IE42418B1

IE42418B1 - New salts of the monophosphoric acid ester of 2,2'-dihydroxy-3,3',5-5'-tetrabromobiphenyl

Info

Publication number: IE42418B1
Application number: IE20176A
Authority: IE
Original assignee: Ciba Geigy Ag
Priority date: 1975-02-03
Filing date: 1976-02-02
Publication date: 1980-07-30
Also published as: TR18885A; NZ179881A; IE42418L; ES444843A1; IL48953A; HU172125B; SU587868A3; IL48953A0

Description

The present invention relates to alkaline-earth metal salts of the monophosphoric acid ester of 2,2'dihydroxy-3,3',5,5'-tetrabromobiphenyl, to a process for the pro- . duction. of such salts, to compositions containing the salts as active ingredients, as well as to the use of the salts in combating liver flukes (Fasciola hepatica).

The monophosphoric acid ester of 2,2'“dihydroxy-3,3', ,5'-tetrabromobiphenyl is already known. In this connection reference is made to the French Patent Specification No. 1,485,647, to the British Patent Specification No. 1,122,244, to the US Patent Specifications Nos. 3,482,016 and 3,662,035, and to the German Patent Specification No. 1,543,792. In these patent specifications there is also a reference-in general ternis of salts of the monophosphoric acid ester of 2,21-dihydroxy-3,31,5,5'-tetrabromobiphenyl.

However, only alkali metal salts are specifically described.

The monophosphoric acid ester of 2,2'-dihydroxy-3,3', ,5'-tetrabromobiphenyl and the alkali metal salts thereof that have hitherto become known have an excellent action against liver flukes. The possibility of the use of these known substances for the control of liver fluke;; is however impaired hy the poor stability in storage, und··.- (he usual conditions, of the substances themselves and of the preparations containing them.

It has now been found that, surprisingly, the acid alkaline-earth metal salts of tlie monophosphoric acid ester of 2,2'-dihydrox-y-3,3',5,5'-tetrabromohiphenyl of the formula wherein M represents magnesium or calcium, which sal is have not been described hitherto, as well as compositions containing these acid alkaline-earth metal salts, have excellent storage stability both under normal storage conditions and in the physiological pH-range.

With regard to their action against liver flukes, the. new alkaline-earth metal salt;; arc at least equally as good as the monophosphoric acid ester of 2,2'-dihydroxy3,3' ,5,5 '-tetrabromohiphenyl and the alkali metal salts thereof that are known, and furthermore - 3 43418 exhibit good physiological compatibility.

In accordance with the present invention, the magnesium and calcium salts of the monophosphoric acid ester of 2,2'dihydroxy-3,3',5,5'-tetrabromobiphenyl are obtained by a . process which comprises reacting the monophosphoric acid ester of 2,2'-dihydroxy-3,3',5,5'-tetrabromobiphenyl, or an alkali-matal salt thereof, in an inert solvent at a pH of from 5 to 6 with a magnesium or calcium salt soluble in the reaction medium.

Suitable inert solvents are·, in particular, water and mixtures of water and ethanol. Where the reaction is performed in an aqueous medium it is essential that a pHrange of 5 to 6 be maintained. This desired pH-range can be obtained by the addition of a substance capable of forming a buffer system, for example sodium, acetate.

Suitable calcium and magnesium salts soluble in the reaction medium are, in particular, the chlorides and the acetates.

The alkaline-earth metal salts of the invention of the monophosphoric acid ester of 2,2'-dihydroxy4 3,315,51-tetrabromobiphenyl can be obtained in an advantageous manner by, for example, reacting a monoalkali metal salt (e.g. the monosodium salt) of the monophosphoric acid ester of 2,2’-dihydroxy-3,3’,5,5'-tetrabromobiphenyl in an aqueous medium with a soluble calcium or magnesium salt (e.g. the chloride) in the molar ratio of 2:1 preferably at room temperature. Furthermore, the alkaline-earth metal salts of the invention are obtainable by treatment of a suspension of the monophosphoric acid ester in water with an aqueous solution of excess calcium chloride or magnesium chloride in a pH-range, of 5 to 6, preferably at room temperature or at slightly elevated temperature. In order to be able to adjust the pH to a value in the desired range, the reaction is performed in the presence of a substance capable of forming a buffer system, e.g. sodium acetate. The alkaline-earth metal salts of the invention can however be obtained also by reaction of the monophosphoric acid ester of 2,2'-dihydroxy-3,3'5,5'tetrabromobiphenyl with calcium chloride or magnesium chloride in the molar ratio of 1:1 in 95% ethanol, and subsequent precipitating of the thus formed acid salt with water. A further possibility for producing the alkaline-earth metal salts of the invention is to react the monophosphoric acid ester of 2,2'-dihydroxy-3,3’,5,5’-tetrabromobiphenyl in 60% ethanol with calcium acetate in the molar ratio of 2:1.

The monophosphoric acid ester of 2,2'-dihydroxy-3,3', ,5'-tetrabromobiphenyl used for the production of the compounds of the invention can be obtained by reaction of 5 2,2'-dihydroxy-3,3',5,5 *-tetrabromobiphenyl with phosphoryl chloride, in the presence of pyridine, to give the cyclic phosphoric acid ester chloride; the conversion thereof into the cyclic phosphate by means of sodium hydroxide solution; and subsequent treatment with, concentrated hydrochloric acid (see German 'Auslegeschrift' No. 1,543,792).

The present invention also provides a composition which, comprises as active ingredient at least one of the alkaline-earth metal salts of the invention together with suitable carriers, excipients or diluents. The compositions Qf the invention can be in the solid, liquid or paste form.

They may be produced in a maimer known per se by the intimate mixing of the alkaline-earth - 6 42418 metal salts of the invention with suitable carriers, excipients or diluents, optionally with the addition also of dispersing agents inert to the active ingredients. Because of the greater ease of applying them, the preferred formulations of the compositions of the invention are formulations in liquid form, e.g. suspensions, and in paste form. The alkalineearth metal salts of the invention are suitable, in particular, for the production of suspensions and pastes having excellent stability in storage.

For the production of suspensions, it is possible to use vegetable oils, paraffin oils, e.thylene glycol stearate, silicone oils, butylhydroxyanisole, aluminiummonostearate, cetyl alcohol, sorbitol-fatty acid esters and stearyl alcohol; and for the production of pastes it is possible to use vegetable oils, paraffin oils, ethylene glycol stearate, silicone oils, butylhydroxyanisole, aluminium-monostcarate, cetyl alcohol, sorbitolfatty acid esters, stearyl alcohol and cured vegetable oils and waxes.

In addition, the alkaline-earth metal salts of the invention Gan, be processed, with varying degrees of concentration, with additions of surfactants and carrier - 7 43418 materials, such as highly dispersed silicic acid, bolus alba, talcum and polyvinylpyrrolidone, into the form of wettable powders that are readily suspendible in water.

Powders produced in this manner can be administered in the form of drenches. Furthermore, the active ingredients can be processed with the use of auxiliaries such as microcrystalline cellulose, highly dispersed silicic acid, gelatine, maize starch, mannitol and magnesium stearate into the form of tablets.

As indicated above, the compounds of the invention can be used against liver flukes. The present invention therefore further provides a method of combatting liver flukes in nonhuman animals, which comprises administering to the animal liable to infection or infected therewith an effective amount of a salt of the invention or of a composition of the invention.

The following Examples illustrate the invention. Throughout the specification, percentages are by weight.

Example 1 6.2 g of monophosphoric acid ester of 2,2'-dihydroxy3, 3',5,5'-tetrabromobiphenyl is suspended in 100 ini of water. After the addition of 25 ml of a 10% aqueous calcium chloride solution, there is added dropwise, with vigorous stirring, a 25% aqueous sodium acetate solution until the reaction mixture has a pH-value of 5 - 6.

Stirring is subsequently maintained for 8 hours at room temperature, and during this time the pH-value is repeatedly corrected to 5-6 by further additions of sodium acetate solution.

The reaction mixture is stirred for a further 15 hours; the reaction product is then filtered off with suction, and washed several times with water. After drying, there is’ obtained 5.6 g of monocalcium salt of the monophosphoric acid ester of 2,2-dihydroxy-3,3',5,5‘-tetrabromobiphenyl, m.p. 2lo-212°c.

Analysis:C24li12Br8°· L0P2Ca ' • 2 : h20 calculated: 23.25% C 1.29% H 51.57% Br found: 23.70% c 1.40% H 51.80% Br calculated: 3.23% Ca 2.91% h2o found.: 3.15% Ca 3. 10% h2o • _ 9 _ 43418 Example 2 6.2 g of monophosphoric acid ester of 2,2’-dihydroxy3,3*,5,5'-tetrabromobiphenyl is suspended in 120 ml of water. There is added 25 ml of a 10% calcium chloride solution as well as 8.2 g of solid sodium acetate (anhydrous). Stirring is maintained for 8 hours at room temperature; filtration with suction is then performed and the residue is repeatedly washed on the suction filter with water. After drying, there is obtained 5.5 g of monocalcium salt of the·monophosphoric acid ester of 2,210 dihydroxy-3,3',5,5’-tetrabromobiphenyl, m.p. 2O3°C, which is identical to the product obtained in Example 1 (mixed melting point).

Example 3 .82 g (0.01 mqle) o£ monophosphoric acid ester of 2,2'-dihydroxy-3,3',5,5'-tetrabromobiphenyl is dissolved in 100 ml of 0.1N NaOH at room temperature viith stirring.

The small amount of undissolved impurities is removed by filtration, and to the filtrate there is slowly added, with stirring, 25 ml of a 10% calcium chloride solution.

After stirring for one hour, the resulting precipitate is filtered off under suction, repeatedly washed with water and then dried. There is obtained 5.5 g of mono10 calcium salt of the monopho'snhoric. acid ester of 2,2'-dihydroxy3,3', 5,5'-tetrabxomobiphenyl, which As identified by mixed melting point with the product produced according to Example 1.

Example 4 24.0 g of monophosphoric acid ester of 2,2'-dihydroxy3, 3' ,5 ,5' -tetrabromohiphenyl dissolved in 200 ml of 60% ethanol is added dropwise at room temperature, with continuous stirring, to a solution of 3.2 g of calcium acetate in 200 ml of 60% ethanol. Stirring is subsequently continued until completion of the reaction, and a further 30 ml of 60% ethanol is added. After one hour, the precipitate is filtered off under suction and dried at 45°C.

Yield: 22.13 g Melting point: 204°G 0 Analysis: C24H12Bl!8OlOI>2Ca ’ 2H2° calculated: 23.25%-C 1.29% H 51.57% Br 3.23% Ca 2.91% H2O found: 23.13% C 1.39% H 51.86% Br 2.94% Ca 3.09% H20 The products obtained in the Examples 1 to 4 were originally · in a crystalline state, partially melting at 183-185OC. Increasing •the temperature causes the melt to harden again and then to malt at the temperatures specified in each of the Examples 1-4 to form a clear melt.

Example 5 600.0 g of monophosphoric acid ester of 2,2'dihydroxy-3,31,5,5'-tetrabromobiphenyl dissolved in 850 ml of 95% ethanol and 111.0 g of CaC^ dissolved in 1300 ml of ethanol are filtered and mixed together; there is then slowly added, with continuous stirring, about 20 litres of water. After the precipitate has settled out, the liquid on top is decanted and the precipitate is washed with water. Recrystallisation from dimethylformamide; m.p.: 210°C. 43418 Example 6 6.2 g of monophosphoric acid ester of 2,2'-dihydroxy3,3 ' ,5,5' - tetrabromobiphenyl is suspended in 100 ml of water. After the addition of 20 ml of a 20% aqueous solution of magnesium chloride, the procedure is carried out in a manner analogous to that described in Example 1. There is obtained 5.3 g of the acid magnesium salt of the acid having a melting point of 190-195°C. The composition corresponds to 2 moles of monophosphoric acid ester per Mg atom.

Analysis: C24tti2Br8°10P2Mg . 2 H20 calculated: 23.59% C found: 23.50% C calculated: 1.99% Mg found: 2.05% Mg 1.32% H 52.32% Br 5.07% 1.40% H 50.90% Br 5.10% 2.95% H20 3.20% H„0 - 14 43418 Example 7 Production of a 15¾ suspension .0 g of aluminium monostearate, 494.8 g of peanut oil and 50.0 g of ethylene glycol stearate are placed into a heatable vessel and heated at 150°C until an opalescent solution is formed. The solution is then allowed to cool to about 40°C, and there are subsequently added, with stirring? 260.0 g of silicone oil 556, 0.2 g of butylhydroxyanisole, 30.0 g of sorbitan monolaurate as well as 150.0 g of the active ingredient. The mixture is vigorously stirred for about 15 minutes with a turbulentchamber mixer until a homogeneous suspension is obtained. 43418 Example 8 Production of a 40¾ suspension 7.5 g of aluminium monostearate, 339.6 g of peanut oil and 40.0 g of hydrogenated peanut oil are placed into a heatable vessel and heated at 150°C until an opalescent solution is formed. The solution is then allowed to cool to about 40°C, and there are subsequently added, with stirring, 200.0 g of silicone oil 556, 0.2 g of butylhydroxyanisole as well as 391.5 g of the active ingredient The mixture is vigorously stirred for about 15 minutes with a turbulent-chamber mixer Until a homogeneous suspension is obtained. - 16 42418 Example 9 Production of a 15% paste 669.8 g of a viscous paraffin oil, 100.0 g of cured castor oil and 80.0 g of hydrogenated peanut oil are heated in a heatable steel vessel at about 90°C. After complete melting of the constituents, the mixture is allowed to cool to about 50°C; there are then worked into the mixture firstly 0.2 g of butylhydroxyanisole and finally 150 g of the active ingredient until a homogeneous paste is obtained.

Example 10 Production of a 40% paste 467.1 g of viscous paraffin oil, 34.0 g of cured castor oil and 86.0 g of hydrogenated peanut oil are heated in a heatable steel vessel at about 90°C. After complete melting of the constituents, the mixture is allowed to cool to about 50°C; there are then worked into the mixture firstly 0.2 g of butylhydroxyanisole and finally 391.5 g of the active ingredient until a homogeneous paste is obtained. 43418 Example 11 Production of a powder suspendtble in. water 2.7 g of highly dispersed silicic acid and 0.13 g of polyoxyethylalkyl ether/urea mixture are mixed together with a suitable mixing device. There are subsequently worked into the mixture, in the given sequence, 5.4 g of polyvinylpyrrolidone K 30, 15.0 g of active ingredient, 20.57 g of talcum as well as 56.2 g of white clay. The homogeneous mixture is ground in a suitable mill (e.g. dowelled disc mill) until the desired particle size is obtained.

For application with water, the finished powder mixtur can be converted into a suspension; and this can be administered with an applicator (such as a drench pistol) to the animal.

Example 12 Production of tablets 120.0 g of active ingredient, 42.0 g of microcrystalline cellulose and 2.0 g of highly dispersed silicic acid are mixed together; the mixture is then put through a sieve having a mesh size of 0.7 mm, and the sieved material is subsequently moistened with the solution of 8.0 g of gelatine in 200.0 g of water.

To this mixture there is added in small portions, with continuous mixing and kneading, 25.0 g of maize starch. The moist mixture is passed through a sieve with a mesh size of 1.1 mm, and subsequently dried.

There is added to the dried granulate 3.0 g of magnesium stearate, and the mixture is pressed to form tablets, with the total weight being so chosen that the amount of active ingredient is in proportion to the body weight of the intended animal species.

Example 13 Production of tablets .0 g of active ingredient and 137.0 g of mannitol are mixed together; the mixture is put through a sieve having a mesh size of 0.7 mm, and the sieved material is subsequently moistened with a solution of 5.0 g of gelatine in 150.0 g of water.

To this mixture there is added in small portions, with continuous mixing and kneading, 25.0 g of maize starch. The wet mixture is passed through a sieve with a mesh size of 1.1 mm, and afterwards dried.

There is added to the dried granulate 3.0 g of magnesium stearate, and the mixture is processed into the form of tablets, with the total weight being so chosen that the amount of active ingredient is in proportion to the body weight of the intended animal species. 43418 Example 14 Production of tablets 120.0 g of active substance, 42.0 g of microcrystalline cellulose and 2.0 g of highly dispersed silicic acid are mixed together; the mixture is put through a sieve of 0.7 mm mesh size, and the sieved material is then moistened with the solution of 8.0 g of gelatine in 200.0 g of water.

To this mixture there is added in small portions, with continuous mixing and kneading, 25.0 g of maize starch.

The wet mixture is then passed through a sieve having a mesh size of 1.1 mm and the material obtained is subsequently dried.

There is added to the dried granulate 3.0 g of magnesium stearate, and the mixture is processed into tablets, with the total weight being so adjusted that the amount of active ingredient is in proportion to the body weight of the intended animal species.

Claims

CLAIMS:

1. Magnesium or calcium salts of the monophosphoric acid ester of 2,2'-dihydroxy-3,3',5,5'-tetrabromohiphenyl, of the general formula in which M represents magnesium or calcium.

2. Process for the production of the magnesium or calcium salts as claimed in claim 1, which comprises reacting the monophosphoric acid ester of 2,2'-dihydroxy-3,3*,5,5'-tetrabromohiphenyl, or an alkali-metal salt thereof, in an inert solvent at pH of from 5 to 6 with a magnesium or calcium salt soluble in the reaction medium.

3. Process according to claim 2, in which the inert solvent is water or a mixture of water and ethanol.

4. Process according to claim 2 or claim 3, in which the calcium or magnesium salt soluble in the reaction medium is a chloride or an acetate.

5. Process according to any one of claims 2 to 4, in which a monoalkali metal salt of the mohophosphoric acid ester of 2,2’-dihydroxy-3,3',5,5' 1 tetrabromobiphenyl is reacted with calcium chloride or magnesium chloride in the molar ratio of 2:1 in an aqueous medium.

6. Process according to claim 5, in which the mono-sodium salt of the monophosphoric acid ester of 2,2'-dihydroxy-3,3',5,5'tetrabromobiphenyl is employed.

7. Process according to any one of claims 2 to 4, in which a suspension of the monophosphoric acid ester of 2,2 *-dihydroxy3, 3 1 ,5,5'-tetrabromobiphenyl in water is treated with an aqueous solution of excess calcium chloride or magnesium chloride.

8. Process according to any one of claims 2 to 4, in which the monophosphoric acid ester of 2,2 1 -dihydroxy-3,3 1 ,5,5 * tetrabromobiphenyl is reacted with calcium chloride or magnesium chloride in the molar ratio of 1:1 in 95% ethanol, and the formed acid salt is subsequently precipitated with water.

9. Process according to any one of claims 2 to 4, in which the monophosphoric acid ester of 2,2'-dihydroxy-3,3',5,5'-tetrabromobiphenyl is reacted with calcium acetate in the molar ratio of 2:1 in 60% ethanol.

10. Process according to any one of claims 2 to 9, in which a substance capable of forming a buffer system is additionally present in the reaction medium.

11. Process according to claim 10, in Which said substance is sodium acetate.

12. Process according to claim 2, substantially as described in any one of Examples 1 to 6.

13. A salt as claimed in claim 1 when prepared by the process of any of claims 2 to 12.

14. A composition which comprises as active ingredient at least one compound as claimed in claim 1 or claim 13, in admixture with suitable carriers, excipients or diluents.

15. A composition as claimed in claim 14, substantially as described in any one of Examples 7, 9 or 11.

16. A composition as claimed in claim 14, substantially as described in any one of Examples 8, 10 or 12 to 14.

17. Method of combatting liver flukes in non-human animals which, comprises administering to the animal liable to infection or infected therewith an effective amount of a salt as claimed in claim 1 or 13 or of a composition as claimed in any one of claims 14 to 16.