GB2181347A - Antidiarrhoeal agents containing guanidine derivatives - Google Patents

Abstract

N-Diamonimethylene-(2,5-dimethyl-1H-pyrrol-1-yl)acetamide and its pharmaceutically acceptable acid addition salts are useful in treating or preventing diarrhoea in mammals and poultry. The compounds, if desired, may be administered with one or more antimicrobial, absorbent, anti-emetic, parasympatholytic or antihistaminic agents, e.g. neomycin, attapulgite, streptomycin, tetracycline, sulphonamides, metronidazole, acetarsole, chloroquine, clioquinol, cyclizine, atropine, pectine, and ion-exchange resins.

Description

SPECIFICATION Antidiarrhoeal agents containing guanidine derivatives This invention relates to antidiarrhoeal agents.

Antidiarrhoeal agents are of value, for example, in the treatment of acute non-infective diarrhoea, chronic diarrhoea caused by functional states such as irritable bowel syndrome and the reduction of the volume of ileostomy discharge. In addition antidiarrhoeal agents are useful adjuncts to more specific measures in providing symptomatic control of chronic diarrhoea associated with inflammatory bowel disease. The class of antidiarrhoeal drugs of most use are the antimotility agents and of these the three drugs most commonly used are codeine phosphate, diphenoxylate and loperamide. All three possess the disadvantage that they are opioid drugs and possess central narcotic activity especially at high dosages. In addition, codeine phosphate and diphenoxylate have the disadvantage that some degree of tolerance to their constipating effect may develop.Accordingly a need exists for an antidiarrhoeal agent which does not possess such disadvantages.

UK Patent Application No. 208010A discloses antidiarrhoeal agents of the general formula

and pharmaceutically acceptable acid addition salts thereof wherein R1 and R2 which may be the same or different represent lower alkyl or trifluoromethyl and R3 and R4 which may be the same or different represent hydrogen or lower alkyl or R3 and R4 together represent dimethylene ortrimethylene.

It has now been found that N-diaminomethylene-(2,5-dimethyl-1H-pyrrol-1-yl)acetamide and pharmaceutically acceptable salts thereof have antidiarrhoeal activity.

In one aspect of the present invention provides the use of N-diaminomethylene-(2,5-dimethyl-1 Hpyrrol-1-yl)acetamide or a pharmaceutically acceptable acid addition salt thereof, in the preparation of an antidiarrhoeal agent in ready-to-use drug form for treating or preventing diarrhoea in mammals or poultry.

The animal is preferably a mammal. The mammal may be, for example, cattle, sheep, swine, rabbit, dog, cat, monkey or the like, but it is preferably a human. In another aspect the invention provides the use of N diaminomethylene-(2,5-dimethyl-l H-pyrrol-l -yl)acetamide, or a pharmaceutically acceptable acid addition salt thereof, in the manufacture of an antidiarrhoeal agent in a package together with instructions for its use in the treatment or prevention of diarrhoea in mammals or poultry.According to other aspects, the invention provides the use of N-diaminomethylene-(2,5-dimethyl-1H-l -yl)acetamide or a pharmaceutically acceptable acid addition salt thereof in treating or preventing diarrhoea in mammals or poultry, the use of N-diaminomethylene-(2,5-dimethyl-1H-pyrroi-1-yl)acetamide or a pharmaceutically acceptable acid addition salt thereof for use as an antidiarrhoeal agent and a method of treating or preventing diarrhoea in mammals or poultry which comprises administering to an animal in need thereof an amount effective for treating or preventing diarrhoea of N-diaminomethylene-(2,5-dimethyl-1H-pyrrol-1-yl)acetamide or a pharmaceutically acceptable acid addition salt thereof.

N-diaminomethylene-(2,5-dimethyl-l H-pyrrol-l -yl)acetam ide and its pharmaceutically acceptable salts are disclosed in UK Specification No. 1,530,675 which also describes processes for preparing the compounds.

For example, a reactive derivative of an acid of general formula (11)

or an acid addition salt thereof may be reacted with guanidine or a salt thereof. The reactive derivative of the acid of general formula (II) may be, for example, an acid chloride or, preferably, an ester particularly a lower alkyl ester. An alternative method of preparing the antidiarrhoeal agents comprises hydrolysing a nitrile of general formula (III)

In a further method of preparing the antidiarrhoeal agents an isothiourea derivative of general formula

(where R5 is lower alkyl, preferably methyl) is reacted with ammonia. An alternative method for preparing the agents comprises reacting an acylcyanamide of general formula (V!

with ammonia.

The antidiarrhoeai agent in the form of the free base may be converted to a pharmaceuticaliy acceptable acid addition salt by, for example, dissolving the free base in a suitable organic solvent and treating the solution with an acid in accordance with conventional procedures for preparing acid addition salts from base compounds.

Examples of pharmaceutically acceptable acid addition salts are those derived from inorganic and organic acids such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic and p-toluenesulphonic acids. - An acid addition salt may be converted into the free base by conventional procedures such as basifying a solution of the acid addition salt.

The antidiarrhoeal agents of the invention may exist in various tautomeric forms or mixtures of such forms as explained in further detail in UK Patent Specification No. 1,530,675. Where in the present specification there is used a name or formula impiying any particular tautomeric form it is to be understood that the name or formula includes any other alternative form or a mixture of such forms.

The antidiarrhoeal activity of the agents of the present invention was demonstrated by the effect on castor oil-induced diarrhoea in rats. The activity of N-diaminomethylene-(2,5-dimethyl-1H-pyrrol-1- yl)acetamide was compared with that of N-diaminomethylene-(trans-2,5-dihydro-2,5.dimethyl-1 H-pyrrol-1 - yl)acetamide and the commercial agent loperamide. In the procedure 6 groups of male rats weighing approximately 150 g were fastened overnight and placed in separate cages. The rats were dosed oraily with either hydroxypropylmethyl celluloselsaline or the test drugs at doses ranging from 30 mg/kg to 3 mg/kg. 1 hour later each rat was given 1.0 ml castor oil orally to induce diarrhoea.Faecal output was coilected on preweighed papers beneath each cage and weighed at intervals during the subsequent 6 hour experimental periods. The results of the testing are given below: Dose Inhibition of faecal output mg/kg Compound p.o. 0--2 hours 0--6 hours N-diaminomethylene- 30 96% (XX) 96% (XX) (2,5-dimethyl-1 H pyrrol.1.yl)acetamide 10 100% (XX) 75% (XX) 3 97% (XX) 40% (X) N-diaminomethylene- 30 100% (XX) 99% (XX) (trans-2,5-di hyd ro- 2,5-dimethyl-1H- 10 100% (XX) 86% (X) pyrrol-1 -yl)acetamide 3 100% (XX) 58% (N.S.) loperamide 30 98% (XX) 97% (XX) 10 100%(XX) 99%(XX) 3 96% (XX) 77% (XX) XX = P < 0.01 X = P < 0.05 N.S. = P > 0.05 The above results indicate that N-diaminomethyiene-(2,5-dimethyl-1H-pyrrol-1-yl)acetamide gives marked protection against diarrhoea at 3 mg/kg and above.

The active ingredients of the present invention may be administered alone or in the form of a pharmaceutical composition. The pharmaceutical compositions comprise N-diaminomethylene-(2,5 dimethyl-1H-pyrrol-1 -yl)acetamide or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier. The compositions may be prepared by a process which comprises bringing the active ingredient into association with the carrier (e.g. by mixing). Any suitable carrier known in the art can be used to prepare the pharmaceutical composition. In such a composition, the carrier is generally a solid or liquid, or a mixture of a solid and a liquid.

Solid form compositions include powders, granules, tablets and capsules (e.g. hard and soft gelatin capsules). A solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99%, e.g. from 0.03 to 99% preferably 1 to 80% of the active ingredient.Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.

Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups and elixirs.

The active ingredient, for example, can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceuticaily acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers or osmo-regulators. Suitable examples of liquid carriers for oral administration include water (particularly containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g.

glycerol and glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).

Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. The quantity of the active ingredient in a unit dose of composition may be varied or adjusted from 0.5 mg or less to 750 mg or more, according to the particular need and the activity of the active ingredient.

The dosage of the present agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Treatment may be initiated with small dosage substantially less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum effect under the circumstances is reached. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects. In general a dose of 1 to 200 mg of the agent should be suitable for an average adult. Preferred oral recommended amounts are 1 to 50 mg particularly 2 to 25 mg.

Diarrhoea is often associated with infections and in such cases it may be advantageous to administer the antidiarrhoeal agent of the present invention together with an antimicrobial agent such as an antibacterial or antiprotazoal agent. The antibacterial agent may be, for example, an antibiotic such as neomycin, streptomycin or dihydrostreptomycin or a sulpha drug such as phthalylsulphathiazole. More than one antibacterial agent may be employed in the composition. Antiprotazoal agents are particularly employed with diarrhoea associated with amoebiasis. Examples of antiprotazoal agents include metronidazole, acetarsol, chlorquine, cliquinol and tetracycline. The antidiarrhoeal agents of the invention may also be administered with an adsorbent (e.g. a clay such as an attupulgite, particularly an activated attupulgite, kaolin or a mixture of kaolin and pectin).These adsorbents help to adsorb toxins which may be associated with a diarrhoeal attack. Vomiting can accompany diarrhoea and therefore the antidiarrhoeal agent of the present invention may be administered together with an anti-emetic, e.g. cyclizine. Antidiarrhoeal agents can be given forthetreatment or prophylaxis of travellers' diarrhoea and for this purpose the antidiarrhoeal agents of the present invention can be administered together with a parasympatholytic or antihistaminic agent (e.g. atropine, hyoscine) useful in the prevention or treatment of motion sickness.

Accordingly the invention also provides a pharmaceutical composition comprising Ndiaminomethylene-(2,5-dimethyl-1H-pyrrol-1 -yl)acetamide or a pharmaceutically acceptable salt thereof and one or more antimicrobial, adsorbent, anti-emetic, parasympatholytic or antihistaminic'agents in association with a pharmaceutical carrier, with the proviso that if the composition contains an adsorbent and no antimicrobial, anti-emetic, parasympatholytic or antihistaminic agent, the adsorbent is not an antacid ingredient nor solely pectin.

The following Examples 1 to 17 illustrate the preparation of pharmaceutical compositions containing the active ingredients ofthe present invention.

EXAMPLE 1 Capsules mg/capsule N-diaminomethylene-(2,5-dimethyl 1H-pyrrol-1 -yl)acetamide hydrochloride 7.14 Mannitol B.P. 113.44 Maize starch, dried B.P. 37.82 Aerosil 200 (colloidal silicon dioxide) 0.80 Magnesium stearate, B.P. 0.80 160.00 Capsules of the above are made by thoroughly mixing together batches of the above ingredients and filling hard gelatine capsules with the mixture.

("Aerosil" is a registered Trade Mark) EXAMPLE 2 Tablets mg/tablet N-diaminomethylene-(2,5-dimethyl- 1H-pyrrol-1 -yl)acetamide hydrochloride 7.14 Calcium Phosphate Dihydrate USP 30.12 Avicel PH101 (microcrystalline cellulose) 60.24 Amberlite IRP 88 (potassium salt of a cation exchange resin of the carboxylic type) 2.00 Magnesium stearate B.P. 0.50 100.00 Tablets of the above composition are made by mixing batches of the ingredients and compressing the mixture to form tablets.

("Avicel" and "Amberlite" are Registered Trade Marks) EXAMPLE 3 Capsules mg/capsule N-diaminomethylene-(2,5-dimethyl 1H-pyrrol-1-yl)acetamide 5.0 Mannitol B.P. 115.58 Maize starch, dried B.P. 37.82 Aerosil 200 (colloidal silicon dioxide) 0.80 Magnesium stearate, B.P. 0.80 160.00 Capsules of the above are made by thoroughly mixing together batches of the above ingredients and filling hard gelatine capsules with the mixture.

EXAMPLE 4 Tablets mg/tablet N-diaminomethylene-(2,5-dimethyl 1 H-pyrrol-1 -yl)acetamide 5.0 Calcium Phosphate Dihydrate USP 30.12 Avicel PH101 (microcrystalline cellulose) 62.38 Amberlite IRP 88 (potassium salt of a cation exchange resin of the carboxylic type) 2.00 Magnesium stearate B.P. 0.50 100.00 Tablets of the above composition are made by mixing batches of the ingredients and compressing the mixture to form tablets.

EXAMPLE 5 Tablets mg/tablet N-diaminomethylene-(2,5-dimethyl- 1H-pyrrol-1 -yl)acetamide 10.00 Avicel (microcrystalline cellulose) 236.25 AcDisol (croscarmellose sodium type A N.F) 2.5 Magnesium stearate 1.25 250.00 mg Tablets of the above composition are made by mixing batches of the ingredients and compressing the mixtures to form tablets.

EXAMPLE 6 Tablets mg/tablet N-diaminomethylene-(2,5-dimethyl 1ll-pyrrol.1 yl)acetamide 5.00 Neomycin sulfate 350.00 Avicel PH 101 89.05 Calcium Phosphate Dihydrate USP 43.45 Amberlite IRP 88 10.00 Magnesium stearate B.P. 2.50 500.00 Tablets of the above composition are made by mixing batches of the ingredients and compressing the mixture to form tablets.

EXAM PLES 7 TO 12 Tablets of the following compositions are made by blending batches of the ingredients and compressing the mixture to form tablets:

Example No. Ingredients (mg) 7 8 9 10 11 12 N-diaminomethylene-(2,5- 5.0 5.0 5.0 5.0 5.0 5.0 dimethyl-1H-pyrrol-1-yl acetamide Avicel PH 101 (micro- 141.65 141.66 123.21 121.99 62.08 crystalline cellulose BPC Calcium Phosphate Dihydrate USP 69.70 69.70 60.54 59.93 29.98 Amberlite IRP 88 7.00 7.00 9.00 5.00 2.00 8 Magnesium stearate BP 1.75 1.75 2.25 1.25 0.50 1 Streptomycin sulphate BP 125.00 - - - - Dihydrostreptomycin - 125.00 - - - sulphate (BP 1958) Metronidazole BP - - 250.00 - - Cyclizine hydrochloride BP - - - 56.83 - Hyoscine hydrobromide BP - - - - 0.43 Starch BP - - - - - 24.00 Pre gelatinised maize starch BP - - - - - 12.00 Attapulgite, activated - - - - - 350.00 350.00 mg 350.00 mg 450.00 mg 250.00 mg 100.00 mg 400.00 mg

EXAMPLES 13TO 17 Capsules of the following compositions are made by blending batches of the ingredients and filling the mixed powders into hard gelatin capsules on a filling machine.

Example No.

Ingredients(mg) 13 14 15 16 17 N-diaminomethylene-(2,5 dimethyl-1H-pyrrol-1 -yl) acetamide 5.0 5.0 5.0 5.0 5.0 Mannitol BP 88.6 88.6 72.96 115.26 143.41 Maize Starch BP 28.84 28.84 23.61 37.71 47.09 Aerosil 200 1.25 1.25 0.80 0.80 2.25 Magnesium Stearate BP 1.25 1.25 0.80 0.80 2.25 Streptomycin sulphate BP 125.00 - - - - Dihydrostreptomycin sulphate (BP 1958) - 125.00 i - - Cyclizine hydrochloride BP - - 56.83 - - Hyoscine hydrobromide BP - - - 0.43 Metronidazole BP - - - - 250.00 250.00 mg 250.00 mg 160.00 mg 160.00 mg 450.00 mg

Claims (6)

1. The use of N-diaminomethylene-(2,5-dimethyl-1H-pyrrol-1 -yl)acetamide or a pharmaceutically acceptable acid addition salt thereof in the preparation of an antidiarrhoeal agent in ready-to-use drug form for treating or preventing diarrhoea in mammals or poultry.

2. The use of N-diaminomethylene-(2,5-dimethyl-1H-pyrrol-1-yl)acetamide or a pharmaceutically acceptable acid addition salt thereof in the manufacture of an anti-diarrhoeal agent in a package together with instructions for its use in the treatment or prevention of diarrhoea in mamrnals or poultry.

3. An antidiarrhoeal pharmaceutical composition comprising N-diaminomethylene-(2,5-dimethyl-1Hpyrrol-1 -yl)acetamide or a pharmaceutically acceptable acid addition salt thereof and one or more antimicrobial, adsorbent anti-emetic, parasympatholytic or antihistaminic agents in association with a pharmaceutical carrier, with the proviao that if the composition contains an adsorbent and no antimicrobial, anti-emetic, parasympatholytic or antihistaminic agent, the adsorbent is not an antacid ingredient nor safely pectin.

4. A composition as claimed in claim 3 in the form of a unit dosage form containing 1 to 200 mg of N diaminomethylene-(2,5-dimethyl-1H-pyrrol-1-yl)acetamide or a pharmaceutically acceptable acid addition salt thereof.

5. A composition as claimed in claim 3 or 4 in the form of a tablet or capsule.

6. A composition as claimed in claim 3 substantially as hereinbefore described with reference to any one of Examples 6 to 17.