GB2051801A - New compound with laxative activity, pharmaceutical compositions which contain it, and a process for its preparation - Google Patents

Abstract

A new compound having laxative activity, namely bis-[p-(1-ethoxy- ethoxy)phenyl]-2-pyridylmethane, pharmaceutical compositions which contain this compound, and a process for preparing the compound by reacting bis-(p-hydroxyphenyl)-2-pyridyl- methane with ethylvinylether in the presence of an acid catalyst such as sulphuric acid.

Description

SPECIFICATION New compound with laxative activity, pharmaceutical compositions which contain it, and a process for its preparation This invention relates to and in one aspect provides a new compound having laxative activity, namely bis-[p-( 1 -ethoxy-ethoxy)phenyl]-2-pyridylmethane of formula (I)

The invention also relates to and in another aspect provides a pharmaceutical composition comprising the compound (I) as its active ingredient, together with a pharmaceutical carrier or diluent.

The invention also relates to and in a further aspect provides a process for preparing the compound (I), comprising reacting bis-(p-hydroxyphenyl)-2-pyridylmethane of formula (II) with ethylvinylether in the presence of an acid catalyst, in accordance with the scheme:

Bis-(p-hydroxyphenyl)-2-pyridylmethane is itself easily obtainable, for example by hydrolysing the corresponding diacetoxy derivative, which is a known commercial product.

The reaction between compound (II) and the ethylvinylether is preferably carried out at a temperature between 0 and 60"C, more preferably between 10 and 30"C. The catalyst used can be any inorganic acid (sulphuric, phosphoric, hydrochloric), or an organic sulphonic acid, or a resin of strongly acid character. The reaction is preferably carried out in the presence of a small quantity of concentrated sulphuric acid.

It is advantageous to operate in inert solvents, such as ethyl ether, tetrahydrofuran or dioxane.

The process according to the invention is illustrated by the following example: EXAMPLE a) bis-p-hydroxyphenyl)-2-pyridylmethane 48 g of bis-(p-acetoxyphenyl)-2-pyridylmethane are suspended in 300 ml of methanol. 23 g of sodium hydroxide dissolved in 100 ml of water are then added. The mixture is heated to 50"The undissolved product rapidly passes into solution. It is allowed to cool to ambient temperature, the methanol is evaporated under vacuum, and 200 ml of water are added followed by 103 ml of 5 N hydrochloric acid. The mixture is cooled to O"C and filtered. In this manner, 35 g of bis-(p-hydroxyphenyl)-2-pyridylmethane (II) are obtained.

b) his- fp-(1-eth ox y-eth ox y)phen yIJ-2-p yridylmethane 14 g of the dihydroxy derivative (II) are suspended in 100 ml of tetrahydrofuran.40 40 ml of ethylvinylether and one drop of concentrated sulphuric acid are added. The mixture is kept stirred for one hour at ambient temperature and is then left to stand at ambient temperature for 24 hours. After this time, all the undissolved substance has passed into solution.

The solvent is evaporated under reduced pressure, the residue is taken up in 250 ml of water containing 2 g of sodium hydroxide, and the mixture is extracted with ethyl ether. After drying the ether solution, the solvent is evaporated and the residue obtained (20 g) is purified by triple chromatography over basic alumina using petroleum ether as eluent.

In this manner, 12 g of a dense oil are obtained which cannot be distilled without decomposition, and is found to be perfectly unitary under thin layer chromatography.

Analysis: forC26H31NO4; 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 of the compound concerned.

The toxicological and pharmaceutical properties of the compound (I), which will be known hereinafter by the term "Mepilax", are given hereinafter.

Acute toxicity The acute toxicity of Mepilaxwas investigated in the mouse and rat orally and subcutaneously.

Maie mice of Sprague-Dawley stock having an average weight of 25 g + 10 and male albino rats of Wistar stock having an average weight of 120 g + 10 were used.

The compound under examination was administered orally by gastric probe dissolved in propylene glycol, and subcutaneously again dissolved in propylene glycol.

No case of mortality occurred either in the rat or the mouse in the 24 hours following oral administration up to a dose of 3000 mg of active ingredient, nor was there any distubance either in the 24 hours or subsequently, with the exception of a marked diarrhoeic effect, but limited to the oral administration state.

Laxative activity 1) The laxative activity of Mepilax was determined using the method of Lish and coll. (1958) by evaluating the intestinal progression of a suspension of vegetable charcoal in order to determine any stimulation or inhibition effects on the intestinal motility.

Materials and methods Male albino rats of Wistar stock having a body weight of approximately 100 g, kept fasting for at least 18 hours, with free access onlyto water.

Products used: Mepilax and, for comparison purposes, the bisodium salt of 4,4'-(2-picolylidene)-bisphenylsulphuric acid (known as sodium picosulphate), both in doses of 37.5 mg/kg by oral administration.

Time 0-The compounds under examination were administered orally.

After 3 hours - A 6% suspension of vegetable charcoal in 5% gum arabic was administered in a dose of 10 ml/kg.

After 3 hours 45 mins. -Theanimal was killed in order to check the intestinal transit.

The results are given in Table 1, in which GX is the sodium salt of4,4'-(2-picolylidene)-bis-phenylsulphuric acid, and MX is Mepilax.

TABLE I Laxative action of GX and-MX in accordance with the test of Lish and coll.

Product No. animals Dose mg/kg Average % variation in oral admin. the migration of the charcoal over45mins.

relative to the pylorus caecum distance Controls 10 37.5 69.68+ 4.98 GX 10 37.5 75.20 +6.41 MX 10 37.5 81.3 + 6.25 2) The laxative activity of Mepilax was also determined by the method of Schmidt and coll. (1962) in which the percentage of diarrhoeic animals was determined after oral administration of Mepilax.

Materials andmethods Female albino rats of Wistar stock having a body weight of about 70-80 g, and kept fasting for about 18 hours with free access only to water.

Products used: Mepilax and the bisodium salt of 4,4'-(2-picolylidene)-bis-phenylsulphuric acid, homogenised in 5% gum arabic and administered in a quantity of 5 ml/kg, this dose being equivalent to 37.5 mg/kg by oral administration.

During the entire experiment the animals were kept in individual cages with a base in the form of a grid, under which blotting paper was placed in order to properly show the feces and their state.

The paper was changed after each determination.

The following tests were carried out at the times stated for determining the state of the feces: Time 0 - The animals, kept fasting for about 18 hours, were treated with the compounds under examination.

After administration, the animals were fed freely.

After 5 hours - The state of the feces was determined.

After 7.5 hours - The state of the feces was determined in animals which had been kept fasting.

After 24 hours - The state of the feces in freely fed animals was determined.

After 30 hours - The state of the feces was determined.

Each zone on the paper comprising obviously diarrhoeic feces was indicated by a + in the determination.

Each group consisted of 10 animals, and one group was also kept as a control and treated only with the suspending substance (gum arabic). In this group, no diarrhoeic feces were noted during the entire duration of the treatment, because of which the results shown relate only to the two groups treated with the laxatives.

The results are shown in Table 2.

TABLE 2 Laxative activity (Schmidt and coll.) MX GX 5h 7.5h 24h 30h 5h 7.5h 24h 30h 1 ++ ++ +++ + +++ +++ ++ 2 + ++ ++ - ++ ++ ++ 3 +++ +++ +++ - + + +++ 4 ++ ++ ++ - +++ +++ +++++ 5 ++ +++ ++ - ++ ++ ++ 6 - + + - ++++ ++++ ++++ 7 ++ ++ ++ + - + ++ 8 ++ ++ + - +++ +++ ++ ++ 9 +++ +++ ++ - ++++ ++++ ++++ 10 +++ +++ ++ - ++++ ++++ ++++ Average % of 2.0 2.3 2.0 0.3 2.5 2.6 2.9 0.2 diarrhoeic animals 90% 100% 100% 30% 90% 100% 100% 10% The duration of the laxative action of GX and MX was determined in the rat for a dose of 37.5 mg/kg by oral administration.

The results of this experiment are contained in Table 3 given below.

TABLE 3 Duration of the laxative action of GX and MX No. Treatment Time during which the Animals animal was diarrhoeic (No.dec.t s.d.) 10 Control mucillage 0 10 GX 37.5 mg/kg by 27.6 + 1.77 oral administration 10 MX 37.5 mg/kg by 27.7 + 2.54 oral administration As is clear from the preceding documentation, Mepilax has an action which is entirely similar to that of sodium picosulphate, which is one of the laxatives most commonly used at the present time, and which has a structure which is evidently analogous to the compound according to the invention.

However, Table 1 shows the superiority of the compound according to the invention because of its more prolonged action. This is confirmed in experiments carried out on the human being. In this respect, both the drugs were administered at different times to more than 30 patients of both sexes having an average age of about 30 years, and being normally affected by constipation. A significantly much greater tolerability was found in the case of Mepilax. In particular, about 75% of the patients observed a considerably more prolonged and less violent action in the case of Mepilax compared with the other drug. Almost all patients also observed a distinct reduction in pains and side-effects when taking Mepilax.

The normal forms of administration can be used for this latter (capsules, pills, suppositories) containing 3 to 10 mg of active principle, together with the normal excipients. In addition, a droplet formulation (water-glycerine medium) such as to enable equivalent quantities of the active principle to be assumed in 5-15 droplets can be used.

Claims (6)

1. Bis-[p-(1-ethoxy-ethoxy)phenyl]-2-pyridylmethane of formula (I).

2. A pharmaceutical composition having laxative activity, comprising bis-!p-( 1 -ethoxy-ethoxy)phenyl]-2- pyridylmethane of formula (I) as claimed in Claim 1 as its active ingredient, together with a pharmaceutical carrier or diluent.

3. A process for preparing bis-[p-(1-ethoxy-ethoxy)-phenyl]-2-pyridylmethane of formula (I) as claimed in Claim 1, comprising reacting bis-(p-hydroxyphenyl)-2-pyridylmethane of formula (II) with ethylvinylether in the presence of an acid catalyst, in accordance with the scheme:

4. A process as claimed in Claim 3, wherein the acid catalyst is sulphuric acid.

5. A process according to Claim 3, substantially as herein described in the foregoing Example.

6. The compound bis-[p-(1-ethoxy-ethoxy)phenyl]-2-pyridylmethane of formula (I) as claimed in Claim 1, for use in a method of treatment of the human or animal body by surgery or therapy or of diagnosis practiced on the human or animal body.