IE50610B1 - Diphenylmethane derivative,processes for its preparation and medicaments containing it - Google Patents

Abstract

For the Contracting States : DE, FR, IT, NL, BE, CH, GB, SE, LI, LU) 1. 2,2'-Dihydroxy-5,5'-methylenedi-(p-toluene-sulphonic acid) and its salts. For the Contracting State : AT 1. Process for the preparation of 2,2'-dihydroxy-5,5'- methylenedi-(p-toluenesulphonic acid) and its salts, characterized in that a) m-cresol-6-sulphonic acid and/or its salts are reacted in an acid medium with formaldehyde and/or formaldehyde donors and, if desired, a resulting salt is converted into the free acid or into another salt, b) m-cresol-6-sulphonic acid and/or its salts are converted, in a basic medium, by means of form-aldehyde and/or formaldehyde donors into 4-hydroxymethyl-m- cresol-6-sulphonic acid and the latter is subjected in an acid medium to a condensation reaction with m-cresol-6-sulphonic acid and/or its salts and, if desired, a resulting salt is converted into the free acid or into a another salt, or c) m-cresol which is substituent in the 6-position by a detachable substituent is reacted, in an acid medium, with formaldehyde and/or formaldehyde donors to give a 5,5'-disubstituted 4,4'-dihydroxy-2,2'-dimethyl diphenylmethane, the substituents in the 5-position and 5'-position are split off and the product is sulphonated in an acid medium with sulphuric acid and/or an agent which splits off sulphonic acid groups and, if appropriate, a resulting salt is converted into the free acid or into another salt.

Description

The invention relates to the compound 2,2'dihydroxy-5,5'-methylenedl-(p-toluenesulphonic acid) and its salts, processes for their preparation and medicaments containing them.

Condensation products having a tanning action which are formed from cresolsulphonic acids and formaldehyde have been known for many years and were first described in German Patent Specification 262,558. U.S.

Patent Specification 2,326,578 mentions, regarding a tanning condensation product obtainable by reacting metacresolsulphonic acids with formaldehyde, that it should also he suitable for curative treatment of diseased tissue. During the following period this has led to the development of medicaments based on condensation pro15 ducts formed from m-cresolsulphonic acids and foimaldehyde, particularly in the field of gynaecology. A corresponding medicament has developed into a widely used product excellent curative properties. As has been possible to demonstrate hy numerous tests, it has an astringent, bactericidal, trichomonacidal, fungicidal and haemostyptic action and it has a selective action on dead or pathologically changed tissue, which becomes coagulated and rejected while healthy tissue is not attacked. It is therefore employed with great success, not only in a multiplicity of ways in gynaecology, but also in urology, surgery, ear, nose and throat therapeutics, gastro: 50610 enterology, proctology and skin diseases.

It is a disadvantage of this product that its active principle consists of a mixture of numerous suhstances. This is because a large number of different compounds are formed in the very complex course of the condensation reaction between m-cresolsulphonic acids and formaldehyde. Hitherto, in spite of using the most modern methods of investigation, it has not been possible to determine its exact composition. Since it is indispensable for a medicament that it should always have the same composition, very great precision is required in carrying out the reaction when preparing the condensation product from m-cresolsulphonic acids and formaldehyde. A deviation from the composition of the mixture which has been optimised empirically would also be very dangerous, because products can easily be formed in the said condensation reaction which later undergo slow chemical decomposition or conversion in an uncontrollable manner, which would, in particular, impair the stability on storage. A further disadvantage of the commercial product is its intense dark brown colouration which is known from experience to have a repugnant effect on some patients. In addition, in spite of careful precautions, it is not always possible to prevent soiling of, and damage to, underwear and bed linen.

Great efforts have been made to eliminate these disadvantages of the medicament, which is very valuable from the therapeutic point of view: German Patent Specification 1,031,799 discloses the preparation of a crystalline, water-soluble condensation product obtained from sulphonated m-cresol by means of formaldehyde. German Offenlegungsschriften 2,245,411 and 2,444,785 describe oligomeric condensation products formed from p-cresolsulphonic acid and formaldehyde of the general wherein y can assume values of 0, 1, 2 and 3. However, hitherto no success has attended these efforts, since the suggested products have either required an economically unjustifiable outlay in their preparation and/or they have not measured up to the commercial product in the degree of stability desired and/or, particularly, in the quality and quantity of their action.

It has now been found, surprisingly, that the new compound 2,2'-dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid) and its salts with organic and inorganic bases can be 20 prepared without difficulties and are equal to the commercially available condensation product formed from metacresolsulphonic acids and formaldehyde in their therapeutic action, while having a lower toxicity. • 50610 The invention relates to the compound 2,2'-dihydroxy-5, 51-methylenedi-(p-toluenesulphonic acid) so3h so3h and its salts. The new compound can also be termed as 5,5'methylenedi-(2-hydroxy-p-toluenesulphonic acid).

Suitable salts are salts with inorganic and organic bases. Pharmacologically unacceptable salts are converted, by methods which are in themselves known, into pharmacologically acceptable salts which are preferred amongst the salts according to the invention. The cations used for the formation of salts are, in particular, the cations of the alkali metals or of the light alkaline earth metals; however, the corresponding cations of organic nitrogen bases, such as amines and aminoalkanols, are also used.

Examples which may be mentioned are the salts of lithium, sodium, potassium, magnesium, calcium, morpholine, methylcyclohexylamine, benzylamine, ethanolamine, diethanolamine, triethanolamine, tris-(hydroxymethyi)aminomethane, 2-amino-2-methylpropanol, 2-amino-2-methyl1,3-propanediol, urea, tetramethylurea, 1,3-dlmethylimidazolidin-2-one, glucamine, N-methylglucamine, glucosamine, N-methylglucosamine, lysine, ornithine, arginine and quinoline.

Preferred salts are those which are readily soluble in water. Readily soluble is understood in 610 this context to mean salts which are soluble in water at 23°C to the extent of more than 3 g/100 ml, preferably to the extent of more than 10 g/100 ml. Examples of preferred readily soluble salts are the alkali metal salts in particular the sodium salt, the ammonium salt and salts with urea.

The invention furthermore relates to a process for the preparation of the oompound 2,2'-dihydroxy-5,5'methylenedi-(p-toluenesulphonic acid) and its salts, which is characterised in that a) m-cresol-6-sulphonic acid and/or its salts are reacted in an acid medium with formaldehyde and/or formaldehyde donors and, if desired, a resulting salt is converted into the free acid, or into another salt b) m-cresol-6-sulphonic acid and/or its salts are converted, by means of formaldehyde and/or formaldehyde donors, in a basic medium, into 4-hydroxymethyl-m-cresol-6-sulphonic acid and the latter is subjected to a condensation reaction in an acid medium with m-cresol-6-sulphonic acid and/or its salts, and, if desired, a resulting salt is converted into the free acid, or into another salt, or c) m-cresol which is substituted in the 6-position with a detachable substituent is reacted, in an acid medium with formaldehyde and/or formaldehyde donors to give a 5,5' -disubs titut ed 4,4'-dihydroxy-2,2'-dimethyldiphenylmethane, the substituents in the 5-position and the 5'position are split off and the product is sulphonated in an acid medium with sulphuric acid and/or an agent which splits off sulphonic acid groups, and, if desired, a resulting salt is converted into the free acid or into another salt.

The reaction with formaldehyde and formaldehyde donors is preferably carried out in an aqueous solution. Formaldehyde is employed in the form of aqueous solutions containing 10 to 50 per cent by weight, preferably 35 to 50 per cent by weight, of formaldehyde. Possible formaldehyde donors are, in addition to hexamethylenetetramine, in particular the oligomers (for example trioxane or tetroxanej and the polymers (for example paraformaldehyde) of formaldehyde, paraformaldehyde being preferred. The condensation reaction with formaldehyde is carried out at temperatures from 10 to 90°C, preferably at temperatures from 20 to 60°C. The reaction time for the reaction with formaldehyde depends on the temperature and depends on the salt in which the partner in the condensation reaction is present. It is appropriate to make the reaction time such that the formation of the desired diphenylmethane derivative takes place as completely as possible, but the formation of higher oligomeric condensation products takes place to as small an extent as possible. Depending on the tenperature selected and the nature of the cresol derivative salt employed, those skilled in the art can determine optimum reaction times between a few hours and several days by means of simple preliminary trials.

Reaction in an acid medium is understood to mean a reaction in the presence of strong acids, such as hydrogen halide acids, preferably hydrochloric acid, sulphuric acid, a sulphonic acid, phosphoric acid or acid cation exchangers. In the reaction of mcresol-6-sulphonic acid with fonnaldehyde it is not necessary to employ a strong acid, since m-cresol-6sulphonic acid is itself a strong acid.

Reaction in a basic medium is understood to mean a reaction in the presence of strong bases, preferably alkali metal hydroxides, hut also alkaline earth metal hydroxides, preferably calcium hydroxide.

Possible detachable substituents in process 10 variant c) for m-cresol which is substituted in the 6position by a detachable substituent are' chlorine, bromine and iodine, preferably chlorine. Preferred substituents are those which can be split off easily by reduction after the reaction, with formaldehyde, of the m-cresol, substituted in the 6-position, to give a 5,5'disubstituted 4,4’ -dihydroxy-2,2' -dimethyldiphenylmethane. If chlorine, bromine or iodine are used as detachable substituents, the splitting off hy reduction is preferably accomplished in a manner which is in itself known hy catalytic hydrogenation, using the hydrogenation catalysts customary for these purposes, such as platinum, palladium and nickel catalysts, preferably platinum catalysts. Possible solvents for splitting off the detachable substituents by reduction are the solvents customary for catalytic hydrogenations, for example water, methanol, ethanol, ethyl acetate, glacial acetic acid or mixtures of these solvents. It is known to those skilled in the art to select the conditions for the action of hydrogen in such a way that, although the detachable substituent is split off as desired, hydrogenation of the aromatic nuclei does not take place.

The sulphonation of 4,4'-dihydroxy-2,2'-dimethyldiphenylmethane to give 2,2'-dihydroxy-5,5'-methylenedi(p-toluenesulphonic acid) is effected in a manner which is in itself known, using 50 to 100% strength, preferably 70 to 100% strength, sulphuric acid. The sulphonation can he carried out in a particularly gentle manner by means of sulphuric acid or sulphur trioxide in solvents such as chloroform or liquid sulphur dioxide. Further examples of possible agents for splitting off sulphonic acid groups are chlorosulphonic acid and amidosulphonic acid.

The reaction mixture formed in the reaction of m-cresol-6-sulphonic acid with formaldehyde can he worked up in a customary manner hy adding solvents suitable for precipitating the desired reaction product and hy filtering off the precipitated reaction product. However, it has proved very advantageous, as an alternative, to precipitate the desired reaction product in the form of a sparingly soluble salt. Suitable salts are those of the sparingly soluble alkaline earth metals and earth metals, those of the alkaline earth metals, particularly those of barium, heing preferred. The use of organic amines, such as, for example, monoalkylamines, dialkylamines and trialkylamines, p-toluidine, a-naphthylamine and β-naphttoylamine, m-nitroaniline, β-phenylethylamine, di-o-tolylguanidine, benzidine, dianisidine, dimethylaniline, m-phenylenediamine, pyridine, morpholine and βίο similar amines, is particularly preferred. Amongst organic amines the use of diamines is preferred and, of these, preferred representatives are those in which the amine groups are linked by one, two or three Cg to alkyl chains, particularly ethylene chains. Examples of preferred diamines are piperazine, diazabicyclo[2.2.2]octane, 1,4-di-C·^ to C^-alkylpiperazines, in particular 1,4-dimethylpiperazine, l-benzyl-4-methylpiperazine, ethylenedi amine or di-C^ to C^-alkylethylenediaminefe)or tetra-C-j. to C^-alkylethylenediamines, in particular tetramethylethylenediamine. Instead of precipitating 2,2'dihydroxy-5,5'-methylenedi-(p-toluene sulphonic acid) in the form of its salts by adding the corresponding bases, it is possible as an alternative to subject the corresponding salts of m-cresol-6-sulphonic acid to a condensation reaction with formaldehyde, whereupon the corresponding sparingly soluble salts of 2,2'-dihydroxy-5,5 methylenedi-(p-toluenesulphonic acid) are formed directly.

Alternatively, it is possible to carry out the condensation reaction of m-cresol-6-sulphonic acid or of a soluble salt of m-cresol-6-sulphonic acid, such as, for example, the ammonium or sodium salt, with formaldehyde in the presence of bases which form sparingly soluble salts with 2,2'-dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid), those bases mentioned above being preferred.

Within the scope of the process according to the invention for the preparation of 2,2'-dihydroxy-5,5'methylenedi-(p-toluenesulphonic acid) it is particularly 50810 advantageous to use, as bases forming sparingly soluble salts with this compound, bases which form, with m-cresol6-sulphonic acid, salts having a greater solubility. It is preferable to use bases, the salts of which with mcresol-6-sulphonic acid have a solubility in water, at 23°C, which is 5 to 50 times, preferably 5 to 20 times, greater than the solubility of the salts with 2,2'-dihydroxy-5,5' -methylenedi- (p-toluenesulphonic acid).

Amongst these preferred bases, tetramethylethylenediamine occupies a preferred position, since the acid can·be liberated particularly advantageously from the salt of the latter with 2,2'-dihydroxy-5,5’-methylenedi-(ptoluenesulphonic acid).

The sparingly soluble salts of 2,2'-dihydroxy5,5 ’-methylenedi-(p-toluenesulphonic acid) are important intermediate products in preparing pure 2,2’-dihydroxy5, 5' -methylenedi- (p-toluenesulphonic acid) in an economical manner.

The invention furthermore relates, therefore, to sparingly soluble salts of 2,2'-dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid) with alkaline earth metal ions, preferably barium ions, earth metal ions and amines, especially diamines .

Salts of 2,2'-dihydroxy-5,5'-methylenedi-(ptoluenesulphcnic acid) with diamines in which the amine groups are linked by one, two or three C2 to C.^ alkylene chains, especially ethylene chains, are preferred.

Salts of 2,2'-dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid) with piperazine, l,4-diazabicyclo[2,2.2]10 octane, 1,4-(11-0^ to C^-alkylpiperazines, especially 1,4-dimethylpiperazine, l-benzyl-4-methylpiperazine, ethylenediamine or di-C^ to C^-alkylethylenediamines or tetra-C-j. to C^-alkylethylenediamines, especially tetramethy lethylenediamine, are particularly preferred. The tetramethylethylenediamine salt of 2,2'-dihydroxy-5,5’methylenedi-(p-toluenesulphonic acid) is very particularly preferred.

The invention furthermore relates to a process for the preparation of the sparingly soluble salts of 2,2’ -dihydroxy-5,51-methylenedi-(p-toluenesulphonic acid), which is characterised in that a) 2,21-dihydroxy-5,51-methylenedi-(p-toluenesulphonic acid) or a readily soluble salt, preferably the sodium or ammonium salt, is reacted in a manner which is in itself known with the corresponding base, or b) m-cresol-6-sulphonic acid or an ammonium or alkali metal salt thereof is reacted with formaldehyde and/or formaldehyde donors in an acid medium, in the presence of organic amines or a salt of m-cresol-6-sulphonic acid with organic amines.

Sparingly soluble salts of 2,2'-dihydroxy-5,5 methylenedi-(p-toluenesulphonic acid) are understood, within the scope of this invention, to mean salts having a solubility in water at 23°C which does not exceed 3 g/100 ml, preferably 1 g/100 ml· The preparation of m-cresol-6-sulphonic acid is known. It is effected by sulphonating m-cresol with customary sulphonating agents, whereupon mixtures of m13 508 JO cresol-4-sulphonic acid and m-cresol-6-sulphonic acid are formed (R.D. Haworth, A. Lapworth, J. Chem. Soc. (London) 1924, 1299)· m-Cresol-6-sulphonic acid can be isolated from these mixtures via its barium salt in accordance with the literature reference quoted.

This separation via the barium salt is not advantageous, for economic reasons, when preparation is carried out on an industrial scale. It has now been found that m-cresol-6-sulphonic acid, which is important as a starting material for the preparation of the new compound 2,2'-dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid), which is very valuable therapeutically, can, surprisingly, be isolated very advantageously via the new compound, ammonium m-cresol-6-sulphonate from the mixtures of m-cresolsulphonic acids formed in the sulphonation of m-cresol. It is thus possible to avoid handling barium salts, which is undesirable. Ammonium m-cresol-6sulphonate is thus an important intermediate product for the preparation of 2,2'-dihydroxy-5,5'~methylenedi-(ptoluenesulphonic acid).

The invention also relates, therefore, to the new compound ammonium m-cresol-6-sulphonate· The preparation of ammonium-m-cresolsulphonate is effected by adding ammonia, in a quantity sufficient to neutralise the acids present in the reaction mixture, to the reaction mixture formed in the sulphonation of m-cresol, for example the reaction mixture formed in the reaction of m-cresol with concentrated sulphuric acid.

The sulphonation mixture can be neutralised by introducing - 50610 gaseous ammonia or by adding aqueous ammonia solution· Neutralisation with concentrated aqueous ammonia solution is preferred· It is expedient to effect the addition of ammonia in such a way that the temperature of -the reaction mixture does not exceed 80 to 100°C. If desired, the heat of neutralisation formed can be removed by cooling, for example by cooling with water or with ice. In one embodiment of the process, unreacted m-cresol is extracted before neutralisation by means of suitable sol10 vents which are immiscible with water, such as, for example, chloroform. The neutralisation is effected in a particularly gentle manner by adding ammonia solution slowly, while cooling, the temperature of the reaction mixture being kept approximately between 0°C and 30°C, preferably at 0°C to 10°C· The ammonium m-cresol-6sulphonate which has been precipitated in the neutralisation is isolated from the reaction mixture by suitable separation operations, such as, for example, centrifuging, filtering or decanting, preferably filtering. The ammonium m-cresol-6-sulphonate obtained can also be freed from residues of the reaction mixture adhering to it by washing with suitable solvents, such as, for example, alkanols, especially isopropanol. A very pure product is obtained after drying subsequently, for example drying in a vacuum drying cabinet.

The invention relates, therefore, to a process for the preparation of ammonium m-cresol-6-sulphonate, which is characterised in that the reaction mixture formed in the sulphonation of m-cresol is neutralised with ammonia.

Ammonium m-cresol-6-sulphonate can be converted, by reaction in a maimer which is in itself known with strong acids or with an acid ion exchanger, into m-cresol6-sulphonic acid, from which, or from the salts of which, 2,2' -dihydroxy-5,5' -methylenedi- (p-toluenesulphonic acid) and its salts can be prepared by 'the process steps indicated earlier in the text. However, it is also possible to convert ammonium m-cresol-6-sulphonate into 2,2'dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid) and its salts direct, by reaction with formaldehyde in accordance with the process steps indicated above. m-Cresol-6-sulphonic acid is liberated from ammonium mcresol-6-sulphonate with the aid of acid ion exchange resins, either in an exchange column or by direct mixing, of a sdlntl.cn of ammonium m-cresol-6-sulphonate and of the ion exchange resin. The ion exchange is preferably carried out in aqueous solution at ambient temperature or at temperatures up to 6OPC. However, the use of other adequately polar solvents, such as, for example, alkanols, preferably isopropanol, also lead to good results. 2>2t-Dihydroxy-5,5' -methylenedi- (p-toluenesulphonic acid) is liberated from its sparingly soluble salts in a manner which is in itself known, by reaction with strong acids· 2,2'-Dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid) is preferably liberated from its salts with the aid of acid ion exchangers. It is possible in this process to bring the sparingly soluble salts into direct contact with the acid ion exchanger or to convert the sparingly soluble salts beforehand into a more readily soluble alkali metal salt, preferably sodium salt, by reaction with alkali metal hydroxide solution, preferably sodium hydroxide solution. 2,2'-Dihydroxy5, 5'-methylenedi-(p-toluenesulphonic acid) is liberated from its salts with the aid of acid ion exchange resins, either in an exchange column or by direct mixing of a solution of a salt of 2,2'-dihydroxy-5,5'-methylenedi10 (p-toluenesulphonic acid) and of the ion exchanger.

The ion exchange is preferably carried out in aqueous solution. However, the use of other adequately polar solvents, such as, for example, alkanols, preferably isopropanol, also leads to good results. The temperature to be chosen in liberating the acid according to the invention with the aid of ion exchangers depends on the solubility of the particular salt in the solvent used.

If readily soluble salts are present, such as, for example, the sodium salt, which is easily soluble in water, it is preferable to carry out the reaction at ambient temperature . In the case of more sparingly soluble salts, the reaction is carried out at 40 to 90°C, preferably 80 to 90°C· A preferred embodiment of the process according to the invention consists in converting, by reaction with an alkali metal hydroxide solution, preferably sodium hydroxide solution, sparingly soluble salts of 2,2'dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid), obtained as intermediate products, into the corresponding alkali metal salt, and liberating the acid from the latter with the aid of an acid ion exchanger.

The compound 2,2'-dihydroxy-5,5'-methylenedi-(ptoluenesulphonic acid) and its salts with organic and inorganic salts have an astringent, bactericidal, trichomonacidal, fungicidal and haemostyptic action. They possess a selective action on dead and pathologically changed tissue, which becomes coagulated and rejected, while healthy tissue is not attacked.

Their toxicity is less than that of the commercial product consisting of a mixture of condensation products formed from m-cresolsulphonic acids and formaldehyde. The table below lists the LDjq values, determined by intravenous administration to mice and rats, ofthe disodium salt of 2,2'-dihydroxy-5,5 methylenedi-(p-toluenesulphonic acid) (A) and of the commercial product (Β), neutralised with sodium hydroxide. Table Type of animal A "50 (mg/kg) B Mice 1,100 380 Mice j 1,050 340 Rats cf7 930 390 Rats 5 990 420 The invention furthermore relates, therefore, to medicaments containing 2,2‘-dihydroxy-5,5,-methylenedi(p-toluenesulphonic acid) and its salts with pharmacologically acceptable inorganic and organic bases· The medicaments according to the invention are οβιο employed in gynaecology particularly for the treatment of vaginitis, vaginal and cervical discharge, cervical erosion and ectopy, for stopping bleeding after sample excisions and removal of cervical polyps, pressure sores in those wearing pessaries and for after-treatment in the case of electrocoagulation· In urology, the medicaments according to the invention are suitable, for example, for the treatment of cystitis, bacterial infection and trichomonas infection, erosions and papillomas and urethritis· In surgery, the medicaments according to the invention can be employed for stopping capillary bleeding and for casting off necrotic tissue after burns and in the treatment of wounds. In dermatology, it j is possible to treat, inter alia, third-degree burns, decubital sores, ulcers of the leg, aphthae, urethral erosions and polyps and opened furuncles, carbuncles and whitlows. In ear, nose and throat therapeutics, the medicaments according to the invention can be employed, in particular, for the treatment of necroses of tissue in radical cavities, ositis externa, aphthous stomatitis, rhagadaes, nose-bleeding and pharyngitis and for stopping bleeding after tonsillectomy. In proctology, the medicaments according to the invention can be employed for the treatment of external and internal haemorrhoids, particularly witn inflammatory side effects and bleeding, fissures pf the anus, anal rhagades, +nal eczemas or anal itch and for the treatment of wounds after operations. The medicaments according to the invention car. be used quite generally for accelerating the healing process of wounds of very varying origins.

The invention also relates, therefore, to the use of 2,2'-dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid) and its pharmacologically acceptable salts with organic and inorganic bases, for the treatment of conditions of disease, in particular those mentioned above. The invention also covers the use of the compounds in the preparation of medicaments which can be enployed for combating the diseases mentioned.

The medicaments according to the invention can be presented as various formulations. The content of active compound in these medicinal forms is generally 0-5 to 95, preferably 1 to 85, % by weight, relative to the final medicament.

Since the new medicament is preferably applied locally, solutions, vaginal suppositories, gels, ointments, suppositories, tablets for local application,or concentrates are particularly preferred formulations.

If they are in the form of a unit dose, the pharmaceutical formulations according to the invention contain, for example as a vaginal tablet, as a vaginal suppository or as a suppository, 10 to 150, in particular 20 to 100, mg of the active compound.

Unit dose for the purposes of the present invention means a physically determined unit which contains an individual amount of the active ingredient mixed with a pharmaceutical diluent for it, or in combination with a pharmaceutical excipient. The amount of the active compound is so chosen that one or more units are usually 610 required for a single therapeutic administration.

However, the unit dose can also be sub-divisible, for example in the case of tablets with breaking grooves, if only a fraction, such as a half or a quarter, of the sub-divisible unit is required for an individual therapeutic administration.

As a rule vaginal suppositories have the same content of active compound per suppository as tablets.

Gels and ointments generally contain 5 to 30 mg of the active compound per gram.

Solutions of active compound generally contain 0.5 to 10, especially 1 to 5, % by weight of active compound.

Active compound concentrates generally contain 10 to 40, especially 20 to 40, % hy weight of'active compound.

Besides the new active compounds, the pharmaceutical formulations can contain, for example, one or more pharmacologically active ingredients belonging to other groups of medicaments, for example sulphonamides, for example sulphathiazole or sulphacetamide; antibiotics, for example neomycin, bacitracin, chloramphenicol or tetracycline; antiseptics, for example 9-amlnoacridine; trichomonacidal active compounds, for example metronidazole; mycostatics, for example nystatin; antiphlogistic agents for example hydro cortisone, or oestrogens, for example diethylstilhoestrol, ethinyloestradiol or mestranol· Insofar as the active ingredients mentioned above, belonging to other groups of medicaments, are ingredients which are chemically incompatible, for example by virtue of sensitivity to acid, with 2,2'21 dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid) and/or its salts, a galenical separation of the incompatible active ingredients is effected in a manner which is in itself known,within the desired formulation.

For example, the incompatible ingredients are incorporated into different layers of a layered tablet or into different pellets filled into a capsule or into different layers of multi-layer suppositories or vaginal suppositories.

The various formulations enable application to be made in a wide variety of ways. Concentrates and solutions are used for treatment by painting and also in ear, nose and throat therapeutics and in dental treatment.

It is also possible to effect a combined application of different formulations of the medicaments according to the invention. For example, a treatment of the affected part of the body is effected every one, two or three days by applying, rinsing or bathing, using a 30 to 40% strength, preferably 36% strength, solution of 2,2'-dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid) and/or its salts· Between these treatments, a gel or ointment or tablets for local treatment, vaginal suppositories or suppositories are applied once or twice a day.

Gels and ointments are in most cases introduced into the vagina by means of a nozzle. Vaginal irrigation can be carried out by means of a vaginal douche. Vaginal suppositories or vaginal tablets are in most cases introduced into the vagina in the evening, when the patient is lying down.

The examples which follow illustrate the invention in greater detail without limiting it. The temperatures listed are quoted in °C. M.p. denotes . melting point.

Examples Example 1 2,21-Dihydroxy-5.51-methylenedi-(p-toluenesulphonic acid) a) A mixture of 100 g (0.446 mol) of m-cresol-6-sulphonic acid dihydrate in 300 ml of water and 28 ml (0*36 mol) of formaldehyde solution (37% strength) is stirred for 5 days at 20-22°C and is then evaporated in vacuo. The oily residue is triturated with 100 ml of acetonitrile and is filtered off. 2,2'-Dihydroxy-5,5'-methylenedi(p-toluenesulphonic acid) is obtained in the form of the trihydrate· Yield: 43 g (42% of theory)· The melting point varies, depending on the water content and is between 132°C (4H20) and 142°C (anhydrous), h) A suspension of 10 g (44.6 mmols) of m-cresol-620 sulphonic acid dihydrate and 1 g of paraformaldehyde in water is stirred for 8 days at 20-22°C. The clear solution is worked up as described under a).

Yield: 4-6 g (45% of theory).

Further quantities of the title compound oan be obtained from the mother liquor by purification by means of column chromatography. c) 500 g of piperazine 2,2'-dihydroxy-5,5,-niethylenedi(p-toluenesulphonate) are dissolved in 500 ml of 50% strength sodium hydroxide solution at 60°. 3 1 of methanol are added at the same temperature and the precipitated sodium salt is filtered off, washed with hot methanol and dried in vacuo- 490 g of this sodium salt are dissolved in 600 ml of water by warming and the solution is cooled to room temperature and poured through an ion exchange column (column dimensions 200 x 10 cm; 2-5 kg of Amberlite IR 120). The eluate is collected until a pH value of 3 to 4 is reached; the solution obtained is evaporated to dryness in vacuo at 40°C and the residue is recrystallised from acetonitrile. d) A K 100/100 Sephadex column (Messrs Pharmazia), holding 7 1 and equipped with a heating jacket, is packed with 5 kg of strongly acidic ion exchanger Amberlite IR 120 and is warmed to 85°C with the aid of a thermostat.

A saturated aqueous solution, at 85°C, containing a total of 2 kg (3-127 mols) of tetramethylethylenediammonium 2,2'-dihydroxy-5,5'-methylenedi-(p-toluenesulphonate) is fed in continuously by means of a hose pump. The acid eluate is evaporated initially ln a thin film evaporator and subsequently in a rotary evaporator to drynessYield: 1,360 g (95% of theory); m.p. 135-l40°C. e) 4 1 of Amberlite IR 120 ion exchanger (acid form, washed with isopropanol) are stirred with 430 g of the disodium salt of 2,2*-dihydroxy-5,5'-methylenedi-(ptoluenesulphonic acid) monohydrate in 1.6 1 of isopropanol for 6 hours at 60-80°C. After cooling, the ion exchanger is filtered off and the filtrate is concentrated in vacuo, finally after adding 500 ml of glacial acetic acid. The distillation residue is triturated with 800 ml of methylene dichloride, whereupon crystallisation takes place.

Yield: 330 g (78% of theory) of 2,2'-dihydroxy-5,5'methylene-di-(p-toluenesulphonic acid) trihydrate; m.p. 135-138°C.

Example 2 Piperazine 2,2'-dihydroxy-5.5'-methylenedi-(p-toluenesulphonate) a) 100 g (0.486 mol) of ammonium m-cresol-6-sulphonate are suspended in 325 ml of 6 N sulphuric acid and the mixture is warmed to an internal temperature of 40°C, while stirring. After adding 35 ml (0-453 mol) of 37% strength formaldehyde solution, the mixture is stirred for 3i hours at the same temperature. It is then cooled in an ice bath and unreacted starting material is filtered off. g of piperazine are also added to the filtrate while it is cold and the crystalline product which is soon precipitated is filtered off after standing for a few hours at room temperature. The residue is washed with water, ethanol and, if necessary, ether and is dried in vacuo at 50-100°C· Yield: 53 g (55% of theory); m.p. >380°C. b) A mixture of 5 g (22 mmols) of m-cresol-6-sulphonio acid dihydrate and 5 ml (62 mmols) of 37% strength formaldehyde solution is stirred for 4 hours at 20 to 22°C, and 1 g of piperazine in 15 ml of water is then added. The precipitate which is formed is filtered off and washed with water and ethanol.

Yield: 3-5 g (66% of theory). c) 2 g (4·3 mmols) of 2,2'-dlhydroxy-5,5'-methylenedi(p-toluenesulphonic acid) are stirred with 0.4 g (4.7 mmols) of anhydrous piperazine in 10 ml of water for 15 minutes. The crystalline precipitate is fil5 tered off.

Yield: 2 g (97% of theory').

Example 3 Tetramethylethylenediammonium 2,2'-dlhydroxy-5, 5' methylenedi-(p-toluenesulphonate) monohydrate a) 1,000 g (4.06 mols) of tetramethylethylenediammonium bis-(m-cresol-6-sulphonate) are suspended in a mixture of 500 ml of water and 212 g (approximately 2.08 mols). of concentrated sulphuric acid. 288 g (266 ml, 3·56 mols) of 37% strength formaldehyde solution are added to the sus15 pension, which has been cooled to 30°C, and the mixture is stirred for 48 hours at 30°C. The suspension is then cooled with ice water and the precipitate is filtered off, washed until neutral and dried in vacuo* Yield: 730 g (69% of theory).

The product can be recrystallised from 3 1 of water.

M.p. 228-232°C. b) 20 ml of 36% strength formaldehyde solution are added to a mixture, heated to 80°C, of 51 g (0.248 mol) of ammonium m-cresol-6-sulphonate, 16.9 g (0.145 mol) of tetramethylethylenediamine and 38·6 g (21 ml, 0<39 mol) of concentrated sulphuric acid in 50 ml of water, and the mixture is stirred for 6 days at 20 to 23°C. The crystalline precipitate formed is filtered off and washed with water and methanol.

Yield: 40 g (62% of theory).

Example 4 1.4- Dimethylplperazlne 2.2'-dlhydroxy-5,51-methylenedi(p-toluenesulphonate) a) A mixture of 10 g (48.7 mmols) of ammonium m-cresol-6sulphonate, 1.3 ml (23«6 mmols) of sulphuric acid (d = 1.84) and 3·5 ml (45-3 mmols) of 37% strength formaldehyde solution is stirred for 30 minutes at 60°C. 1·95 ml (14·5 mmols) of 1,4-dimethylpiperazine are then added in portions of 0-1 ml in the course of a further 3 hours, at the same temperature. The precipitate is isolated after cooling· Yield: 6-3 g (52% of theory); m.p. 286-289°C. b) 2.7 ml (35-3 mmols) of 36% strength formaldehyde solution are added to a mixture of 10 g (38 mmols) of 1.4- dimethylpiperazine m-cresol-6-sulphonate and 3.8 g of concentrated sulphuric acid in 10 ml of water at 45°C, the mixture is stirred for 12 hours at the same temperature and the precipitate is filtered off.

Yield: 6.1 g (64% of theory). c) 3.15 ml of concentrated sulphuric acid and 2.17 g (0.019 mol) of 1,4-dimethylpiperazine are added to a solution of 7-8 g (0.038 mol) of ammonium m-cresol-6sulphonate in 10 ml of water. After 15 minutes 2.7 ml of 36% strength formaldehyde solution are added and the mixture is stirred for 22 hours at 50°C.

The precipitate is filtered off and dried in vacuo.

Yield: 5-4 g (57% of theory). d) A mixture of 3 g (13·4 mmols) of m-cresol-6-sulphonic acid dihydrate and 0.32 g (2-2 mmols) of hexamethylenetetramine in 10 ml of water Is stirred for 43 hours at 45°C. 0.76 g (6.2 mmols) of 1,4-dimethylpiperazine in 10 ml of water is then added and the pH is adjusted to 1 with dilute hydrochloric acid. After stirring for 1 hour the precipitate is filtered off, washed with water and methanol and dried in vacuo.

Yield: 1-2 g (36% of theory). e) A mixture of 3·6 g (90 mmols) of sodium hydroxide, g (44.6 mmols) of m-cresol-6-sulphonic acid dihydrate and 3.4 ml (44-3 mmols) of 36% strength formaldehyde solution in 20 ml of water is stirred for 30 hours at 22 to 25°C- The solution is neutralised with dilute hydrochloric acid and is evaporated to dryness in vacuo. 6-3 g of residue are obtained, which, after reprecipitation from ethanol/water, decomposes above 270°C. 2 g of this product (the sodium salt of 4-hydroxymethylene-mcresol-6-sulphonic acid) are heated with 2 g of m-cresol6-sulphonic acid dihydrate in 20 ml of water for 8 hours at 90°C. 1.1 ml of 1,4-dimethylpiperazine are then added and the pH is adjusted to 4. The precipitate is filtered off, washed with water and dried.

Yield: 1.2 g (30% of theory).

Example 5 1,4-Diazabicyclo[2.2.2]octane 2,21-dlhydr oxy-5.51-methylenedi-(p-toluenesulphonate) a) A mixture of 10-2 g (50 mmols) of ammonium m-cresol-6sulphonate, 40 ml of water, 5-6 ml of concentrated sulphuric acid, 2.8 ml (25 mmols) of l,4-diazabicyclo[2.2.2]50610 octane and 4 ml of 36% strength formaldehyde solution Is stirred for 4 hours at 45°C· After cooling, the precipitate is filtered off, washed with water and methanol and dried.

Yield: 8.4 g (67% of theory) of the salt formed from 1 mol of 2,2'-dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid) and 1 mol of 1,4-diazabicyclo[2.2.2]octane. M.p. >300°C. b) Solutions of 4.6 g (10 mmols) of 2,2’-dihydroxy-5,5’10 methylenedi-(p-toluenesulphonic acid) tetrahydrate in ml of water and of 1.1 g (10 mmols) of 1,4-diazabicyclo[2.2.2]octane in 20 ml of water are combined, while stirring. The precipitate is filtered off, washed with water and dried.

Yield: 4-9 g (98% of theory).

Example 6 Disodium 2,21 -dihydroxy-5,51 -methylenedi- (p-toluenesulphonate) monohydrate 522-6 g (1 mol) of tetramethy lethylenediammonium 20 2,2'-dihydroxy-5,5'-methylene-(p-toluenesulphonate) monohydrate are introduced into a solution, warmed to 60°C, of 220 g (5·5 mols) of sodium hydroxide in 800 ml of water, while passing in nitrogen, and the organic base which has been liberated is distilled off. The viscous residue is poured into a vigorously stirred mixture of 240 ml of glacial acetic acid and 800 ml of methanol- The finely crystalline precipitate is filtered off, washed with methanol and dried in vacuo.

Yield: 431 g (96% of theory) ;m.p. approximately 29O°C (decan29 position)· Example 7 1,2-Bthylenediammonium 2,2'-dihydroxy-5.51-methylenedl(p-tolueneaulphonate) .8 g (12.9 mmols) of 2,2'-dihydroxy-5,5’methylenedi-(p-toluenesulphonic acid) tetrahydrate and Ο.78 g (I2.9 mmols) of 1,2-ethylenediamine are mixed in 20 ml of water and the crystalline precipitate is filtered off.

Yield: 5-2 g (90% of theory); m.p. >270°C.

Example 8 1-Methylpiperazine 2,21-dlhydroxy-5.51-methylenedi-(ptoluenesulphonate) 0-7 ml of 1-methylpiperazine are added to 3 g (6-5 mmols) of 2,2'-dihydroxy-5»5’-methylenedi-(p-toluenesulphonic acid) tetrahydrate in 15 ml of ice-cold methanol and the precipitate is filtered off.

Yield: 3 g (95% of theory); m.p, 318°C (decomposition). Example 9 1,4-Dibenzylpiperazine 2,21-dihydroxy-5.51-methylenedi(p-toluenesulphonate) Solutions of 4.6 g (10 mmols) of 2,2'-dihydroxy5, 5'-methylenedl-(p-toluenesulphonic acid) tetrahydrate in 100 ml of water and of 2.7 g (10 mmols) of 1,4-dibenzylpiperazine in 30 ml of 2 N sulphuric acid are combined.

The precipitate is filtered off, washed with water and methanol and dried.

Yield: 6.5 g (98% of theory); mpu 260°C (decomposition)· Example 10 l-Methyl-4-benzylplperazine 2,2'-dlhydroxy-5, 5' methylenedi-(p-toluenesulphonate) The title compound is obtained in 83% yield analogously to Example 9, using l-methyl-4-benzylpiperazine. M.p. approximately 19O°C (decomposition).

Example 11 Dimorpholine 2,2'-dihydroxy-5»51-methylenedi-(p-toluenesulphonate) 1.22 ml (14 mmols) of morpholine are added to a solution of 3 g (6·5 mmols) of 2,2’-dihydroxy-5,5’methylenedi-(p-toluenesulphonic acid) tetrahydrate in 15 ml of methanol. The precipitate formed is filtered off and dried in vacuo.

Yield: 3-6 g (98-5% of theory); m.p. 205-206°C.

Example 12 Barium 2,2' -dihydroxy-5,5' -methylenedi- (p-toluenesulphonate) A solution of 6.1 g (25 mmols) of barium chloride dihydrate in 20 ml of water is added to a solution of 11.5 g (25 mmols) of 2,2’-dihydroxy-5»5’-methylenedi— (ptoluenesulphonic acid) tetrahydrate in 50 ml of water.

The precipitate is filtered Off, washed with water and. acetone and dried.

Yield: 12 g (92% of theory); m.p: decomposes above 196°C.

Example 13 Diurea salt of 2,2'-dihYdroxy-5,5'-methylenedi- (ptoluenesulphonic acid) Solutions of 100 g (0.217 mol) of 2,2’-dihydroxy5,5'-methylenedi-(p-toluenesulphonic acid) tetrahydrate in 150 ml of methanol and of 26 g (0.434 mol) of urea in 150 ml of methanol are mixed and stirred for half an hour. After cooling to 0°C, the precipitate Is filtered off and the filtrate is concentrated in order to isolate more of the substance.

Yield: 95 g (86% of theory); m.p. approximately 2oo°c t (decomposition).

Example 14 Ammonium m-cresol-6-sulphonate 1C 7.08 g (69.4 mmols) of concentrated sulphuric acid (D = 1.84) are added dropwise at 22°C and in the course of about 5 minutes to 7-5 g (69.4 mmols) of m-cresol, while stirring. The reaction mixture is then warmed to 50°C and stirred for 3 hours at this temperature. It is then cooled to room temperature, diluted with 20 ml of water and extracted with 6 times 20 ml of chloroform in order to remove unreacted m-cresol. The aqueous phase is cooled to 0°C, 8' ml of 25% strength ammonia solution are added and stirring is continued for 1 hour at 0°C. The ammonium m-cresol-6-sulphonate vrtiich has been precipitated is filtered off and rinsed with isopropanol. The precipitate is pure as shown by thin layer chromatography and it is dried in a vacuum cabinet at 60°C.

Yield: 4.2 g (30% of theory); impt 255-257°C (decomposition). Example 15 m-Cresol-6-sulphonic acid 100 g (0.488 mol) of ammonium m-cresol-6-sulphonate are dissolved in 200 ml of water by warming to 610 90°C and the solution is poured onto an ion exchange column containing 300 g of moist Amberlite IT 120 (acid form), kept at 90°C. Evaporating the aqueous eluate at 5O°C in vacuo and recrystallising the residue from acetonitrile gives m-cresol-6-sulphonic acid in the form of the dihydrate.

Yield: 104 g (95% of theory); m.p. 90-93°C.

Example 16 Tetramethylethylenediammonium m-cresol-6-sulphonate a) 2,000 g (9-63 mols) of ammonium m-cresol-6-sulphonate are added in portions, with vigorous stirring, to a solution, heated to 95°C, of 700 g (17-5 mols) of sodium hydroxide in 3 1 of water. In order to remove completely the ammonia which has been liberated, the mixture is boiled for ? further 2 hours while passing in nitrogen. This solution is added to a mixture of 820 g (9-4 mols) of concentrated sulphuric acid and 6 1 of water. The crystals precipitated redissolve when 560 g (4-82 mols) of 1,2-bis-(dimethylamino)-ethane are subsequently added to the hot mixture. After cooling, salt which has been precipitated is filtered off, washed and dried.

It contains 0-5 mol of base to 1 mol of m-cresol-6-sulphonic acid.

Yield: 2,044 g (86% of theory); m.p, 183-185°C. b) The same product is obtained in a virtually quantitative yield if, instead of the ammonium salt, the free m-cresol-6-sulphonic acid (dihydrate) is reacted with an equivalent quantity of l,2-bis-(dimethylamino)-ethane in water. 50810 c) Another procedure consists in using 1,2-bis-(dimethy1amino)-ethane in chlorobenzene to expel the ammonia from the ammonium m-cresol-6-sulphonate instead of sodium hydroxide in aqueous solution. For example, 242 g (86% of theory) of the title compound are obtained from 233 g (1·14 mols) of ammonium m-cresol-6-sulphonate in 250 ml of chlorobenzene and 190 ml (1.26 mols) of 1,2-bis(dimethylamino)-ethane' after heating at approximately 160°C (30 to 60 minutes), filtering and adding 75 ml of glacial acetic acid to the filtrate; m.p. 182-184°C.

Example 17 1,4-Dlmethylpiperazine m-cresol-6-sulphonate a) 30 ml (0.223 mol) of 1,4-dimethylpiperazine are added to a solution of 100 g (0.445 mol) of m-cresol-6-sulphonic acid dihydrate in 300 ml of water. After stirring for 0-5 hour at 0°C, the precipitate is filtered off, washed with water and methanol and dried.

Yield: 109 g (93% of theory); nup. 236-238°C. The salt contains 0.5 mol of 1,4-dimethylpiperazine per mol of m-oresol-6-sulphonic acid and 1 mol of water of crystallisation · b) The same salt is obtained if ammonium m-cresol-6sulphonate is employed as the starting material. After adding equimolar quantities of hydrochloric acid and semiequimolar quantities of 1,4-dimethylpiperazine, the salt is formed in a virtually quantitative yield.

Example 18 Morpholine m-cresol-6-sulphonate 100 g (0-49 mol) of ammonium m-cresol-6-sulphonate and 47 ml (0·54 mol) of morpholine in 200 ml of water are heated for 10 hours at 100°C and the solution is evaporated to dryness in vacuo. The residue is taken up in 200 ml of acetone and the insoluble residue is filtered off and washed with acetone and etherYield: 106 g (79% of theory); m.p. 167-17O9C.

Example 19 l-Benzyl-4-methylpiperazine m-cresol-6-sulphonate Solutions of 4.1 g (20 mmols) of ammonium m-oresol10 6-sulphonate in 45 ml of water and of 2.6 g (10 mmols) of l-benzyl-4-methylpiperazine dihydrochloride in 15 ml of water are combined, while stirring, and the precipitate is filtered off.

Yield: 3-9 g (53% of theory); m.p. 142-146°C.

Example 20 1.4- Dibenzylpiperazine m-cresol-6-sulphonate 11.6 g (92% of theory) of the title compound are obtained in the same maimer as that described in Example 6 from 5·3 g (20 mmols) of dibenzylpiperazine, dissolved in 30 ml of 2 N sulphuric acid and 8.2 g (40 mmols) of ammonium m-cresol-6-sulphonate in 200 ml of water; m.p 223°C.

Example 21 1.4- Diazabicyclof2.2.2]octane m-cresol-6-sulphonate Solutions of 2.24 g (10 mmols) of m-cresol-6sulphonic acid dihydrate in 10 ml of viater and of 0-55 g (5 mmols) of l,4-diazabicyclo[2.2.2joctane in 10 ml of viater are combined, while stirring, and the precipitate is filtered off.

Yield: 1.4 g (57% of theory); m.p. 250°C.

Example 22 Barium m-cresol-6-sulphonate 100 g (0.48 mol) of ammonium m-cresol-6-sulphonate are warmed with 200 ml of water and 10 ml of concentrated hydrochloric acid until a clear solution is formed, 50 g (0-2 mol) of barium chloride dihydrate, dissolved in 120 ml of water, are then added, and the precipitate is filtered off.

Yield: 77 g (75% of theory); m.p. > 250°C· Example 25 Ethylenediammonium di-(m-cresol-6-sulphonate) 0-7 g (12 mmols) of ethylenediamine are added to a solution of 5 g (22 mmols) of m-oresol-6-sulphonic acid dihydrate in 20 ml of water, and the precipitate is filtered off.

Yield: 3-4 g (70% of theory); rn.pi 226-229°C.

Example 24 Piperazine di-(m-cresol-6-sulphonate) 1.4 g (69% of theory) of the title compound are obtained in the same way as that described in Example 23 from 2 g of m-cresol-6-sulphonic acid dihydrate and 0-4 g of piperazine in 10 ml of water· M.p. 254-256°C (decomposition)· Example 25 1-Methylpiperazine m-cresol-6-sulphonate 100 g (0-49 mol) of ammonium m-cresol-6-sulphonate and 48-6 g (0·49 mol) of 1-methylpiperazine in 200 ml of water are boiled for 7 to 8 hours and the mixture is then evaporated to dryness in vacuo. The residue is triturated with 50 ml of acetone and the precipitate is filtered off.

Yield: 69 g (49% of theory); m.p. 129-131°C (from methanol).

Example 26 Concentrate for application as a paint Preparation of a hatch of 100 kg: 36 kg of 2,2'dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid) are introduced into 64 kg of distilled water in a V2A vessel, while stirring. After stirring for 1 hour the solution is homogeneous and it is filled into glass bottles holding 100 ml.

Example 27 Vaginal suppositories Preparation of a batch of 100,000 vaginal suppositories containing 90 mg of active compound: kg of 2,2'-dihydroxy-5,51-methylenedi-(p-toluenesulphonic acid) are dissolved in 9 1 of distilled water. 57 kg of polyethylene glycol 4,000 and 225 kg of polyethylene glycol 1,500 are melted at 70°· The aqueous solution of the active compound is introduced into this melt, while stirring After cooling to 50°, the finished composition is poured into ovule-shaped moulds, each holding 3 g· Example 28 Vaginal tablets Preparation of a batch of 1QO,OOO vaginal tablets containing 90 mg of active compound: 90 kg of lactose and 17 kg of carboxymethylcellulose are mixed and the mixture is moistened with a solution of 9 kg of 2,2*-dihydroxy50610 ,5'-methylenedi-(p-toluenesulphonic acid) in 50 1 of denatured alcohol and granulated through a sieve having an inner mesh width of 1.5 mm. The granules are dried in a fluidised bed drier to a relative moisture content of 50 to 60% and are mixed with 4 kg of talc and, after sieving, are compressed to form tablets weighing 1,200 mg.

Example 29 Gel g of gel oontains 18 mg of active compound; preparation of a batch of 25 kg: 18-750 kg of polyethylene glycol 400 and 5-000 kg of polyethylene glycol 20,000 are melted at 60° to 70°C. A 36% strength solution of 2,2'-dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid) is stirred into the melt. The gel is cooled to 20°C, while stirring well, and is filled into tubes holding 50 g.

Example 30 Ointment g of ointment contains 50 mg of active compound; preparation of a batch of 25 kg: 8-750 kg of polyethylene glycol 400 and 13-750 kg of polyethylene glycol 550 are melted at 50°C. After cooling to 40°C, 1.250 kg of 2,2'-dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid), dissolved in an equal quantity of water, are introduced.

The mixture is stirred until the ointment has reached a temperature of 25°C. The ointment is filled into tubes holding 50 g.

Example 31 Suppositories suppository contains 100 mg of active compound; preparation of a batch of 10,000 units: 1 kg of diurea salt of 2,2'-dihydroxy-5,5’-methylenedi- (p-toluenesulphonic acid), together with 0.1 kg of colloidal silicon dioxide, is ground to a particle size less than 30 pm and is incorporated by stirring into 18.9 kg of hard fat (Adeps solidus) which has been melted at 40°C, and is cast to form suppositories.

Claims (17)

1. 2,2’-Dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid) and its salts.

2. 2,2'-Dihydroxy-5,5' -methylenedi-(p-toluenesulphonic acid) and salts thereof which are soluble in water at 23°C to the extent of more than 10 g/100 ml.

3. · 2,2 * -Dihydroxy-5,5 1 -methylenedi- (p-toluenesulphonic acid) and its sodium, ammonium and urea salts.

4. Process for the preparation of 2,2'-dihydroxy5, 5'-methylenedi-(p-toluenesulphonic acid) and its salts, characterised in that a) m-cresol-6-sulphonic acid and/or its salts are reacted in an acid medium with formaldehyde and/or formaldehyde donors and, if desired, a resulting salt is converted into the free acid or into another salt, b) m-cresol-6-sulphonic acid and/or its salts are converted, in a basic medium, by means of formaldehyde and/ or formaldehyde donors into 4-hydroxymethyl-m-cresol-6sulphonic acid and the latter is subjected in an acid medium to a condensation reaction with m-cresol-6-sulphonic acid and/or its salts and, if desired, a resulting salt is converted into the free acid or into another salt, or c) m-cresol which is substituted in the 6-position by a detachable substituent is reacted, in an acid medium, with formaldehyde and/or formaldehyde donors to give a 5,5'-disubstituted 4,4'-dihydroxy-2,2'-dimethyldiphenylmethane, the substituents in the 5-position and 5'-position are split off and the product is sulphonated in an acid 610 medium with sulphuric acid and/or an agent which splits off sulphonic acid groups and, if appropriate, a resulting salt is converted into the free acid or into another salt. 5· Process according to Claim 4, characterised in that a) m-cresol-6-sulphonic acid or its ammonium or alkali metal salt, in the presence of organic amines, preferably diamines, or the salts of m-cresol-6-sulphonic acid with organic amines, preferably diamines, are reacted, in an acid medium, with formaldehyde and/or formaldehyde donors and, if desired, a resulting salt is converted into the free acid or into another salt, b) m-cresol-6-sulphonic acid or its ammonium or sodium salt, in the presence of organic amines, preferably diamines, or the salts of m-cresol-6-sulphonic acid with organic amines, preferably diamines, are converted, in a basic medium, by means of formaldehyde and/or formaldehyde donors, into a salt of 4-hydroxymethyl-m-cresol-6-sUlphonic acid with organic amines, preferably diamines,, and this salt is subjected, in an acid medium, to a condensation reaction with m-cresol-6-sulphonic acid or its ammonium or sodium salt in the presence of organic amines, preferably. diamines,or to a condensation reaction with a salt of m-cresol-6-sulphonic acid with an organic amine, preferably a diamine, and, if desired, a resulting salt is converted into the free acid or into another salt, or c) m-cresol which is substituted in the 6-position bychlorine, bromine or iodine is reacted, in an acid medium, with formaldehyde and/or formaldehyde donors to give 5,5'41 dichloro-4,4'-dihydroxy-2,2'-dimethyldiphenylmethane,

5. ,5'-dibromo-4,4'-dihydroxy-2,2'-dimethyldiphenylmethane or 5,5'-diiodo-4,4'-dihydroxy-2,2'-dimethyldiphenylmethane, the substituents in the 5-position and 5'-position are 5 split off by catalytic hydrogenation and the product is sulphonated, in an acid medium, with sulphuric acid and/ or an agent which splits off sulphonic acid groups, and, if desired, a resulting salt is converted into the free acid or into another salt. 10

6. Process according to Claim 5, characterised in that a) m-cresol-6-sulphonic acid or its ammonium or sodium salt in the presence of tetramethylethylenediamine, or the salt of m-cresol-6-sulphonic acid with tetramethylethylene 15 diamine, is reacted with formaldehyde in an acid medium, and, if desired, the resulting salt is converted, if desired via the sodium salt, into the free acid or into another salt, b) m-cresol-6-sulphonic acid or its ammonium or sodium 20 salt in the presence of tetramethylethylenediamine, or the salt of m-cresol-6-sulphonic acid with tetramethylethylenediamine in the presence of an alkali metal hydroxide, is converted by means of formaldehyde into the tetramethylethylenediamine salt of 4-hydroxymethyl-m-cresol-625 sulphonic acid and this salt is subjected, in an acid medium, to a condensation reaction with m-cresol-6-sulphonic acid or its ammonium or sodium salt in the presence of tetramethylethylenediamine, or to a condensation reaction with the tetramethylethylenediamine salt of m-cresol-6-sulphonic acid, and, if desired, the resulting salt is converted, if desired via the sodium salt, into the free acid or into another salt, or c) 6-chloro-m-cresol-is reacted, in an acid medium, with 5 formaldehyde and/or formaldehyde donors to give 5,5'-dichloro4,4'-dihydroxy-2,2'-dimethyldiphenylmethane, the latter is converted by hydrogenation over a piatinum catalyst into 4,4'dihydroxy-2,2'-dimethyldiphenylmethane and the latter is sulphonated in an acid medium with concentrated sulphuric acid. 10

7. Process according to one of Claims 4, 5 or 6, characterised in that obtained salts are converted into the free acid or into other salts with an acid ion exchanger.

8. Medicaments containing as active ingredients 2,2'dihydroxy-5,5'-methylenedi(p-toluenesulphonic acid) and/or its 15 pharmacologically acceptable salts.

9. Salts of 2,2'-dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid) which have a solubility in water at 23°C of less than 3 g/100 ml.

10. Salts according to claim 9, characterised in that they 20 are salts with organic amines.

11. Salts according to claim 10, characterised in that they are salts with organic diamines.

12. Salts according to claim 11, characterised in that the two amino groups in the diamines are linked by one, two or 25 three C 2 to C 4 alkylene chains.

13. Salts according to one of claims 11 and 12, characterised in that the organic diamine is piperazine, 1,4-diazabicyclo (2.2.2] octane, 1,4-dimethylpiperazine, l-benzyl-4-methylpiperazine, ethylenediamine or tetramethylethylenediamine.

14. Process for the preparation of salts of 2,2'dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid) with 5 organic amines, characterised in that a) 2,2'-dihydroxy-5,5'-methylenedi-(p-toluenesulphonic acid) or one of its salts is reacted with the organic amine, or b) m-cresol-6-sulphonic acid or its ammonium or alkali metal salt in the presence of organic amines, or a salt 10 of m-cresol-6-sulphonic acid with organic amines, is reacted, in an acid medium, with formaldehyde and/or formaldehyde donors.

15. Pharmaceutical preparations containing at least one compound according to Claims 1 to 3 or Claims 9 - 13 in 15 admixture with one or more solid or liquid pharmaceutically acceptable carriers.

16. A process for the preparation of 2,2'-dihydroxy5, 5' -methylenedi (p-toluenesulphonic acid) and its salts substantially as described with reference to the specific 20 examples hereinbefore set forth.

17. 2,2'-dihydroxy-5,5 1 -methylenedi-(p-toluenesulphonic acid) and its salts whenever prepared by a process claimed in a preceding claim.