DE3021785C2 - - Google Patents

Description

In one respect, the invention relates to and indicates a new connection with a laxative effect, namely bis- [p- (1-ethoxy-ethoxy) phenyl] -2-pyridylmethane with of structural formula (I)

The invention further relates to a pharmaceutical composition with compound (I) as active ingredient in connection with a pharmaceutical Carrier or diluent.

Finally, the invention relates a process for the preparation of the compound (I), wherein Bis- (p-hydroxyphenyl) -2-pyridylmethane according to the structural formula (II) in the presence of an acid catalyst with ethyl vinyl ether according to the following scheme:  

Bis- (p-hydroxyphenyl) -2-pyridylmethane itself can be win light, for example by hydrolysis of the corresponding Diacetoxy derivative that is commercially available is.

The reaction between the compound (II) and the ethyl vinyl ether preferably takes place between 0 ° C and 60 ° C, preferably between 10 ° C and 30 ° C. Any can be used as the catalyst inorganic acid (for example sulfuric acid, Phosphoric acid, hydrochloric acid), or an organic sulfonic acid or finally a strongly acidic resin. Preferably finds the reaction in the presence of a small one Amount of concentrated sulfuric acid instead.

It is expedient to work in inert solvents, for example diethyl ether, tetrahydrofuran or dioxane.

The method of the invention is illustrated by the following Example explained:

example a) Bis- (p-hydroxyphenyl) -2-pyridylmethane

48 g of bis (p-acetoxyphenyl) -2-pyridylmethane are in 300 ml Methanol suspended. Then 23 g in 100 ml of water  dissolved sodium hydroxide added. The mixture will heated to 50 ° C. The unsolved product goes in quickly Solution. Allow to cool to room temperature, the methanol is evaporated under vacuum, and 200 ml of water and then 103 ml of 5N hydrochloric acid are added. The The mixture is cooled to 0 ° C. and filtered. To this 35 g of bis- (p-hydroxyphenyl) -2-pyridyl- methane (II).

b) bis- [p- (1-ethoxyethoxy) phenyl] -2-pyridylmethane

14 g of the dihydroxy derivative (II) are dissolved in 100 ml of tetrahydrofuran suspected. 40 ml of ethyl vinyl ether are added and a drop of concentrated sulfuric acid. The mixture is left at room temperature for one hour stirred and then at room temperature for 24 hours ditched. After this time, the whole is unresolved Substance has gone into solution.

The solvent is evaporated under reduced pressure, the rest in 250 ml of water containing 2 g of sodium hydroxide, and the mixture is extracted with diethyl ether. After drying the ether solution, the solvent evaporated, and the residue obtained (20 g) is through Triple chromatography over basic alumina with petroleum ether cleaned as eluent.

This results in 12 g of a dense oil that is not can be distilled without decomposing; in thin layer chromatography it turns out to be a completely uniform substance.

Analysis:
On C₂₆H₃₁NO₄:
calculated C: 74.11%; H: 7.36%; N: 3.32%; found C: 74.34%; H: 7.31%; N: 3.38%.

Spectroscopic data (IR, NMR) confirm the structure the connection in question.

The toxicological and pharmaceutical properties Compound (I), hereinafter referred to as "Mepilax" will be described below.

acute toxicity

The acute toxicity of Mepilax has been demonstrated in mice and rats investigated with oral and subcutaneous administration.

Male Sprague-Dawley mice were used with an average weight of 25 g ± 10 and albino rat male the Wister breed with an average weight of 120 g ± 10.

The compound to be examined was administered orally, with the gastric tube, dissolved in propylene glycol, and subcutaneously, also dissolved in propylene glycol.

The rats and mice left within 24 hours. after oral administration no animal, taking doses up to 3000 mg of active substance were given; just as little faults occurred within this 24 hours or after a, apart from a clear diarrhea effect, which was only seen with oral administration.

Laxative effect

1) The laxative effect of Mepilax was determined by the method by Lish and Mitarb. (1958) determined by the intestinal passage a suspension of biochar has been observed any stimulating or hindering effects to determine intestinal motility.  

material and methods

Wister Albino rat male with a body weight of about 100 g had to fast for at least 18 hours, but had free access to water.

Products used: Mepilax and for comparison purposes Disodium salt of 4,4 ′ - (2-picolylidene) -di-phenylsulfuric acid, known as sodium picosulfate, each in cans of 37.5 mg / kg; oral administration.

Time 0: The compounds to be examined were oral administered. After 3 hours: a 6% suspension of biochar in 5% gum arabic was administered; dose 10 ml / kg. After 3 hours 45 minutes: The animal was sacrificed to the intestinal passage to check.

The results can be found in Table 1, in which the GX Sodium salt of 4,4 '- (2-picolylidene) -di-phenylsulfuric acid and MX mean Mepilax.

Table 1

Laxative effects of GX and MX (after the test by Lish et al.)

2) The laxative effect of Mepilax has also been shown  the method of Schmidt u. Employee (1962) determined at which is the percentage of diarrheal animals after oral Administration of Mepilax has been determined.

material and methods

Albino rat female of the Wister breed with a body weight from about 70 to 80 g had to fast for about 18 hours, but had free access to water.

Products used: Mepilax and the disodium salt of 4,4 '- (2-picolylidene) -di-phenylsulfuric acid, homogenized in 5% gum arabic and administered in one dose of 5 mg / kg, which corresponds to a dose of 37.5 mg / kg; oral administration.

Throughout the experiment, the animals were kept in individual cages held, the bottom of which was designed as a grid, under the blotting paper was laid out to the excrement and to be able to determine their condition perfectly.

The paper was replaced after each determination.

The following tests were performed at the times indicated to determine the condition of the excrement:  

Test duration (h) treatment of rats

0 Start of fasting 18 Administration of the compound to be examined End of fasting and start of free feeding 23 Examination of excrement 25.5 Examination of excrement
Interruption of feeding 42 Examination of excrement
Resumption of free feeding 48 Examination of excrement

Every zone on paper that is obvious Diarrhea excrement was found at the examination marked with a +.

Each group included 10 animals, and also became a control group set up in which the animals only use the slurry (Gum arabic) were fed. In this group were present throughout the investigation no diarrhea excrement, why the results shown only apply to those with laxatives treated two groups.

The results can be found in Table 2.  

Table 2

Laxative effect (Schmidt and co-workers)

The duration of the laxative effect of GX and MX was in rats for a dose of 37.5 mg / kg (oral administration).

The test results are summarized in Tables 3 and 4.

Table 3

Duration of the laxative effect of GX and MX

Table 4

Evaluation of the duration of the laxative effect in rats

As can be seen from the above, Mepilax has one Effect completely comparable to that of Sodium picosulfate, which is one of the most commonly used today Laxatives and its structure are obvious is analogous to the compound of the invention.

Table 1 leaves the superiority of the invention Connection because of its longer lasting effect detect. This could be confirmed by experiments on humans. For this purpose, both drugs were made into different Times on more than 30 patients of both sexes spent; the patients had an average age 30 years old and usually suffered from constipation. Mepilax was much better tolerated. In particular, about 75% of the patients gave a significant longer lasting and less violent effect for Mepilax over the other drug. Almost all patients also noted a decrease in pain and Side effects noted when using Mepilax.

Mepilax can be given in the usual forms of administration (capsules, tablets, suppositories) that are in addition to the usual drug carriers 3 to 10 mg of active ingredient contain. The drug can also be in the form of drops (water Glycerin medium) are taken, with an equivalent Amount of active ingredient contained in 5 to 15 drops is.  

Comparison of the compound Mepilax with Bis- (p-acetoxy-phenyl) -2-pyridylmethane, known as bisacodyl (US-27 64 590) 1. The laxative effect, measured in the excrement of mice

The Schmidt and Seeger (1956) method was used.

Male SMC mice weighing 18 to 20 g, those who had fasted for 18 hours were named Compounds administered orally in 5% gum arabic: the Control group received 10 ml / kg of the vehicle. After administering the compounds to be tested the animals were fed normally and received water At will.

The excrement was collected for 24 hours, and the Animals that provided liquid excrement were identified as viewed diarrhea. The results are expressed than the percentage of animals that had diarrhea.

Results

Table 5 below shows that Mepilax is 51% Efficacy in the mouse, an animal for the low Responsiveness to laxative agents is known while Bisacodyl proved to be complete under the same conditions proved inactive.  

Table 5

Effect on mouse excrement after administration of Mepilax and Bisacodyl

2. Effect on the intestinal level of ink in the rat

The modified method according to Hackental et al. (1963) was applied.

Male Sprague-Dawley rats weighing 100 to 120 g was added with wheat semolina for 36 hours fed and then fasted for up to 12 hours at the beginning of the experiment.

The compounds were homogenized in ink and orally administered in doses of 25 and 50 mg / kg. The Control group received only ink. After administering the Medicinal compounds and the ink became the animals with a mixture of 100 g of wheat semolina and 40 ml of water fed. The time between each animal was between the administration and appearance of the ink in the excrement certainly. The excrement was collected and analyzed for their ink content.

Another attempt was made by administration of the drug compounds at a dose of 50 mg / kg 3 hours after each administration of the ink.

Results

As can be seen from Table 6, Mepilax proved at a dose of 25 mg / kg after about 6 hours as effective, and bisacodyl was found to be effective after 4 hours effective; when increasing the dose to 50 mg / kg or at  Administration of the compounds 3 hours after taking the ink the publication times were shortened for both Links.

The longer release time when administered of Mepilax is considered a beneficial effect because the effect on intestinal passage is less is violent.

Table 6

Effect of Mepilax and Bisacodyl on the passage of ink through the gut in the rat

3. Duration of laxative effects in the rat

Male Wistar rats weighing 100 to 120 g, which had been fasting for 18 hours, became the Oral drug compounds at a dose of 100 mg / kg as a 5% solution in gum arabic in a volume of 10 ml / kg administered. The animals were then treated with a sweet food and water (100 g / 40 ml) free for 12 hours  fed. The excrement was hourly over 48 hours collected away; the animals that delivered liquid excrement were considered to have diarrhea.

The duration of the effect was determined, measured on the last hour, at which still failures can be observed were.

Results

As shown in Table 7, at Mepilax, the amount of time during which the animals have diarrhea, much longer.

Table 7

Duration of laxative effects in the rat after oral administration of Mepilax and Bisacodyl

Claims (3)

1. Bis- [p- (1-ethoxyethoxy) phenyl] -2-pyridylmethane of the formula 2. Pharmaceutical composition with a laxative effect, characterized due to their content of bis- [p- (ethoxy-ethoxy) phenyl] -2- pyridylmethane of formula (I) in claim 1 as Active ingredient in conjunction with a pharmaceutical carrier or Diluent. 3. A process for the preparation of bis- [p- (1-ethoxyethoxy) phenyl] -2-pyridylmethane of the formula (I) in claim 1, characterized in that bis- (p-hydroxyphenyl -2-pyridylmethane of the formula (II) with ethyl vinyl ether in the presence of an acid catalyst in the following manner: