Oxirane carboxylic acid derivative and its manufacturing method

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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514255, 514336, 514406, 514407, 514444, 514461, 514471, 514472, 514473, 549549, 549518, 549 60, 549472, 549473, 544406, 544407, 544409, 5462817, 5483657, A61K 31335, A61K 3138, C07D30702, C07D24102, C07D40100

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active

060136669

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to oxirane carboxylic acid derivative expressed by the following formula (1), its manufacturing method and antidiabetic agent containing it. ##STR1## Wherein A is one selected from the radicals expressed by the following (i), (ii), (iii) and (iv); ##STR2## R.sup.1 represents a lower alkyl; (wherein, R.sub.2 .about.R.sub.13 represent independently hydrogen, halogen, alkoxy, lower alkyl, hydroxy, alkenyl, alkynyl, cyano or amino group; B is independently nitrogen or carbon; X is oxygen or sulfur; n denotes 0, 1 or 2).


BACKGROUND OF ART

The diabetic patients tend to suffer from some disorders such as inhibition of glucose uptake, inhibited glycolysis and increasing beta-oxidation of fatty acid in their peripheral tissues, which cause the use of fat for their body's energy source instead of glucose and lead to some diseases such as hyperglycemia, hyperlipidemia and hyperketonemia.
The beta-oxidation of fat in diabetic patients occurs in a mitochondrial substrate. Carnitine palmitoyl transferase I (CPT I) is an enzyme to transport a higher fatty acid from cytoplasm to a mitochondrial substrate, and plays an vital role in limiting the beta-oxidation rate.
Therefore, CPT I inhibitors will be utilized as an effective antidiabetic agent in that they may inhibit the beta-oxidation of higher fatty acids, increase the availability of glucose and exert the hypoglycemic, hypolipidemic and hypoketonemic effects.
The typical compounds belonging to the above mentioned CPT I inhibitors include palmoxirate, clomoxir(POCA) and etomoxir, and these compounds are characterized in that all of them have oxirane carboxylic acid in their most active site.
The inhibitory action of these oxirane carboxylic acid derivatives against the CPT I has yet to be elucidated up to now but it has been assumed that since these derivatives have the stable covalent bonding in the active sites of CPT I within cytoplasm, their inhibition action against the CPT I may contributed to the treatment of diabetes. Therefore, a possible mode of action is that when some nucleophilic substance at the active site of CPT I initiates to attack the epoxide ring structure of oxirane carboxylic acid derivatives, the opened epoxide ring forms a new hydroxyl group , and at the same time CPT I and oxirane carboxylic acid derivative is covalently bonded, thus the CPT I activity is inhibited.
However, the phase II clinical trials of etomoxir had not been continued owing to some side effects associated with prolonged administration, such as enlarged heart and toxicity in the liver, but its cause has not been explicitly known up to now.


DISCLOSURE OF INVENTION

Based on the mechanism that these oxirane carboxylic acid derivatives have exerted inhibitory actions against the CPT I, the inventor et al. have extensively studied to develop some promising compounds with blood glucose lowering effects, thus showing remarkable antidiabetic activities and less side effects. To this end, the inventor et al. have come to know that as a result of screening various kinds of derivatives having oxirane carboxylic acid positioned at their most active sites, oxirane carboxylic acid derivative of the formula 1 with opened epoxy ring at oxirane structure has proven to have an excellent antidiabetic activity and less side effects. In consequence, this invention has been completed.
An object of this invention is to provide oxirane carboxylic acid derivative expressed by the following formula 1. ##STR3## Wherein: A is one selected from the radicals expressed by the following (i), (ii), (iii), (iv) and (v); ##STR4## R.sub.1 represents a lower alkyl; (wherein, R.sub.2 .about.R.sub.13 represent independently hydrogen, halogen, alkoxy, lower alkyl, hydroxy, alkenyl, alkynyl, cyano or amino group; in particular, R.sub.2 is hydrogen, bromine or chlorine; R.sub.3 is hydrogen, methyl, n-buthyl, chlorine or methoxy; R.sub.4 is hydrogen or methoxy; R.sub.5 is hydrogen or bromine; R.sub.6, R.sub.7, R.sub.9, R.sub.12 are hydrogen; R.sub.8 is hydrogen, methyl, ch

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