CH616413A5 - Process for the preparation of 2,4-diamino -5-(3',4',5'-trimethoxybenzyl)pyrimidine intended as a potentiator for sulphacetamide contained in pharmaceutical preparations in addition to polymixin - Google Patents

Description

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2nd

PATENT CLAIM Process for the preparation of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine, which as a potentiator for, in a pharmaceutical preparation intended for use on the eye or on the ear, which also contains polymixin in Contains form of a pharmaceutically acceptable salt, sulfacetamide contained is determined, characterized in that a correspondingly substituted / 3-amino-a-benzylacrylonitrile of the formula

CH-Z

wherein Z is an aliphatic, aromatic or heterocyclic amino group -NR'R ", where R 'or R" can also be hydrogen, with guanidine.

The invention relates to a process for the preparation of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine, which as a potentiator for, in a pharmaceutical preparation intended for use on the eye or on the ear, which also contains polymixin in the form of a pharmaceutically acceptable salt, sulfacetamide contained is determined.

The process is characterized in that an appropriately substituted / 3-amino-a-benzylacrylonitrile of the formula

CH-Z

where Z is an aliphatic, aromatic or heterocyclic amino group —NR'R ”, where R ′ or R ″ can also be hydrogen, is reacted with guanidine.

It has long been known that trimethoprim [2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine] potentiates the antimicrobial activity of the sulfonamides (see US Pat. No. 2,909,522). and that combinations of the two active ingredients are very often used particularly for the treatment of bacterial infections. However, the treatment has hitherto generally been restricted to infections which require oral or parenteral administration of the active compounds, so that the corresponding preparations have been on the market for a few years.

It is also known that the polymixins are distinguished as antimicrobial agents, particularly in the treatment of gram-negative infections, and that certain polymixins can be used together with trimethoprim and sulphamethoxazole. For example, Chemotherapy 18 (1972) pages 119-129 describes that the oral administration of a combined dose of trimethoprim and sulphamethoxazole, followed by polymixin B for a short time, is very effective in treating certain types of salmonellosis. A triple combination of Trime-5 thoprim, sulphamethoxazole and Polymixin E was also used for in vitro tests against Gram-negative bacteria [cf. J. Clin. Path. 23 (1970) 757-764],

In recent years, it has become apparent that there has been a need for a new and improved, broad-spectrum formulation for use on the eye or ear to treat the variety of bacterial infections that can affect the eye and ear. Such a preparation, if it really has an antibacterial effect when used on the eye or on the ear, must meet various strict criteria. The preparation should be stable over a long period of time, not lose its effectiveness, not discolour, not form insoluble substances or complexes and should not irritate the eye or the ear.

A preparation for use on the eye 20 and ear has now been found which fulfills the criteria mentioned above and has an antimicrobial broadband effect, in particular a corresponding antibacterial effect. This preparation contains as active ingredients a combination of trimethoprim, sulfacetamide (N-acetylsulphanilamide) and a polymixin prepared by the process according to the invention. This is somewhat surprising since it is known that the polymixins lose their effectiveness under certain conditions, that the sulfacetamide base can be easily oxidized and in particular tends to discolor in solution 30 and that the trimethoprim and some sulfonamides can form insoluble complexes. In fact, after 24 months of storage at 5 and 25 ° C, a satisfactory effectiveness could still be demonstrated for all active ingredients.

In in vitro tests, these preparations have great antibacterial activity even in dilutions of at least 1: 300 against those bacteria which are usually responsible for infections of the ears and eyes or infections around or in the ear or eye. For example, the preparations against St. pyogenes, 40 Staph. aureus, N. gonorrhoeae, Morax. phenylpyrovich, Mo-rax. nonliquifaciens, St. pneumoniea I, Ps. aeruginosa and H. influenzae.

The preparations can be used to treat acute and chronic conjunctivitis, bacterial conjunctivitis, infected enucleation cavities, corneal ulcers, creatitis, episcleritis and blepharitis. In particular, the solutions containing the three active ingredients mentioned above are particularly effective in the treatment of severe cases of broken through chronic otitis media which have not responded to previous treatments with known active ingredients such as gentamicin, chloramphenicol, neomycin and colymycin.

The present preparations are also very suitable as aids in surgery in the case of dacryocystitis. They can also be used prophylactically before or after eye surgery and after serious eye injuries and when removing foreign bodies from the eye.

The sulfacetamide and the polymixin are preferably present in an antibacterially effective amount and the trimethoprim which has been prepared using the process according to the invention in an amount which potentiates the sulfacetamide. Preferably the preparation contains 0.05 to 65 0.66% (weight by volume) sulfacetamide, 0.005 to 1.0% (weight by volume) trimethoprim and 0.01 to 0.3% (weight by volume) polymixin, most however, 0.1 to 0.5% (weight per volume) sulfacetamide, 0.1 is preferred

3rd

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up to 0.5% (weight per volume) trimethoprim and 0.05 to 0.15% (weight per volume) polymixin. The quantitative ratios of the active ingredients mentioned above relate to the respective bases. The rest of the preparation is taken up by the carrier and, if necessary, by other excipients.

In order to achieve a therapeutic effect, i. H. To treat bacterial infections, the ratio of sulfacetamide to trimethoprim as base or to polymixin as base should be 20: 1 to 0.1: 1 (weight per weight), preferably 10: 1 to 0.1: 1 (weight per weight), and most preferably 5: 1 (weight per weight).

While the present preparation is not limited to any particular polymixin, and consequently all polymixins described in The Merck Index, 1968, 8th edition, pages 848, 278 and 279 can be used, polymixin B is preferred Shape.

Suitable pharmaceutically acceptable, water-soluble salts of polymixin which are suitable for the present preparation are preferably the sulfates and the hydrochlorides.

It is particularly desirable that trimethoprim is present in the preparation in the form of a pharmaceutically acceptable, water-soluble mono-acid addition salt which consists of a simply protonated trimethoprim and an anion of a pharmaceutically acceptable acid. Suitable pharmaceutically acceptable acids are acids which have a pKa which is lower than that of the sulfacetamide. Suitable acids are, for example, mineral acids, e.g. As sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid, and organic acids such as methanesulfonic acid, and carboxylic acids with 1-20 carbon atoms, preferably 1-10 carbon atoms, e.g. B. tartaric acid, citric acid, lactic acid, embonic acid, salicylic acid, glutamic acid, glutaric acid, naphthalic acid and ethylenediamine-tetraacetic acid. Lactic acid and sulfuric acid are currently particularly preferred for this purpose. All of these recommended trimethoprim salts can be prepared simply by reacting the trimethoprim with a pharmaceutically acceptable acid.

The active ingredients are preferably packaged in the form of an aqueous solution or an ointment preparation.

The amount of polymixin per 100 ml of solution or per 100 g of ointment can be between 500,000 and 2,000,000 units, preferably 1,000,000 to 1,200,000 units.

1,200,000 units of polymixin correspond to 0.15 g of polymixin B, based on the base.

Preparations in the form of an aqueous solution expediently have a pH of 4 to 6.5, preferably 4.5 to 5.5, and in particular 5.0 ± 0.3.

In the present solutions, suitable pH-regulating compounds can be the pharmaceutically acceptable acids mentioned above, such as hydrochloric acid. Under certain conditions, pharmaceutically acceptable bases such as sodium hydroxide and potassium hydroxide can also serve the same purpose. If necessary, the compounds regulating the pH are normally present in an amount of 0.02 to 1.0% (weight per volume), a proportion of 0.03 to 0.07% (weight per volume) being preferred.

In addition, the solution can also contain compounds which adjust the toxicity, such as sodium chloride, which in an amount of 0.3 to 1.2 g per 100 ml solution, preferably 0.6 to 1.0 g per 100 ml solution, can be present.

The viscosity-increasing and film-forming active ingredients, such as “Methocel 65 HG”, 4000 Hz (hydroxypropyl methyl cellulose) can also be incorporated into an aqueous solution in order to prolong the contact of the solution with the mucous membrane.

If necessary, other excipients, such as preservatives, e.g. B. «Thiomersal» (from Eli Lilly & CO.), Benzalkonium chloride and 2-phenylethanol can be used.

Suitable carriers for ointment preparations are soft paraffin and polyethylene glycol.

Here, too, other excipients, such as, for example, preservatives, can optionally be incorporated into the ointment preparation.

With both preparations, it is desirable to add local anesthetics to increase stability.

The preparation of the preparations can be carried out in the usual manner, e.g. B. by mixing trimethoprim, sulfacetamide and a polymixin in the form of a pharmaceutically acceptable, water-soluble salt with a pharmaceutically acceptable carrier for preparations for use on the eye and / or on the ear.

In the preparation of aqueous solutions for use on the eye and / or the ear, the sulfacetamide and the trimethoprim are usually dissolved as a salt in the solvent at an elevated temperature, for example at 85 to 90 ° C, although lower temperatures can also be used. In this case, the sulfacetamide can be added to the water, regardless of whether the trimethoprim salt is already present or not. In any case, however, it is preferable to ensure that the pH and the volume of the solution are such that the formation of an insoluble salt is avoided.

The polymixin can be easily dissolved in the solution at room temperature with or without stirring.

In the preparation of an ointment preparation for use on the eye and / or the ear, the polymixin as salt, the sulfacetamide and the trimethoprim can be mixed with the ointment base, either as free bases or as salts, which are usually «methocell», glycerol, propylene glycol or is a soft paraffin, and then, for example in a ball mill, are ground to the desired consistency.

It is understood that the present aqueous solutions and ointments for use on the eye and ear are sterile and that the water used to prepare them is distilled.

The present aqueous solutions are usually applied in or around the eye or ear in an amount of 0.02 to 0.1 ml drops, the solutions containing the active compounds in the concentration described above. One or two drops of the solution are usually given 1 to 4 times a day. For example, in the treatment of bacterial infections of the eye or infections around or in the eye (e.g. in conjunctivitis) two drops of 0.07 ml each of a solution containing 1 mg per ml trimethoprim, 5 mg per ml sulfacetamide and 10,000 units per ml of polymixin B, administered 2 to 4 times a day. Eye ointments are usually applied to the wall of the conjunctival sac of the eye in an amount of approximately 0.02 to 0.1 ml, with the application being carried out once to four times a day.

example

2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine a) 32 g / 3-anilino-a-3,4,5-trimethoxybenzyllacrylonitrile and a solution of 19 g guanidine hydrochloride and 13 g Sodium methylate in 100 ml of denatured ethanol is heated under reflux for 2 hours. 31 ml of solvent are evaporated and the mixture is cooled to 5 ° C. The crystals of 2,4-diamino-5- (3 ', 4', 5'-trimethoxy-benzyl) pyrimidine obtained are collected and denatured

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Washed ethanol and acetone. Yield: 27 g (94% of theory), melting point 198 to 200 ° C.

If methanol is used instead of denatured ethanol, 2,4-diamino-5- (3 ', 4', 5'-trimethoxy-benzyl) pyrimidine is obtained in 86% yield after refluxing with ostium. With isopropanol, the reaction takes 2 hours and the yield is 78%.

b) In the same way as described under (a), the above-mentioned compound is obtained from / 3-2,4-dimethylanilino-a-3,4,5-trimethoxybenzyl-acrylonitrile (melting point 123 to 125 ° C) Reaction time of 4 hours in a yield of 92%.

c) In the same yield as described under (a), the above-mentioned compound is obtained from /? - 3,4,5-trimethoxyanilino-a-3,4,5-trimethoxybenzyl acrylonitrile (melting point 156 to 161 ° C) Reaction time of 3 hours in a yield of more than 90%.

Preparation of the starting compounds for the process variants mentioned under (a) to (c): a) / 3-anilino-a-3,4,5-trimethoxybenzylacrylonitrile stage 1

157 g / 3-morpholino-a-3,4,5-trimethoxybenzyllacrylonitrile are treated with 75 ml concentrated hydrochloric acid in 180 ml water for 15 minutes at 60 ° C. The reaction mixture is cooled, extracted first with 100 ml, then with 75 ml and finally again with 75 ml of chloroform and the extracts are washed again with 75 ml of water. After removal of the solvent, 132 g /? - hydroxy-a-3,4,5-tri-

methoxybenzylacrylonitrile as a thick oil (theoretical yield).

Level 2

132 g of the / 3-hydroxy-a-3,4,5-trimethoxybenzylacrylonitrile obtained by the procedure described above are heated to reflux temperature in 50 g of aniline-containing benzene for 10 minutes. The solvent is removed by evaporation in vacuo. 165 g of the title compound are obtained in crystalline form, which corresponds to a practically theoretical yield.

b) /? - 2,4-DimethylaniIino-a-3,4,5-trimethoxy-benzylacrylonitrile 25 g ß-Hydroxy-a-3,4,5-trimethoxybenzylacrylonitrile, 15 70 ml denatured ethanol and 14 ml 2,4- Dimethylaniline are heated together under reflux for 1 hour. The solvent is removed by evaporation in vacuo and the residue is poured into ice water. The viscous solid obtained is collected and recrystallized from 100 ml of methanol. 11 g of the title compound are obtained in crystalline form; Melting point 123 to 125 ° C.

c) β -3,4,5 -trimethoxy anilino-a-3,4,5-trimethoxy-benzylacrylonitrile 25 The procedure described under (b) is repeated using 3,4,5-trimethoxyaniline. The title compound is obtained in 65% yield. Melting point 156 to 161 ° C after recrystallization from denatured ethanol.

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