups;
Z is hydrogen or an amino group;
Y is
amino,
a group of the formula
—CH2C(═O)R
wherein R is a lower alkyl, (lower)alkoxy, hydroxy, amino or a C6-C10 aryl group, said aryl group optionally substituted by one or more lower alkyl, lower alkoxy, halo, di(lower)alkylamino, hydroxy, nitro or alkylenedioxy groups;
a group of the formula
—CH2R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl, or C6-C10 aryl group, said aryl group optionally substituted with up to two groups which are halo, hydroxy, lower alkoxy or di(lower)alkylamino groups;
or
a group of the formula
—CH2C(═O)N(R″)R″′
wherein (a) R″ is hydrogen and R″′ is a lower alkyl group, optionally substituted by a C6-C10 aryl group, or a C6-C10 aryl group, said aryl groups optionally substituted by one or more lower alkyl, halo, or (lower)alkoxylcarbonyl groups;
or (b) R″ and R″′ are both lower alkyl groups;
X is a pharmaceutically acceptable anion;
and
any said alkyl, alkynyl or alkoxy can be substituted with one or more halo, amino or lower alkylamino groups.

16 more elements

A method of, in an animal, treating (i) diabetes or treating or ameliorating (ii) adverse sequelae of diabetes, (iii) kidney damage, (iv) damage to blood vasculature or atherosclerosis, (v) hypertension, (vi) retinopathy, (vii) peripheral neuropathy, (viii) cataracts, (ix) osteoarthritis, (x) Alzheimer's disease or (xi) damage to a tissue caused by contact with elevated levels or reducing sugars or (xii) improving the elasticity or reducing wrinkles of the skin of an animal or (xiii) increasing RBC deformability in an animal, the method comprising administering an amount effective therefor of one or more of the following compounds:

3-aminothiazolium salt;
3-amino-4,5-dimethylaminothiazolium salt;
2,3-diaminothiazolinium salt;
3-(2-methoxy-2-oxoethyl)-thiazolium salt;
3-(2-methoxy-2-oxoethyl)-4,5-dimethylthiazolium salt;
3-(2-methoxy-2-oxoethyl)-4-methylthiazolium salt;
3-(2-phenyl-2-oxoethyl)-4-methylthiazolium salt;
3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium salt;
3-amino-4-methylthiazolium salt;
3-(2-methoxy-2-oxoethyl)-5-methylthiazolium salt;
3-(2-phenyl-2-oxoethyl)-5-methylthiazolium salt;
3-[2-(4′-bromophenyl)-2-oxoethyl]thiazolium salt;
3-[2-(4′-bromophenyl)-2-oxoethyl]-4-methylthiazolium salt;
3-[2-(4′-bromophenyl)-2-oxoethyl]-5-methylthiazolium salt;
3-[2-(4′-bromophenyl)-2-oxoethyl]-4,5-dimethylthiazolium salt;
3-(2-methoxy-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium salt;
3-(2-phenyl-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium salt;
3-[2-(4′-bromophenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium salt;
3,4-dimethyl-5-(2-hydroxyethyl)thiazolium salt;
3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium salt;
3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium salt;
3-(2-methoxy-2-oxoethyl)benzothiazolium salt;
3-(2-phenyl-2-oxoethyl)benzothiazolium salt;
3-[2-(4′-bromophenyl)-2-oxoethyl]benzothiazolium salt;
3-(carboxymethyl)benzothiazolium salt;
2,3-(diamino)benzothiazolium salt;
3-(2-amino-2-oxoethyl)thiazolium salt;
3-(2-amino-2-oxoethyl)-4-methylthiazolium salt;
3-(2-amino-2-oxoethyl)-5-methylthiazolium salt;
3-(2-amino-2-oxoethyl)-4,5-dimethylthiazolium salt;
3-(2-amino-2-oxoethyl)benzothiazolium salt;
3-(2-amino-2-oxoethyl)4-methyl-5-(2-hydroxyethyl)thiazolium salt;
3-amino-5-(2-hydroxyethyl)-4-methylthiazolium salt;
3-(2-methyl-2-oxoethyl)thiazolium salt;
3-amino-4-methyl-5-(2-acetoxyethyl)thiazolium salt;
3-(2-phenyl-2-oxoethyl)thiazolium salt;
3-(2-methoxy-2-oxoethyl)-4-methyl-5-(2-acetoxyethyl)thiazolium salt;
3-(2-amino-2-oxoethyl)-4-methyl-5-(2-acetoxyethyl)thiazolium salt;
2-amino-3-(2-methoxy-2-oxoethyl)thiazolium salt;
2-amino-3-(2-methoxy-2-oxoethyl)benzothiazolium salt;
2-amino-3-(2-amino-2-oxoethyl)thiazolium salt;
2-amino-3-(2-amino-2-oxoethyl)benzothiazolium salt;
3-[2-(4′-methoxyphenyl)-2-oxoethyl]-thiazolinium salt;
3-[2-(2′,4′-dimethoxyphenyl)-2-oxoethyl]-thiazolinium salt;
3-[2-(4′-fluorophenyl)-2-oxoethyl]-thiazolinium salt;
3-[2-(2′,4′-difluorophenyl)-2-oxoethyl]-thiazolinium salt;
3-[2-(4′-diethylaminophenyl)-2-oxoethyl]-thiazolinium salt;
3-propargyl-thiazolinium salt;
3-propargyl-4-methylthiazolinium salt;
3-propargyl-5-methylthiazolinium salt;
3-propargyl-4,5-dimethylthiazolinium salt;
3-propargyl-4-methyl-5-(2-hydroxyethyl)-thiazolinium salt;
3-[2-(3′-methoxyphenyl)-2-oxoethyl]-thiazolium salt;
3-[2-(3′-methoxy phenyl)-2-oxoethyl]-4 methyl-5-(2′-hydroxyethyl)-thiazolium salt;
3-[2-(3′-methoxyphenyl)-2-oxoethyl]-benzothiazolium salt;
2,3-diamino-4-chlorobenzothiazolium salt;
2,3-diamino-4-methyl-thiazolium salt;
3-amino-4-methyl-5-vinyl-thiazolium salt;
2,3-diamino-6-chlorobenzothiazolium salt;
2,6-diamino-benzothiazole dihydrosalt;
2,6-diamino-3-[2-(4′-methoxyphenyl)-2-oxoethyl]benzothiazolium salt;
2,6-diamino-3-[2-(3′-methoxyphenyl)-2-oxoethyl]benzothiazolium salt;
2,6-diamino-3-[2-(4′-diethylaminophenyl)-2-oxoethyl]benzothiazolium salt;
2,6-diamino-3-[2-(4′-bromophenyl)-2-oxoethyl]benzothiazolium salt;
2,6-diamino-3-(2-phenyl-2-oxoethyl) benzothiazolium salt;
2,6-diamino-3-[2-(4′-fluorophenyl-2-oxoethyl]benzothiazolium salt;
3-acetamido-4-methyl-5-thiazolyl-ethyl acetate salt;
2,3-diamino-5-methylthiazolium salt;
3-[2-(2′-naphthyl)-2-oxoethyl]-4-methyl-5-(2′-hydroxyethyl)-thiazolium salt;
3-[2-(3′,5-4′-di-tert-butyl-4′-hydroxyphenyl)-2-oxoethyl]-4-methyl-5-(2′-hyd roxyethyl)-thiazolium salt;
3-[2-(2′,6′-dichlorophenethylamino)-2-oxoethyl]-4-methyl-5-(2′-hydroxyethyl)-thiazolium-salt;
3-[2-dibutylamino-2-oxoethyl]-4-methyl-5-(2′-hydroxyethyl)-thiazolium salt;
3-(2-(4′-carbethoxyanilino)-2-oxoethyl]-4-methyl-5-(2′-hydroxyethyl)-thiazol ium salt;
3-[2-(2′,6′-diisopropylanilino)-2-oxoethyl]-4-methyl-5-(2′-hydroxyethyl)-th iazolium salt;
3-[2-(4′-carbmethoxy-3′-hydroxyanilino)-2-oxoethyl]-4-methyl-5-(2′-hydroxyethyl)-thiazolium salt;
2,3-diamino-4,5-dimethylthiazolium mesitylene sulfonate;
2,3-diamino-4-methyl-5-hydroxyethyl-thiazolium mesitylene sulfonate;
2,3-diamino-5-(3′,4′-trimethylenedioxyphenyl)-thiazolium mesitylene sulfonate;
3-[2-(4′-benzodioxan-6-yl)-2-oxoethyl]-4-methyl-5-(2′-hydroxyethyl)-thia zolium salt;
3-[2-(3′,4′-trimethylenedioxyphenyl)-2-oxoethyl]-4-methyl-5-(2′-hydroxyethy l)-thiazolium salt;
3-[2-(1′,4-benzodioxan-6-yl)-2-oxoethyl]-thiazolium salt;
3-[2-(3′,4′-trimethylenedioxyphenyl)-2-oxoethyl]-thiazolium salt;
3-[2-(3′,5′-di-tert-butyl-4′-hydroxyphenyl)-2-oxoethyl]-thiazolium salt;
3-[2-(3′,5′-di-tert-butyl-4′-hydroxyphenyl)-2-oxoethyl]-4-methyl-thiazolium salt;
3-[2-(3′,5′-di-tert-butyl-4′-hydroxyphenyl)-2-oxoethyl]-5-methyl-thiazolium salt;
3-[2-(3′,5′-di-tert-butyl-4′-hydroxyphenyl)-2-oxoethyl]-4,5-dimethyl-thiazo lium salt;
3-[2-(3′,5′-di-tert-butyl-4′-hydroxyphenyl)-2-oxoethyl]-benzothiazolium salt;
3-[2-(4′-n-pentylphenyl)-2-oxoethyl]-thiazolinium salt;
3-[2-(4′-n-pentylphenyl)-2-oxoethyl]-4-methyl-5-(2′-hydroxyethyl)-thiazolin ium salt;
3-[2-4′-diethylaminophenyl)-2-oxoethyl]-4-methyl-5-(2′-hydroxyethyl)-thiazo linium salt;
3-(2-phenyl-2-oxoethyl)-4-methyl-5-vinyl-thiazolium salt;
3-[2-(3′,5′-tert-butyl-4′-hydroxyphenyl)-2-oxoethyl]-4-methyl-5-vinyl-thiazolium salt;
3-(2-tert-butyl-2-oxoethyl)-thiazolium salt;
3-(2-tert-butyl-2-oxoethyl)-4-methyl-5-(2′-hydroxyethyl)-thiazolium salt;
3-(3′-methoxybenzyl)-4-methyl-5-(2′-hydroxyethyl)-thiazolium salt;
3-(2′,6′-dichlorobenzyl)-4-methyl-5-(2′-hydroxyethyl)-thiazolium salt;
3-(2′-nitrobenzyl)-4-methyl-5-(2′-hydroxyethyl)-thiazolium salt;
3-[2-(4′-chlorophenyl)-2-oxoethyl]-thiazolium salt;
3-[2-(4′-chlorophenyl)-2-oxoethyl]-4-methyl-5-(2′-hydroxyethyl)-thiazolium salt;
or
3-[2-(4′-methoxyphenyl)-2-oxoethyl]-4-methyl-5-(2′-hydroxyethyl)-thiazolium salt.

98 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/470,482Filed 22 Dec 1999 · division
Priority: 18 Jan 1995
Granted: 27 Aug 2002
Term ends: Not estimatedThe source records don’t support an estimate.

Classification25 codes

G01N 33/6842
General methods of protein analysis not limited to specific proteins or families of proteins: proteomic analysis of subsets of protein mixtures…
A61K 8/49
Containing organic compounds: containing heterocyclic compounds
A61K 31/425
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: thiazoles
A61K 31/426
Thiazoles: 1,3-Thiazoles

Family

Application08/375,155Parent of this continuation-in-part · filed 18 Jan 1995
Application08/473,184Parent of this continuation-in-part · filed 7 Jun 1995
Application08/588,249Parent of this division · filed 18 Jan 1996
US 5,656,261 AParent of this continuation-in-part · filed 12 Aug 1997
Application08/971,878Parent of this division · filed 19 Nov 1997
US 6,007,865 AParent of this division
US 5,853,703 AParent of this division
Application08/588,249Parent of this continuation-in-part
US 6,440,749 B1This patent

From the US filing history. Foreign family members aren’t listed.