Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-12-26
2002-12-10
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S023000, C549S429000, C549S483000, C549S484000
Reexamination Certificate
active
06492338
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a pharmaceutical composition or a reagent having an aldose reductase inhibitory activity.
BACKGROUND ART
Aldose reductase (hereinafter referred to as AR) is an enzyme involved in a polyol pathway, one of glucose-metabolic pathways, in a living body. The polyol pathway consists of two pathways, i.e., a pathway of reducing glucose to sorbitol involving AR; and a pathway of dehydrogenating sorbitol to D-fructose involving sorbitol dehydrogenase (hereinafter referred to as SDH). It is known that the polyol pathway exists in a number of tissues including brain, liver, pancreas, kidney, adrenal gland, testis, seminal vesicle, placenta, erythrocytes, lens, retina and peripheral nerve. However, the physiological significance of the polyol pathway has been confirmed only in the seminal vesicle, in which it acts as a pathway for producing energy source for sperms. It is believed that, in other sugar-metabolic pathways in normal cells, most of the glucose incorporated into a cell is converted into glucose 6-phosphate by the action of hexokinase to be metabolized in a glycolytic pathway, while only several percents of the glucose is metabolized through the polyol pathway [Tsuyoshi Tanimoto, Pharmacia, 24:459-463 (1988)].
When influx of glucose into a cell increases, the glucose which the glycolytic pathway fails to process is brought to the polyol pathway. The SDH activity is lower than the AR activity. Therefore, an intermediary metabolite, sorbitol, is produced in large quantities if the influx of glucose continues. Sorbitol is highly polar and, therefore, does not efficiently diffuse outside the cell. Thus, sorbitol is accumulated with the cell, resulting in the increase in intracellular osmotic pressure [Tsuyoshi Tanimoto, Pharmacia, 24:459-463 (1988)]. Examples of tissues in which glucose present in blood (blood sugar) unlimitedly flows into cells include insulin-independent tissues such as central nervous system, blood cells and medulla glandulae [Medical Dictionary, 17th edition, Nanzando, Co. Ltd. (1990)].
Diseases due to the accumulation of sorbitol have been reported. For example, diabetic cataract has been reported to be caused as a result of the following steps: AR in lens of eyeballs converts glucose and galactose into corresponding sugar alcohols. The sugar alcohols are inappropriately accumulated in the lens to increase the osmotic pressure. The increased osmotic pressure damages the lens to cause the cataract [see J. H. Kinoshita et al., Biochimica et Biophysica Acta, 158:472 (1968) and references cited therein]. Various harmful influences due to accumulation of sorbitol in lens, peripheral nerve cord and kidney in a diabetic animal have also been reported [see A. Pirie et al., Experimental Eye Research, 3:124 (1964); L. T. Chylack Jr. et al., Investigative Ophthalmology, 8:401 (1969); and J. D. Ward et al., Diabetologia, 6:531 (1970)].
Among complications of diabetes in which blood sugar value is elevated, AR is involved in, for example, cataract, retinopathy, peripheral neuropathy and/or nephropathy. It is essential to inhibit the activity of AR, which is responsible for the above-mentioned complications, as strongly as possible in order to prevent, ameliorate or treat them.
Other diabetic complications include, for example, infectious diseases due to decrease in phagocytosis in leukocytes and diabetic coma [Shin-ban Katei No Igaku, 11th edition, Jiji Press, Ltd. (1996)] and arteriosclerosis due to atheromatous degeneration in great vessel walls [Medical Dictionary, 17th edition, Nanzando, Co. Ltd. (1990)].
OBJECTS OF INVENTION
The main object of the present invention is to develop a compound having an AR inhibitory activity and to provide a pharmaceutical composition for a disease due to AR or a composition for inhibiting AR which contains the compound as its active ingredient.
The other objects and advantages of the present invention will be apparent from the description below.
SUMMARY OF INVENTION
The present inventors demonstrated that 2,5-dihydroxytetrahydro-2-furancarboxylic acid, as well as optical isomers and salts thereof have carcinostatic activities (WO 98/32749). As a result of intensive studies, the present inventors have found that these compounds have highly selective ability of inhibiting an AR activity. Thus, the present invention has been completed.
Thus, the first aspect of the present invention relates to a pharmaceutical composition for treating or preventing a disease due to an AR activity, which contains at least one compound having an AR inhibitory activity selected from the group consisting of 2,5-dihydroxytetrahydro-2-furancarboxylic acid of formula 1:
as well as derivatives, optical isomers and pharmacologically acceptable salts thereof.
The second aspect of the present invention relates to a composition for inhibiting AR, which contains at least one compound having an aldose reductase inhibitory activity selected from the group consisting of 2,5-dihydroxytetrahydro-2-furancarboxylic acid, as well as derivatives, optical isomers and salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
2,5-Dihydroxytetrahydro-2-furancarboxylic acid is produced, for example, by heating glucaric acid.
Glucaric acid (also called as saccharic acid) is represented by molecular formula C
6
H
10
O
8
(molecular weight 210.14). Glucaric acid is a dicarboxylic acid produced by oxidizing D-glucose, or an oligosaccharide or a polysaccharide that contains D-glucose with nitric acid or the like. It can also be produced by oxidizing D-glucuronic acid with bromine water.
For example, a reaction of glucaric acid at 121° C. for 4 hours results in a reaction mixture containing 2,5-dihydroxytetrahydro-2-furancarboxylic acid. 2,5-Dihydroxytetrahydro-2-furancarboxylic acid can be purified and isolated from the reaction product by subjecting it to reverse phase column chromatography.
2,5-Dihydroxytetrahydro-2-furancarboxylic acid can also be produced by hydrating &agr;-ketoglutarate semialdehyde. &agr;-Ketoglutarate semialdehyde can be produced according to a known method [Journal of Bacteriology, 116:1364-1354 (1973)].
Any derivatives of 2,5-dihydroxytetrahydro-2-furancarboxylic acid may be used in the present invention as long as they have an AR inhibitory activity. Examples of the derivatives include, but are not limited to, a compound of formula 2:
wherein R
1
, R
2
and R
3
may be the same or may be different each other, and are hydrogen, an aliphatic group, an aromatic group or an aromatic aliphatic group; m and n are 1 or 0, provided that in case of m=n=0, R
1
, R
2
and R
3
are not simultaneously hydrogen.
Examples of aliphatic groups include linear alkyl groups of 1-30 carbons, branched alkyl groups such as isopropyl group, isobutyl group, sec-butyl group, tertbutyl group, isopentyl group, neopentyl group and tertpentyl group, linear alkenyl groups such as etenyl group, allyl group, trans-1-propenyl group, cis-1-propenyl group, cis-8-heptadecenyl group, cis-8-cis-11-heptadecadienyl group, cis-8-cis-11-cis-14-heptadecatrienyl group, cis-5-cis-8-cis-11-heptadecatrienyl group, cis-4-cis-7-cis-10-nonadecatrienyl group, cis-4-cis-7-cis-10-cis-13-nonadecatetraenyl group, cis-4-cis-7-cis-10-cis-13-cis-16-nonadecaheptaenyl group, cis-12-henicosenyl group and cis-3-cis-6-cis-9-cis-12-cis-15-cis-18-henicohexaenyl group, as well as branched alkenyl groups such as isopropenyl group, cis-1-methyl-1-propenyl group, trans-1-methyl-1-propenyl group, trans-1-methyl-1-propenyl group and trans-1-ethyl-1-propenyl group.
Examples of aromatic groups include phenyl group, naphthyl group, biphenyl group, pyrrolyl group, pyridyl group, indolyl group, imidazolyl group, tolyl group, xylyl group, o-chlorophenyl group, o-bromophenyl group, o-nitrophenyl group and o-methoxyphenyl group.
Examples of aromatic aliphatic groups include phenylalkyl groups of 1-15 alkyl group carbons (e.g., benzyl group or phenetyl group), stylyl group and cinnamyl group.
The compou
Akiyama Kaori
Kato Ikunoshin
Sagawa Hiroaki
Ueno Harumi
Browdy and Neimark , P.L.L.C.
Takara Shuzo Co. Ltd.
Wilson James O.
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