DE2444785A1 - Antimicrobial p-cresol-2-sulphonic acid oligomers - active against Trichomonas foetus, bacteria and yeasts - Google Patents

Abstract

Medicaments contain one or more active ingredients of formula (I) (where Y is 0, 1, 2 or 3). (I) have bactericidal and haemostyptic props., and a selective tanning effect on pathologically altered tissue. They may be used in veterinary medicine, esp. in veterinary gynaecology and obstetrics, and in human medicine in the treatment of non-specific vaginal flux and Trichomonas infections. Despite the low Ph of aq. soln. of (I), their use does not lead to adverse effects on healthy tissue, while necrotic material is removed. (I) stimulate the healing process and lead to the coagulation of inflamed tissue. Pref. dosage forms are those for local application.

Description

New oligomeric compounds, processes for their preparation and them containing medicinal products.

The invention relates to oligomeric condensation products from p-cresol sulfonic acid with formaldehyde, process for the preparation of these condensation products and them containing medicinal products.

In German Patent No. 1,031,799, the manufacture of a tanning is described acting, water-soluble condensation product of m-cresol sulfonic acid and formaldehyde described.

This product has valuable therapeutic properties.

In the magazine Svensk. Kemisk. Tides. 1950, pages 113 to 120, studies on condensation products of p-cresol and p-cresol sulfonic acid with formaldehyde are described. In this reference, the general formula I is for the condensation products specified. Here x can have the values from 0 to 2.

In the following, the compound with x = 0 is used as a dimer, with x = 1 referred to as trimer and with x = 2 as tetramer.

The manufacturing information for the dimer is given in the cited literature incomplete, so that a reworking of the manufacturing instructions for the dimer not possible. The dimer should also not have any tanning properties. There is also no therapeutic properties of the condensation products the speech.

The present invention relates to the preparation of oligomeric condensation products of the general formula I from p-cresol sulfonic acid and formaldehyde where Y can take the values 0, 1, 2 and 3. The compound with Y = 3 is called pentameres.

The inventive method is characterized in that one p-cresol sulfonic acid with formaldehyde at 10 to 90 OC, in particular between room temperature and 800 C, optionally in the presence of small amounts of sulfuric acid implements.

The degree of polymerization Y of the reaction products obtained is through determines the reaction conditions.

A molar ratio of p-cresol sulfonic acid is used to prepare the dimer : Formaldehyde from 1: 0.5 to 1: 0.9. In particular, the molar ratio is i: 0.5 to 1: 0.7. By using sulfuric acid in catalytic amounts one can improve the yield of the dimer.

In the production of the dimer1 but also in the production of the other oligomers up to Y = 3, care must be taken that the reaction does not proceeds with formation of higher molecular weight oligomers with Y> 3. The polycondensation undesirable water-insoluble higher molecular weight products can result from various Measures to be prevented: 1. One chooses a molar ratio p-cresol sulfonic acid that is all the higher : Formaldehyde the lower the molecular weight the desired reaction product is, i.e. one selects z.

B. for the preparation of the dimer a molar ratio of 1: 0.6 up to 1: 0.5.

2. One works in the more dilute solutions, the lower the molecular weight is the desired reaction product.

For example, 1 mole of p-cresol sulfonic acid is used to prepare the dimer 3 to ffi moles of water.

3. If you work at an elevated reaction temperature, you work the higher the molar ratio p-cresol sulfonic acid: formaldehyde works In the more dilute solutions, the reaction breaks after the shorter the reaction times the lower the molecular weight the desired reaction product is. During the response time for the preparation of the dimer at a molar ratio of p-cresol sulfonic acid: formaldehyde from 1: o, 6 in the presence of 3 to 5 moles of water per mole of p-cresolsulfonic acid several Days, the reaction time must be at 800 C and a molar ratio of p-cresol sulfonic acid : Formaldehyde of 1: 0.5 in the presence of 10 to 15 moles of water per mole of p-cresol sulfonic acid can be reduced to a few hours to prevent the formation of higher molecular weight condensation products to prevent.

It is expedient to use for the preparation of the polycondensation products p-cresolsulfonic acid in an anhydrous form or in a hydrous form. The water content of the p-cresol sulfonic acid can be up to 50 wt. Va.

Formaldehyde is expediently used in an aqueous solution, with a formaldehyde content of 20 to 40% by weight.

In the preparation of the dimer at elevated temperature, one can use the The end point of the reaction can be easily recognized by the color of the reaction mixture changes from colorless to reddish. The reaction mixture must then immediately be cooled 1 to avoid undesired condensation higher molecular weight Products to prevent.

For the preparation of the tri-, ~ tetra- and pentamer, it is expedient of molar ratios of p-cresol sulfonic acid: formaldehyde of 1: 0.67 or 1: 0.75, respectively.

i: 0.8 to 1: 2 assumed. In many cases this will be done as well Mixtures of the oligomers obtained which, like the dimer, also have a tanning effect or used as active pharmaceutical ingredients.

The trimer can also be prepared by adding 1 mol of the compound of the formula II sulfonated with 2 moles of sulfuric acid at room temperature.

The preparation of the trimer is in the Swedish work mentioned described.

The isolation of the oligomers or oligomer mixtures after completion Polycondensation is expediently carried out by suppressing the electrolytic Dissociation of the sulfonic acid residues of the oligomers by adding concentrated hydrochloric acid. The undissociated oligomers precipitate, especially when the solution is used cools down or if the solution is left to stand for a long time.

The oligomers of the general formula I * are soluble in water through their equivalent gel, through the C, H, S analysis and through the C112 and Characterize CH3 proton signals of the nuclear magnetic resonance spectra.

These inventive tanning products, i.

individual compounds of the general formula I or mixtures thereof, have a good therapeutic effectiveness due to their bactericidal and hemostypical properties Properties and their selective effect on pathologically altered tissue.

The tanning effect of the compounds is based on that of Küntzel im 9'Gerbereichemischen Taschenbuchti on page 205 (1955) described tanning test determined.

The oligomers according to the invention show action on various strains of Trichomonas fetus and various bacterial and yeast strains in in vitro and in vivo experiments. The experimental method used is veterinary Umschau, Volume 10, page 137.

The active ingredients according to the invention therefore find in the veterinary and in human medicine use. In particular, the new active ingredients in the Veterinary gynecology and obstetrics are used. In human medicine, the new active ingredients in the treatment of unspecific FluorVaginalis and trichomonas infections used. Despite the low pH of aqueous solutions, their use leads to no corrosion of the healthy living tissue, while celcrotic, dead tissue Material is repelled.

Stimulation occurs under the influence of the new active ingredients the healing processes and the coagulation of inflammatory changed epithelia, Cell aggregates and mucus.

The new drug, which by the content of one or more of the oligomeric active ingredients can be in various preparation forms are present.

The active ingredient content of these dosage forms is usually 0.5 to 95, preferably 1 to 85% by weight, based on the finished drug.

Since the new drug is preferably used locally, solutions are Vaginal balls, gels, tablets for topical use or concentrates especially preferred forms of preparation.

The pharmaceutical preparations according to the invention contain if they are in the form of a unit dose, e.g. as a vaginal tablet, as a vaginal ball, 10 to 150, in particular 20 to 100 mg of the oligomeric active ingredient.

"Unit dose" in the sense of the present invention is a physically determined unit that is an individual amount of the active ingredient in admixture with a pharmaceutical diluent therefor or together with a pharmaceutical carrier contains understood. The amount of Active ingredient chosen so that one or more units usually for a single therapeutic administration may be needed.

However, the unit dose can also be subdivided, e.g. with Notched tablets when used for a single therapeutic delivery only a fraction, such as a half or a quarter, of the subdivisible unit is needed.

Vaginal balls usually have the same active ingredient content per ball like tablets. Gels usually contain 5 to 30 mg of the oligomeric active ingredient per gram of gel, active ingredient solutions usually contain 0.5 to 10, in particular 1 to 5% by weight of active ingredient.

Active ingredient concentrates usually contain 10 to 40, in particular 20 to 40% by weight of active ingredient.

In addition to the new oligomeric active ingredients, the pharmaceutical Preparations, for example, one or more pharmacologically active ingredients from other drug groups, for example sulfonamides e.g. sulfathiazole, Sulfacetamide, antibiotics e.g. neomycin, bacitracin, chloramphenicol, tetracycline, Antiseptics e.g. 9-aminoacridine, trichomonacidal agents e.g. metronidazole, mycostatics e.g. nystatin, anti-inflammatory drugs e.g. hydrocortisone or estrogens e.g. diethylstilboestrol, Ethinyl estradiol or mestranol.

The different forms of preparation allow a versatile Way of application. Concentrates and solutions are used for spotting treatment, too Used in ear, nose and throat medicine and in dental treatment.

Gels and ointments are usually inserted into the vagina with an extension tube.

Vaginal balls or vaginal tablets are usually given in the evening while lying down inserted into the vagina.

The following examples explain the invention in more detail without restricting it. The temperatures listed are given in OC.

Example 1 a) 2 kg of pure p-cresol are concentrated with 2.1 kg Sulfuric acid heated to 1200 ° C. for 2 hours with stirring. The cooled solution will diluted with 720 ml of water. Crystallized from the solution cooled in the refrigerator p-cresol sulfonic acid, which is centrifuged off. The precipitate is with petroleum ether washed to remove residual p-cresol.

3.157 g of p-cresol sulfonic acid with a content of 73% by weight are Obtained p-cresol sulfonic acid.

The p-cresol sulfonic acid still contains about 0.5% by weight of sulfuric acid and about 26.5 wt% water.

b) 3.8 kg of pure p-cresol are mixed with 3.8 kg of concentrated sulfuric acid Heated to 1200 C for 2 hours. The cooled solution is diluted with 8 l of water, and freed from excess sulfuric acid with barium hydroxide. The precipitate obtained is consumed and washed with petroleum ether. There are 6,196 g of p-cresol sulfonic acid obtained with a content of about 77 wt .-% p-cresol sulfonic acid. The product is Free of sulfuric acid and contains about 23% by weight of water.

The p-cresol sulfonic acid obtained according to a) or b) can either with Water can be brought to a lower p-cresol sulfonic acid content, or in a Rotavapor be brought to a higher p-cresol sulfonic acid content at 40 to 500 C.

c) To 57 g of a p-cresol sulfonic acid containing sulfuric acid (content 83% by weight), while cooling with water, 11.4 g of a 36.1% by weight formaldehyde solution are obtained admitted. After 2 days, 2 to 3 times the volume of the reaction mixture is used the condensation product precipitated with concentrated hydrochloric acid and over in vacuo Dried caustic soda. 22 g of white crystals with a melting point of 118 ° C. are obtained Sodium hydroxide consumption of 164 mg sodium hydroxide per gram of condensate. The relationship the CH2 and CH3 proton signals of the nuclear magnetic resonance spectrum indicate that the pure dimer is present (Y = 0).

The product is effective against bacteria and yeast.

d) 100 g sulfuric acid-free p-cresol sulfonic acid (content 77 wt. are with 51 g of 36.1% aqueous formaldehyde solution while maintaining room temperature Treated 2 days. Then it is concentrated hydrochloric acid with 4 times the volume the reaction product is precipitated and dried in vacuo.

59.8 g of a brownish condensate with a melting point of 1280 are obtained C received. The sodium hydroxide consumption of the product is 126 mg sodium hydroxide solution / g condensate. The condensate obtained is a mixture of the oligomers with Y = 2 and 3, which is less contains than 10% by weight of dimers. The condensate shows a bactericidal, trichomonacidal and fungicidal effect.

Example 2 1200 g of sulfuric acid-free p-cresol sulfonic acid (content 53% by weight) with 141 g of 36% aqueous formaldehyde solution for 1.5 hours 80 OC heated. After the color change of the solution from colorless to reddish-yellow the solution was immediately cooled to 400 ° C. and the condensation product was concentrated with 3.7 l Hydrochloric acid precipitated. 189 g of the dimeric condensate are obtained (by nuclear magnetic resonance spectrum proven).

Example 3 50 g of 77% strength by weight sulfuric acid-free p-cresol sulfonic acid are mixed with 5 mol of water and 17.1 g of 36.1% by weight formaldehyde solution for 3.5 hours held at 800 C. Precipitation with twice the volume of concentrated hydrochloric acid provided 35.3 g of a green condensate.

The sodium hydroxide consumption is 129 mg / g condensate.

The nuclear magnetic resonance spectrum shows that the condensate is approx. 40 Contains% by weight of dimers and 60% by weight of a mixture of trimers and tetramers. The condensate has a bactericidal, trichomonacidal and fungicidal effect.

If desired, the oligomer mixtures are separated by chromatography.

Example 4 Concentrate for Inking Treatment Production of a Batch of 100 kg: 1. Dimer of example 1 c): 36,000 kg 2. distilled water 64,000 kg 36 kg of the dimer are distilled in 64 kg in a V2A container with stirring Water entered. After stirring for 1 hour, the solution is homogeneous and comes in glass bottles 100 ml each filled.

Example Vaginal Balls Manufacture a batch of 100,000 vaginal balls 90 mg active ingredient: 1. Dimer of Example 2 9,000 kg 2. Distilled water 9,000 kg 3. Polyethylene glycol 4000 Average molecular weight 4000 57,000 kg 4. Polyethylene glycol 1500 Average molecular weight 1500 225,000 kg 9 kg of dimers are distilled in 9 liters Dissolved in water.

57 kg of polyethylene glycol 4000 and 225 kg of polyethylene glycol 1500 will be used melted at 700 C. The aqueous solution of the is in this melt with stirring Dimers entered.

After cooling to 500 C, the finished mass becomes ovular 3 g each poured.

Example 6 Vaginal Tablets Manufacture of a batch of 100,000 vaginal tablets at 90 mg active ingredient: 1. Dimer of Example 1 c 9,000 kg 2. Milk sugar 90,000 kg 3. carboxymethyl cellulose 17,000 kg 4. talc 4.000 kg 90 kg lactose and 17 kg of carboxymethyl cellulose are mixed with a solution of 9 kg of the dimer Moistened in 50 l denatured alcohol and passed through a sieve of the clear mesh size of 1.5 mm granulated.

The granulate is in the fluidized bed dryer up to a relative Moisture from 50 to 60%, dried, mixed with the specified amount of talc, wnd-after compressed into tablets of 1200 mg each by sieving.

Example 7 Gel 1 g of gel contains 18 mg of active ingredient, raw materials for production a batch of 25 kg: 1. Polyethylene glycol 400 18.750 kg 2. Polyethylene glycol 20,000 5,000 kg 3. 36% strength aqueous solution of the dimer according to Example 2 1.250 kg Die Substances listed under 1 and 2 are melted at 60 to 700 C. In the The 36% solution of 3 is stirred into the melt. With good stirring it will be Gel cooled to 200 C and filled into tubes of 50 g each.

Claims (1)

Claim Medicines, characterized by the content of one or more of the active ingredients of the general formula I * where Y is 0, 1, 2 or 3.