DE1900772A1 - Dimethyl biguanide derivative - Google Patents

Description

Dimethyl biguanide derivative The invention relates to the salt of a Molecule of p-chloro-phenoxy-acetic acid and one molecule of N, N-dimethyl-biguanide.

This salt has the formula It can be prepared by reacting the acid and the base in essentially equimolecular amounts in a common solvent, in particular ethanol.

A production example will now be described.

Example 257.4 g of p-chloro-phenoxy-acetic acid are, if necessary, under dissolved in 300 ml of absolute ethyl alcohol by gentle warming. In 150 ml of the same 178.7 g of N, N-dimethyl biguanide are dissolved in the solvent.

These two solutions are mixed together.

The crystallization of the salt goes very quickly when the temperature rises in front of you. The mixture is at the reflux temperature of the alcohol for 30 minutes The mixture is then cooled, the crystals are separated off and washed with 95 g alcohol.

It is dried in a drying oven and 342 g (78%) of a product are obtained that melts at 189 to 191.

The salt of the invention, hereinafter referred to as CE 3310, is a wide crystalline powder which is soluble in water but slightly soluble in alcohol and is insoluble in acetone, benzene and chloroform.

The compound CE 3310 has been studied pharmacologically, whereby it has been compared with the known effects of N, N-dimethyl biguanide. A toxicological one test was carried out on the mouse, rat and rabbit.

1. Oral acute toxicity in the mouse The compound CE 3310 was used suspended in an aqueous solution with 5% gum arabic and homogeneous groups of 10 male mice in a dose of 0.5 ml suspension per 20 g body weight administered.

The DL50 was made using the Litchfield & Wilcoxon method 3 g / kg determined.

The DL50 of N, N-dimethyl-biguanide determined by the same method was 3,500 g / kg.

2. Acute buccal toxicity in the rat.

The compound CE 3310 was administered to the rat buccally at a dose of 1 ml of the same suspension administered per 100 g of body weight.

The DL50 of the compound CE 3310 was determined to be 2.350 g.

3. Acute buccal toxicity in the rabbit.

The same suspension was given at a dose of 5 ml / kg body weight administered. After 72 hours, the mortality in groups of 5 rabbits each established.

The DL50 was 1,500 g / kg.

4. Chronic toxicity The compound CE 3310 was used for 3 months Groups of 10 sensual and female rats at doses of 200, 100 and 10 sg / kg administered orally0 The compound CE 3310 did not cause any Growth disturbance of the animals and no pathological changes whatsoever. It was no mortality observed.

It was also considered the most important at the time of the killing taken from the animals for anatomical pathological purposes and immersed in bouin liquid preserved organs no pathological changes in the internal tissue structure established.

5. Teratogenic trials.

Compound CE 3310 was given to a group of 10 pregnant rabbits administered by the oral route at doses of 150 and 5 mg / kg. This did not result in any Causes disruption of pregnancy.

C-section taken from one third of the rabbits No malformation was observed in the fetuses.

The boys bent in normal times showed the same growth like the boys of the comparative Canes.

6. Hypoglycemic effect.

a) With the mouse.

The buccal routes administered at doses of 250 and 500 mg / kg Connection C! 3310 showed a noticeable difference in mice compared to N, N-dimethyl-biguanide Increase in the hypoglycemic effect. The glycemia was known after Methods of microdosing determined. The blood was passed through groups of 10 mice Cut open the aorta. The duration of the connection CE 3310 became tested by administering the product at different times prior to sacrifice.

The results are given in the following table: Compounds doses% of reducing glycemia mg / kg 1 hour 3 hours 5 hours CE 3310 500 45% 48% 32% 250 27% 34% 18% N, N-Dime- 200 31% 39% 17% thylbi guanid 100 18% 26% 18% As can be seen, the hypoglycemic effect of the compound CE 3310 is always coarser than that of the N, N-dimethyl-biguanide in corresponding doses.

In separate investigations, the connection CE 3310 showed a higher hypoglycemic effect than its two components, p-chloro-phenoxy-acetic acid and the N, N-dimethyl biguanide. The effect of compound CE 3310 was on these Try 15% higher.

b) In the rat.

The effect of the compound CE 3310 at a dose of 500 mg / kg was larger than that of the N, N-dimethyl biguanide in the corresponding can. At a Equimolecular dose of 500 mg / kg, the two products acted differently: the caused by the connection CE 3310 Hypoglycemia was 13% higher, than that found after administration of N, N-dimethyl-biguanide.

These results were also found in the rabbit.

7. Other pharmocological effects.

An overall test that was as complete as possible showed that the connection CE 3310 has no side effects whatsoever that make its use therapeutic Purposes.

In particular, it was observed in both the rabbit and the dog when high doses (1 g / kg) are administered, there is no noticeable change in pressure established.

When tested on various severed organs, the connection showed CE 3310 also does not have any anticholinergic, sympatholytic or antispasmodic Effects and no antihistamine effect.

With regard to the intestinal intake, there were also no changes whatsoever of the intestinal passage and minor irritation of the intestinal mucosa.

By administering the compound OB 3310 in doses of 100 to 500 mg / kg by the oral route was not found in the dog, Kanische or rat Changes in kidney volume and diuresis. The connection CE3310, the is not very toxic, does not appear to have any teratogenic effects, and is phramcological affects the glucose content of the blood, can in ddr human medicine in all diabetic Conditions applied that require the use of a stronger hypoglycemic Mtttels may require.

Their pharmacological effect is much higher than theirs Components, especially N, N-dimethyl biguanide.

It can be administered in particular in the form of capsules, coated tablets, tablets which contain the active ingredient in amounts of 0.1 to 1.5 g per unit and optionally mixed with other active ingredients.

Example for a tablet ANP 3310 0.350 g potato starch 0.037 g polyvinyl acetate 0.025 g corn starch 0.008 g talc The compound CE 3310 became clinical applied in the form of tablets with doses of 250 mg.

The patients with non-keto-atidotic diabetes were included treated according to the following criteria: plethoric, newly discovered diabetes, diabetes, who has never or only been treated orally for a short time, diabetes, in which diet alone failed to bring the glycemia back to normal.

Biologically, the glycaemia fluctuated between 0.140 and 0.250%, the Glycosuria for 24 hours was less than 40 g. The urea and kidney function tests were normal.

The daily dose varied between 250 and 1500 mg CE 3310. The duration the treatment lasted at least 1 month. The effectiveness of the treatment was increasing assessed the glycemia, which is evident in all cases at doses of 250 to 1500 mg CE 3310 normalized. These doses correspond to approximately 100 to 600 mg of N, N-dimethyl biguanide.

Compared to the known remedies, they contain about 50% less biguanide, which increases the therapeutic range. Clinical tolerance was excellent. A kidney balance carried out at the end of the treatment has nothing Malfunctions shown.

Claims (2)

Claims 1. Salt from one molecule of p-chloro-phenoxy-acetic acid and one molecule of N, N-dimethyl-biguanide of the formula 2. Antidiabetic agent consisting of the salt from one molecule of p-chloro-phenoxy-acetic acid and one molecule of N, N-dimethyl biguanide and pharmaceutically acceptable additives.