Aldose reductase inhibitor and process for preparation thereof

Details Aldose reductase inhibitor and process for preparation thereof Aldose reductase inhibitor and process for preparation thereof

2001-12-21

2004-11-23

Weber, Jon P. (Department: 1651)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ketone doai

C435S041000, C435S069200, C435S189000

Reexamination Certificate

active

06822003

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel aldose reductase inhibitor. More particularly, the present invention relates to a novel aldose reductase inhibitor of formula I derived from cultures of
Aspergillus niger
CFR 1046 and pharmaceutically acceptable derivatives thereof.
BACKGROUND OF THE INVENTION
Diabetes mellitus and its disabling complications which include blindness, renal failure, limb amputation, myocardial infarction affect millions of people (Schumacher, M. P.
Diabetes
44 (1995)1355-1361). In the absence of or in cases of insufficient insulin, glucose accumulates in the blood of diabetics. Certain cells such as those in the peripheral nerves, the lens of the eye, or parts of the kidneys, however, do not need insulin to get glucose. As a result, maximum damage such as blindness, neuropathy and kidney damage occurs in such sites in diabetics. Nerve damage in diabetes is largely caused by loss of the insulating myelin sheath around nerves, which in turn causes message transmission to be erratic and painful, or non-existent. The reason this occurs is that when glucose enters these cells, it is converted into sorbitol by the enzyme aldose reductase (Alditol: NADP
+
1-oxidoredutase, EC 1.1.1.21) which catalyses the NADPH-linked reduction of a broad group of aldoses to respective alduronic acids (Wilson K. W., Boren K. M. and Gabbay K. H.,
Science
257 (1992) 3). Sorbitol is then slowly converted into fructose by sorbitol dehydrogenase. Neither sorbitol nor fructose can cross the membrothe and leave the cell easily, thereby causing damage as they accumulate. The resulting changes include changes in osmotic pressures, alterations in redox state of pyridine nucleotides (increased NADH/NAD
+
ratio) and depleted intracellular levels of myoinositol (Larson E R, Lipinski C A and Sarges R
Med Res Revs
8 (1988) 159-186).
Since diabetics have larger than normal amounts of glucose in the blood, the damage can lead to the above-mentioned problems. Certain substances present naturally in foods, block aldose reductase and prevent cell damage. Vitamin C, Alpha Lipoic Acid, Licorice, and various citrus or other antioxidants, e.g. quercetin, are aldose reductase inhibitors (Kim H. Y. and Oh J. H.,
Biosci. Biotech. Biochem
63 (1999) 184-188). Inhibitors against these enzymes thus have a potential application in both the food and medical sector.
Traditionally in Japan, some kampo medicines (traditional oriental herbal prescriptions) have long been used for the treatment of diabetic neuropathy (Aida, K, Tawata, M., Shindo, H., Onaya, T., Sasaki H., Yamaguchi, T., Chin, M., Mitsuhashi.
Planta Med
, 56 (1990) 254-258). The authors investigated the components of
Glycyrrhizae radix
, a constituent of some kampo medicines, and isolated six compounds (GUs 9-17). Among these, GU-17, identified as isoliquiritigenin, had the most potent aldose reductase inhibiting activity.
Isoliquiritigenin inhibited rat lens aldose reductase with an IC
50
of 3.2×10(−7) M, using DL-glyceraldehyde as a substrate. It inhibited sorbitol accumulation in human red blood cells in vitro, with an IC
50
of 2.0×10(−6) M. Isoliquiritigenin, when administered via an intragastric tube to diabetic rats, suppressed sorbitol accumulation in the red blood cells, the sciatic nerve, and the lens as effectively as ONO-2235. These results suggest that isoliquiritigenin may be effective in preventing diabetic complications.
Among the natural compounds, flavonoid compounds such as quercetin, quercetrin, naringinin and hesperidin are reported to be useful and potent aldose reductase inhibitors (Aida, K., Tawata, M., Shindo, H., Onaya, T., Sasaki H., Yamaguchi T., Chin, M., Mitsuhashi.
Planta Med
, 56 (1990) 254-258).
The presently known chemically synthesized aldose reductase inhibitors are Tolrestat, a chemically synthesised inhibitor with an IC
50
of 3.5×10
−8
M; and Sorbinil (Hollis H D, Johnson J L and Werbel L M.
J Med Chem
. 27 (1984) 255-256).
Some inhibitors obtained through the fermentation route are Thiazocins obtained from the fermented broth of Actinosynnema sp (Ozasa T, Yoneda T, Hirasawa M, Suzuki K, Tanaka K, Kadota S and Iwanami M.
J Antibiot
44 (1991) 768-773), Thermorubrin and 2-hydroxy acetic acid from Thermoactinomyces sp UTA 8 (Hayashi K, Dombou M, Sekiya M, Nakajima H
J. of Antibiot
. 48 (1995) 1345-1346), Salfredins from Crucibulum sps (Matsumoto K, Nagashima K, Kamigauchi T,
J of Antibiot.
48 (1995) 439-446) and YUA001 from Corynebacterium sp (Bahn Y, Park J, Bai D, Takase S, Yu J,
J of Antibiot
. 51 (1998) 902-907) which has an IC
50
of 1.8 mM against pig kidney aldose reductase.
The search is constantly on for new sources of aldose reductase inhibitors from natural sources that are inexpensive and show better activity.
OBJECTS OF THE INVENTION
It is an object of the invention to locate and identify new natural sources for aldose reductase inhibitors that are more economical and show better activity.
It is another object of the invention to provide new aldose reductase inhibitors that show improved activity and are obtained from natural sources.
A further object of the invention is to provide process for the extraction of aldose reductase inhibitors that are economical and more efficient.
SUMMARY OF THE INVENTION
These and other objects of the invention are achieved by a novel aldose reductase inhibitor derived through the fermentation of certain microorganisms.
Accordingly, the present invention relates to a novel aldose reductase inhibitor of the formula I below and its pharmaceutically acceptable derivatives
In one embodiment of the invention, the aldose reductase inhibitor is a rat lens aldose reductase inhibitor.
In another embodiment of the invention, the aldose reductase inhibitor of formula I is 2, 6, dihydroxy, 8, hexoxy, 1, 4, naphthaquinone.
The invention also relates to a process for the isolation of a novel aldose reductase inhibitor of the formula I below
the process comprising culturing
Aspergillus niger
CFR 1046 and isolating said aldose reductase inhibitor.
In another embodiment of the invention, the aldose reductase inhibitor isolated from
Aspergillus niger
CFR 1046 is 2, 6, dihydroxy, 8, hexoxy, 1, 4, naphthaquinone.
In one embodiment of the invention, the aldose reductase inhibitory compound of formula I is isolated from
Aspergillus niger
CFR 1046 by fermentation.
In another embodiment of the invention, naphthaquinone is isolated from fermentates of
Aspergillus niger
CFR 1046 by solvent extraction.
In another embodiment of the invention, naphthaquinone is isolated from fermentates of
Aspergillus niger
CFR 1046 by column chromatography.
In another embodiment of the invention, naphthaquinone is isolated from fermentates of
Aspergillus niger
CFR 1046 by crystallization.
In a further embodiment of the invention, the compound of formula I is extracted from
Aspergillus niger
CFR 1046 from fermented potato dextrose broth using ethyl acetate solvent followed by column chromatography and crystallization.
In another embodiment of the invention, the compound of formula I isolated from
Aspergillus niger
CFR 1046 is converted to a pharmaceutically acceptable derivative.
In a further embodiment of the invention, the pharmaceutically acceptable derivative comprises acid or base addition products such as salts of this compound are also useful.
In a further embodiment of the invention, the addition products contain hydrochloride, hydrobromide, sulfate, sodium, potassium, calcium and the like ions.


REFERENCES:
Boghosian, Robert A. and McGuinness, Eugene T. Pig Brain aldose reductase: A kinetic study—. 1981. International J. Biochemistry, 13(8), pp. 909-914.*
Wittenveen, C.F.B. et al. L-arabinose and D-xylose catabolism in Aspergillus niger, 1989. J. General Microbiology, 135(8), pp. 2163 to 2171.

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