Chromone derivative, and aldose reductase inhibitor comprising s

Details Chromone derivative, and aldose reductase inhibitor comprising s Chromone derivative, and aldose reductase inhibitor comprising s

1994-05-12

1996-05-28

Chan, Nicky

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

549400, A61K 3135, C07D31116

Patent

active

055212166

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP93/00699, filed May 26, 1993.


TECHNICAL FIELD

The present invention relates to chromone derivatives with an inhibitory action on aldose reductase which are effective for the treatment of complications due to diabetes, as well as to synthetic intermediates and utilities of said derivatives.


TECHNICAL BACKGROUND

In recent years, attention is drawn to the accumulation of sorbitol in cells via a polyol pathway, i.e. a metabolic pathway of glucose, as a causative factor of various complications of diabetes such as cataract, retinosis, keratopathy, nephrosis, peripheral nervous system disorder, etc. The polyol pathway, proved to occur widely in various internal organs by immunotissue-chemical means, is a metabolic pathway in which aldoses such as glucose, galactose, etc., are converted through polyols e.g. sorbitol, galactitol, etc., into ketoses such as fructose, etc.
The enzyme catalyzing the conversion of aldoses into polyols in the first step of this pathway is called aldose reductase, and is considered the rate-limiting enzyme in the polyol pathway. It was reported that various complications in patients with diabetes are effectively prevented and cured by inhibiting aldose reductase and lowering sorbitol production and accumulation (Pharmacia, 24: 459 (1988)).
Under the circumstances, the development of pharmaceuticals with an inhibitory action on aldose reductase has been desired.
As pharmaceuticals with an inhibitory action on aldose reductase, Japanese Patent Appln. LOP Publication No. 228,914/89 discloses chromone derivatives Capillarisin (R.dbd.H) and 7-methyl Capillarisin (R.dbd.CH.sub.3) isolated from the herb of Artemisia capillaris thumb, represented by formula: ##STR2##
Known compounds with a similar structure to Capillarisin include the chromone derivatives of formula (A): ##STR3## wherein R1, R2, R3, R4 and R5 are set out in Table 1 (for example, Japanese Patent Appln. LOP Publication Nos. 169,586/90, 114,768/79 and 322,066/88 and Journal of the Pharmaceutical Society of Japan, 96: 841 (1976) and 96: 855 (1976)). However, it has not be made evident whether these chromone derivatives have any inhibitory action on aldose reductase.


TABLE 1 ______________________________________ R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 ______________________________________ CH.sub.3 H O OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 O OCH.sub.3 CH.sub.3 C.sub.2 H.sub.5 H O OCH.sub.3 C.sub.2 H.sub.5 C.sub.2 H.sub.5 C.sub.2 H.sub.5 O OCH.sub.3 C.sub.2 H.sub.5 COCH.sub.3 COCH.sub.3 O OCH.sub.3 COCH.sub.3 H H S OCH.sub.3 H H CH.sub.3 O H H CH.sub.3 CH.sub.3 O H CH.sub.3 CH.sub.3 H O H H H H O H H H H O H CH.sub.3 CH.sub.3 H O H CH.sub.3 ______________________________________


DESCRIPTION OF THE INVENTION

The object of the present invention is to provide chromone derivatives which can be easily synthesized without using Capillarisin as a starting material and which exhibits aldose reductase inhibition superior to that of Capillarisin.
The present first invention relates to the chromone derivatives represented by formula (1): ##STR4## wherein R1 and R2 are the same or different and independently represent a hydrogen atom or a lower alkyl group.
In the above formula (1), the lower alkyl groups represented by R.sub.1 or R.sub.2 are C.sub.1-6 alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 1-ethylpropyl and hexyl groups.
For the chromone derivative (1) of the present invention, at least one of R.sub.1 and R.sub.2 in the above formula (1) is preferably a branched-chain alkyl group, such as an isopropyl group, represented by formula (3): ##STR5## wherein R.sub.7 and R.sub.8 are the same or different and independently represents a methyl or ethyl group.
Examples of the present chromone derivative (1) are 5,7-dihydroxy-2-(4-hydroxyphenylthio)chromone,5-hydroxy-2-(4-hydroxyphenyl thio)-7-methoxychromone, 2-(4-hydroxyphenylthio)-5,7-dimethoxychromone, 5,7-diethoxy-2-(4-hydroxyphe

REFERENCES:
Komiya et al., Journal of the Pharmaceutical Society of Japan, vol. 96, No. 7, Jul. 1976, pp. 841-854.
Komiya et al., Journal of the Pharmaceutical Society of Japan, vol. 96, No. 7, Jul. 1976, pp. 855-862.
Tanimoto, Pharmacia, vol. 24, pp. 459-463, 1988.
Igarashi et al. CA. 117: 233,854f (1992)-Abstract of WO92 09594, Jun. 11, 1992.

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