DE2603631A1 - NEW SALTS OF THE MONOPHOSPHORIC ACID ESTER OF 2,2'-DIHYDROXY-3,3 ', 5,5'-TETRABROMBIPHENYL - Google Patents

Description

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Germany

New salts of the monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5, 5' -tetrabrorrfa iphenyls

The present invention relates to new alkaline earth salts of the monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl, the production of the new salts, agents that contain the new salts as an active ingredient, as well as the Use of the new salts to combat liver fluke (Fasciola hepatica).

The monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyls is already known. In this context, reference is made to the French patent specification 1,485,647, British 1,122,244, U.S. 3,482,016 and 3,662,035, and German Reference 1,543,792. Salts of the monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl are also used in these patents generally mentioned, but only alkali salts are specifically described.

The monophosphoric acid ester of 2,2 ', dihydroxy-3,3', 5,5'-tetrabromobiphenyl and its previously known alkali salts have an excellent action against Liver fluke. The possibility of using these known substances for combating liver fluke is, however, by the low storage stability of the substances themselves and the agents made from them under normal conditions impaired.

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It has now been found, surprisingly, that the acidic alkaline earth salts not described so far of the monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5' tetrabromobiphenyls of the formula I.

Br / N \ OH

Il

- P-O

Me

2+

in which Me means magnesium or calcium, as well as agents containing these acidic alkaline earth salts, both have excellent stability under normal storage conditions as well as in the physiological pH range. With regard to their action against liver fluke, the new alkaline earth salts are the monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyls and its Alkali salts that have become known to date are at least equal and are also characterized by good physiological properties Compatibility.

The new alkaline earth salts of 2,2'-dihydroxy-3,3 ', -5,5'-tetrabromobiphenyl are obtained by adding the monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl or one of its alkali salts in an inert solvent with a magnesium or soluble in the reaction medium Calcium salt converts at pH 5 to 6.

The main inert solvents used are water and mixtures of water with ethanol. At the When working in an aqueous medium, it is essential that a pH range of 5 to 6 is maintained. This desired pH range can be adjusted by adding a buffer substance, e.g. Sodium acetate j to be adjusted,

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The main calcium and magnesium salts which are soluble in the reaction medium are the chlorides and the acetates into consideration

The new alkaline earth salts of the monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl can, for example, advantageously be obtained by adding a monoalkali salt of the monophosphoric acid ester of 2,2'-dihydroxy-3,3 * , 5,5'-tetrabromobiphenyls in an aqueous medium with a soluble calcium or magnesium salt in a molar ratio of 2: 1 at room temperature. Furthermore, the new alkaline earth salts of the formula I can be prepared by treating a suspension of the monophosphoric acid ester in water with an aqueous solution of excess calcium or magnesium chloride in a pH range from 5 to 6 at room temperature or slightly elevated temperature. To set the desired pH range, the reaction is carried out in the presence of a buffer substance, for example sodium acetate. The new alkaline earth metal salts of the formula I can, however, also be prepared by reacting the monophosphoric acid ester of 2.2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl with calcium or magnesium chloride in a molar ratio of 1: 1 in 95% ethanol and then precipitating the formed acidic salt with water. Another possibility for the preparation of the new alkaline earth metal salts of the formula I consists in converting the monophosphoric acid ester of 2> .2 '-dihydroxy-3,3', 5,5 'tetrabromobiphenyl in 60% ethanol with calcium acetate in a molar ratio of 2: 1 . Finally, the new alkaline earth salts can also be produced in such a way that one. -Dihydroxy-3,3 2,2' ^1, 5,5'-tetrabrcmbiphenyls reacting alkali metal salt of the Monophosphorsäureesters in aqueous medium at pH 5 to 6 with the equivalent Menge- a soluble calcium or magnesium salt.

609832/1006

■ * 2603531

The one for the preparation of the compounds according to the invention used monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl can by reacting the tetrabromobiphenyl with phosphoryl chloride in the presence of pyridine to the cyclic Phosphoric acid ester chloride, its transfer into the cyclic phosphate by means of sodium hydroxide solution and then Treatment with concentrated hydrochloric acid can be obtained (see German Auslegeschrift No. 1.543.792).

The agents according to the invention are characterized in that they contain an acidic alkaline earth salt of the monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl in addition to the usual carriers and additives. The means according to the invention can solid _? be liquid or paste-like. They are produced in a manner known per se by intimately mixing the new alkaline earth metal salts of the formula I with suitable carriers, optionally with the addition of dispersion media which are inert towards the active ingredients. Among the agents according to the invention, liquid formulations, such as suspensions, and pasty formulations, are preferred because they are easier to apply. The new alkaline earth salts of the formula I are particularly suitable for the production of suspensions and pastes with excellent storage stability.

Vegetable oils, paraffin oils, ethylene glycol stearate, silicone oils, Buty! Hydroxyanisole, aluminum monostearate, cetyl alcohol, sorbitol fatty acid ester and stearyl alcohol and. of pastes vegetable ode paraffin, ethylene glycol stearate, silicone oils, butylhydrox ^ y-, anisole, aluminum monostearate, cetyl alcohol, sorbitol fatty acid ester, / alcohol, hardened vegetable oils and waxes are used will.

In addition, the new alkaline earth salts of the formula I can be processed in different concentrations with the addition of surfactants and carrier materials such as highly disperse silica, bolus alba _} talc, polyvinylpyrrolidone to form wettable powders which are easily suspended in water Powders produced in this way can be administered in the form of drenching.

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Furthermore, the active ingredients can be used with auxiliaries such as microcrystalline cellulose, highly dispersed silicic acid, gelatin, corn starch, Mann Lt and magnesium stearate Tablets are processed.

example 1

6.2 g monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl are suspended in 100 ml of water. After adding 25 ml of a 10% aqueous calcium chloride solution becomes a 25% aqueous solution with thorough stirring Sodium acetate solution was added dropwise until the reaction mixture has a pH of 5-6. Then 8 hours at Stirred room temperature and during this time the pH several times by further addition of sodium acetate solution to a value corrected from 5-6.

The mixture is stirred for another 15 hours, filtered off with suction and washed several times with water. After drying, 5.6 g of the monocalcium salt of 2,2-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl are obtained. from melting point 210-212 ⁰ C.

Analysis: C 24 ^H 12 ^{B ir} 8 O 10 ^P 2 ^Approx Calculated: 23, 25th % C Found: 23 7th Ί C.

1.29% H 51.57% Br 3.23 % Ca 2.91 % W ₇ 1.4 % H 51.8 % Br 3.15%. 3.1 % H ₀ O approx

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Example 2

6.2 g of monophosphoric ^{acid ester of 2,2 1} -dihydroxy-3,3 ¹ , 5,5'-tetrabromobiphenyl are suspended in 120 ml of water. 25 ml of a 10% strength calcium chloride solution and 8.2 g of solid sodium acetate (anhydrous) are added.

The mixture is stirred for 8 hours at room temperature, filtered off with suction and washed the arrears on the ITutsche several times with 'iasser. After this Drying gives 5.5 g of the monocalcium salt of 2,2-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl of melting point 2O3 ° C, which is identical to the product obtained in Example 1 (Mixed melting point).

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Example 3

5.82 g (0.01 M) monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl are dissolved in 100 ml of 0.1 N NaOH with stirring at room temperature. One filtered from a little unyellow impurities and the filtrate is slowly mixed with 25 ml of a 10% calcium chloride while stirring Ib "sung.

The deposited precipitate is filtered off with suction after stirring for one hour, washed several times with water and dried. This gives 5.5 g monocalcium salt of 2,2'-dihydroxy-3,3 ^1, 5,5 'tetrabrombiphenyls, the product produced by mixed melting point with that according to Example 1 was identified.

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ORIGINAL INSPECTED

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Example 4

24.0 g Monophosphorsäureester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabrombiphenyls dissolved in 200 ml of 60 _o sodium 7 are ethanol with continuous stirring at room temperature to a solution of 3.2 g of calcium acetate in 200 60% ethanol is added dropwise, then stirring is continued until the end of the reaction and a further 30 ml 60% ethanol are added. After one hour

the precipitate is filtered off with suction and dried at 45.degree. Yield: 22.13 g Melting point: 204 ^° C

Analysis: C. 25th % H 29 7th
Io Br 57 7th
Yes Approx 23 7th
Yes H ₀ 0 7th
/ ο Ber. : 23 13th 7th
/ ο 1. 39 7th
/ ο 51. 86 Ί
/ ο 3. 94 Ί
Io 2. 91 7th
/ ο Found: 23 1. 51. 2. 3. 09

The products obtained in Examples 1 to 4 rearrange with partial melting at 183-185 °. A clear one The melt is then obtained at the temperatures indicated in each case.

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Example 5

600.0 g Monophosphorsäureester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabrombiphenyls dissolved in 850 ml _o 95 7 sodium ethanol and 111.0 g of CaCl ₂ dissolved in 1300 ml of ethanol are filtriiert mixed together and slowly adding approx. 20 liters of water while stirring constantly. After the precipitate has settled, the supernatant is decanted off and the precipitate is washed with water. Recrystallization from dimethylformamide.

Melting point: 210 ⁰ C.

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Example 6

6.2 g monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl are suspended in 100 ml of water. After adding 20 ml of a 20% aqueous solution of Magnesium chloride is carried out analogously to Example 1. This gives

5.3 g of the acidic magnesium salt with a melting point of 190-195 ° C The composition corresponds to 2 moles of monophosphoric acid ester per Mg atom.

Analysis : ^C 24 ^H 12 ^Br 8 ° 10 ^P 2 ^Ms " ^{2 H} 2 °

Calc .: 23.59% c 1.32% H 52., - 32% Br 5, 07% ρ 1.99% Mg Found: 23.5 X C 1.4 X H 50.9 X Br 5.1 X P 2.05 X Mg

Calc .: 2.95% H ₂ O
Found: 3.2% H _o 0

- li -

Example 7 Preparation of a 15% suspension

15jO g of aluminum monostearate, 494.8 g of peanut oil and 50.0 g of ethylene glycol stearate are placed in a heatable kettle and heated to 150 ° C. until an opalescent solution has formed. The solution is then ^{allowed to cool to approx. 40 °} C. and, with stirring, 260.0 silicone oil 556, 0.2 g butyl hydroxyanisole, 30.0 g sorbitan monolaurate and 150.0 g of the active substance are added. The mixture is stirred intensively for approx. 15 minutes with an aera vortex chamber stirrer until a homogeneous suspension has formed.

609832/1008

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Example 8 Preparation of a 40% suspension

7j5 g aluminum monostearate, 339.6 g peanut oil and 40.0 g of hydrogenated peanut oil are placed in a heatable vessel and heated to 150 ⁰ C until a solution has formed opalescente.

The solution is then allowed to cool to about 40 ° C. and 200.0 g of silicone oil 556 and 0.2 g of butyl hydroxyanisole are added with stirring as well as the active ingredient.

The mixture is stirred intensively with the vortex chamber agitator for about 15 minutes until a homogeneous suspension originated.

60983 2/1008 original inspected

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Example 9 Making a 15% fast

669.8 g of liquid paraffin oil, 100.0 g of hydrogenated castor oil and 80.0 g of hydrogenated peanut oil vzerden in a heatable Stahlbeliälter to about 90 ⁰ C heated. Upon complete melting of the components is allowed to cool, the Mischxang to about 50 ⁰ C and works only 0.2 g of butylhydroxyanisole and finally the active substance a is formed until a homogeneous paste.

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Example 10 Making a 40% paste

467 j 1 g of viscous paraffin oil, 34.0 g of hardened castor oil and 86.0 g of hydrogenated peanut oil are heated to approx. 90 ^° C. in a heatable steel container.

After the components have melted completely, the hybrid is ^{allowed to cool to approx. 50 °} C. and only 0.2 g of butylhydroxyanisole and finally the active substance are incorporated until a homogeneous paste is formed.

609832-08

Example 11 Production of a powder that can be suspended in water

2.7 g of highly disperse silica and 0.13 g of polyoxyethyl alkyl ether-urea mixture vyerden mixed together with a suitable mixer. Afterward 5.4 g of polyvinylpyrrolidone K 30, 15.0 g of active ingredient, 20.57 g of talc as well as 56.2 g white clay, mixed with it.

The homogeneous mixture is made on a suitable mill (e.g. pin mill) ground to the desired particle size is reached.

The finished powder mixture can be floated into a suspension for application with water and with an applicator (like "drench gun") administered to the animal.

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Example 12 Tablet manufacturing

12OjO g of active substance, 42.0 g of microcrystalline cellulose and 2) 0 g of highly disperse silica are mixed, through Beat a sieve of 0.7 mm mesh size and then moistened with the solution of 8.0 g of gelatin in 200.0 g of water.

This mixture is with constant mixing - kneading 25, Og Cornstarch added in small portions. The moist mass is beaten through a sieve with a mesh size of 1.1 mm and then dried.

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

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Example 13 Tablet production

30.0 g of active ingredient and 137.0 g of mannitol are mixed, passed through a sieve of 0.7 mm mesh size and then moistened with a solution of 5.0 g of gelatin in 150.0 g of water.

25.0 g of corn starch are added in small portions to this mixture with constant mixing - kneading. The wet mass is through a sieve of 1.1 mm mesh size and then dried.

The dried granules are mixed with 3.0 g of magnesium stearate and the mixture is compressed to give tablets _s wherein the total weight is chosen so that the amount of active ingredient is in proportion to the body weight of the targeted animal species.

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Example 14 Tablet production

120.0 g of active substance j 42.0 g of microcrystalline cellulose and 2.0 g of highly disperse silica are mixed, passed through a sieve with a mesh size of 0.7 mm and then moistened with the solution of 8.0 g gelatin in 200.0 g water,

This mixture is with constant mixing - kneading 25, Og Corn starch added in small portions. The moist mass is beaten through a sieve of 1.1 mm mesh size and then dried.

3.0 g of magnesium stearate are added to the dried granules and the mixture is compressed into tablets, the total weight being chosen so that the amount of active ingredient in Proportion to the body height of the targeted animal species.

832/1006

Claims (8)

Claimed 1. Alkaline earth salts of the monophosphoric acid ester of 2,2'-dihydroxy-3 ₃ 3 ¹ , 5,5'-tetrabromobiphenyl of the general formula Br Il ο — ρ — ο Me 2+ in which Me means magnesium or calcium. 2. Process for the preparation of the alkaline earth metal salts of the general formula according to claim 1, characterized in that the monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5j5'-tetrabromobiphenyl or one of its alkali metal salts in an inert solvent with one in the reaction medium soluble magnesium or calcium salt at pH 5 to 6. 3. The method according to claim 2, characterized in that a monoalkali salt of the monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl with calcium or magnesium chloride in a molar ratio of 2: 1 in an aqueous medium. 4. The method according to .Anspruch 2, characterized in that the monophosphoric acid ester of 2,2'-dihydroxy-3 »3 ' _t 5,5'-tetrabromobiphenyl as a suspension in water with an aqueous solution of calcium or magnesium chloride in the presence a buffer substance in the pH range from 5 to 6. eO9832 / 10Oi 26Ü3S31 5. The method according to claim 2, characterized in that the monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl with calcium or magnesium chloride in a molar ratio of 1: 1 in 95% ethanol and then the acid salt formed precipitates with water. 6. The method according to claim 2, characterized in that the monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl with calcium acetate in a molar ratio of 2: 1 in 60% ethanol. 7. The method according to claim 3, characterized in that that the monosodium salt of the monophosphoric acid ester of 2,2'-dihydroxy-3,3 ', 5,5'-tetrabromobiphenyl with soluble calcium or magnesium chloride in a molar ratio of 2: 1 in an aqueous medium. 8. Agent against liver fluke, characterized} by the content of at least one compound according to claim 1 in a mixture with carriers and / or distribution agents. β-, ¹ 609832/100 ^