DE3423691C1 - Pharmaceutical compositions for controlling mycobacterioses - Google Patents

Abstract

Pharmaceutical combination composed of (A) at least one of the compounds 4,4'-diaminodiphenyl sulphone, p-aminosalicylic acid, streptomycin, rifampicin, benzaldehyde thiosemicarbazone, trimethoprim or isonicotinic hydrazide or a pharmacologically acceptable acid addition salt thereof and (B) at least one benzylamine which is substituted in positions 3 and/or 5 by fluorine, chlorine or bromine and whose amino group is free or substituted by linear alkyl with 1 to 5 carbon atoms. A compound which is particularly preferred as component (B) is N-methyl-3,5-dichlorobenzylamine, whereas the compound 4,4'-diaminodiphenyl sulphone is particularly preferred as component (A). Pharmaceutical combinations of this type show, by comparison with the individual components, a superadditive and thus synergistic activity and they are particularly suitable for controlling mycobacterioses, especially tuberculosis and, in particular, leprosy. They are furthermore also distinguished in that they are relatively resistant to the organisms to be controlled therewith, since the rapid development of resistance which occurs on monotherapy with only compounds according to component (A) is greatly delayed or even virtually abolished by constituents (B).

Description

It is already known (Arzneimittel -forschung 22, 1235 (1972)), the p-aminosalicylic acid, streptomycin, Rilampicin, benzaldehyde thiosemicarbazone, Isonicotinic acid hydrazide (INH) and, to a lesser extent, 4,4'-diaminodiphenyl sulfone (DDS) has an inhibitory effect on the causative agent of hyperculosis, namely mycobacterium tuberculosis. These substances are therefore already being used successfully in therapy of tuberculosis. An effect against the related Mycobacterium leprae, namely the causative agent of leprosy, contain these substances with the exception of rifampicin and 4,4'-diaminodiphenylsulfone, however, practically not.

The latter in particular is characterized by a particularly high level of effectiveness against Mycobacterium leprae, so that it has been used as a for more than 40 years Standard therapeutic agent used to treat leprosy.

Lcider now shows 4,4'-diaminodiphenyl sulfone even at low dosage undesirable side effects, such as primarily anemia, drug eruptions and liver damage. Its bacteriostatic type of action and its toxicity now require limited dosage along with the extremely long generation time of the leprosy bacteria (about 12 to 14 days), however, for decades and frequently even lifelong application, with monotherapy also increasing in scope leads to the formation of resistance (Int. J.

Lepr. 44, 140 (1976) and Int. J. Lepr. 44, 143 (1976)).

It has also been known for years (drug research 22, 1235 (1972)) that combinations of 4,4'-diaminodiphenyl sulfone with substances such as Rifampicin and the like, a super additive and thus synergistic activity against Mycobacterium leprae. However, all of these substances are proportionate expensive, so the treatment of leprosy mainly for financial reasons worldwide is mainly carried out in monotherapy with 4,4'-diaminodiphenyl sulfone. Independent Of course, such combinations also have those above in connection with 4,4 ~ Diaminodiphenylsulfone mentioned side effects.

It is also known that certain compounds from the class the benzylamines, such as those in position 3, for example by fluorine, chlorine or bromine substituted N-butylbenzylamines, specific antifungal properties (Pharmazie 31, 374 (1976) and Pharmazie 32, 119 (1977)). The known from this N-butyl-3-chlorobenzylamine possesses against Mycobacterium tuberculosis H37Rv for example a minimum inhibitory concentration of 64.0 mg / ml. The antifungal Effects of these known, possibly also halogen-substituted benzylamines are depending on the respective substituents on the ring or on the amino group now partially good, but still far from being as effective as the antifungal agents mentioned above and not belonging to the benzylamines, such as 4,4'-diaminodiphenyl sulfone, p-aminosalicylic acid, streptomycin, rifampicin, benzaldehyde thiosemicarbazone, Trimethoprim or isonicotinic acid hydrazide.

Finally, it is known from US-PS 37 81 443 that N-alkylbenzylamines, which in the phenyl nucleus can also be substituted by halogen, among other things, as medicaments suitable for the treatment of hormonal disorders, which in any case the physiological harmlessness such connections shows.

The known drugs for combating mycobacteriosis, for example, and in particular of tuberculosis and / or especially of leprosy, are the above statements not to be regarded as completely satisfactory. The object of the invention is therefore Providing new drugs for the treatment of such disease states, and these means should work better, less so, compared to the known means toxic and possibly also cheaper. As a result of the in halogen-substituted benzylamines or halogen-substituted benzylamines present in these drug combinations pharmacologically acceptable acid addition salts thereof (component B) also as a result distinguish that the values otherwise given for the compounds according to component (A) are proportionate rapid formation of resistance to the organisms to be controlled is greatly delayed or is practically eliminated entirely.

This object is now achieved according to the invention by what is stated in the claims 1 to 3 resulting drug combinations solved. Which in it as a component, namely, component (B), halogen-substituted benzylamines present are largely new compounds, some only as medicinal products (agents against mycobacteria or for the treatment of hormonal disorders) known compounds in uncombined form and finally only as intermediate products without mentioning any compounds known to have pharmacological activity.

The invention is therefore based on the surprising finding that a combination of mainly 4,4'-diaminodiphenylsulfone or p-aminosalicylic acid, Streptomycin, rifampicin, benzaldehyde-thiosemicarbazone, trimethoprim or isonicotinic acid hydrazide or a pharmacologically acceptable acid addition salt thereof (component (A)) with a halogen-substituted benzylamine with that specified in claim 1 general formula (I) or a pharmacologically acceptable acid addition salt of which (component (B)) to the bacteria responsible for mycobacterioses, namely mycobacteria, leads to a strikingly synergistic effect. In such Combinations, an inhibition of the growth of the causative bacteria is observed, which have a purely additive effect of the individual compounds that make up the respective Combination exists, sometimes goes far beyond. A particularly pronounced superadditive A combination of 4,4 ~ diaminodiphenyl sulfone and one of the compounds from the general formula (I), but also p-aminosalicylic acid and streptomycin show a strong synergistic effect and deal with Rifampicin, benzaldehyde thiosemicarbazone, trimethoprim and isonicotinic acid hydrazide also shows a certain synergism. Of course, the extent of that is achievable Effect in a certain way also dependent on the particular one used as the combination partner halogen-substituted benzylamine of the general formula (I).

The easy accessibility and low cost of the halogen-substituted ones Benzylamines of the general formula (I) now make it possible to replace the previously mainly used carried out monotherapy in the treatment of mycobacteriosis, in particular from tuberculosis and especially from leprosy, through combination therapy. this has a prevention of the resistance effect to those present as component (A) Active ingredients, especially against 4,4'-diaminodiphenyl sulfone, rifampicin and isonicotinic acid hydrazide, to the Episode. Additional significant advantages of such combinations are the shortening of the treatment time and the strong reduction of the side effects the active ingredients according to component (A), especially 4,4'-diaminodiphenyl sulfone, with a possible significantly lower dosage. The one caused by the side effects Restriction of the usability of these highly effective and leading compounds per se in tuberculosis therapy and leprosy therapy can thus be reversed will.

It was surprisingly found that by suitable Combination of N: alkyl radicals and halogen atoms in benzylamines in the position 3 or in positions 3 and 5 new halogen-substituted benzylamines obtained that have superior antifungal activity. For example the already mentioned minimum inhibitory concentration of the well-known N-butyl-3-chlorobenzylamine (Pharmazie 31, 374 (1976)) when replacing the butyl radical in the N position with a Methyl radical, so that the compound N-methyl-3-chlorobenzylamine results, of 64.0 Fg / ml decreased to 10.2 cug / ml (Mycobacterium tuberculosis H37Ra). Another substantial improvement in the antifungal effect is mainly also due to achieved a dihalogen substitution in positions 3 and 5 of benzylamines, as from a considerably better compared to the N-alkyl-3-halogenobenzylamines Effect on atypical mycobacteria such as Mycobacterium marinum or Mycobacteriumlufu, can be seen. This result is particularly important for the simultaneous treatment several mycobacteriosis important, so that with such halogen-substituted Benzylamines treat tuberculosis as well as leprosy and other mycobacteriosis permit.

It is particularly important here that the dihalogen compounds in particular not only for the treatment of tuberculosis, but also primarily for a treatment suitable for leprosy. The effectiveness of the new halogen-substituted benzylamines and the other benzylamines previously known only without a drug effect against Mycobacterium leprae is, among other things, in the test model strains already mentioned Mycobacterium marinum and Mycobacterium lufu have been confirmed.

The drug combination according to the invention contains as active ingredients Serving components (A) and (B) preferably in a mixing ratio based on weight, roughly the quotient (MHKAZ MHKB) from the respective minimum inhibitory concentrations (MIC values) of components (A) and (B), namely the quotient of the MIC value for component (A) and the MIC value for component (B), since with such a mixing ratio there is an optimal synergistic effect.

On the basis of such a type of calculation, for the one according to the invention Drug combination from the individual compounds according to component (A) and the compounds of the general formula (I) according to component (B) the following general, preferred and particularly preferred mixing ratios in percent by weight: table I Component (A) Component (B) General Mi- Preferred Mi- Particularly preferred ratio mixing ratio added mixing (A) to (B) (A) to (B) ratio (A) to (B) 4,4'-diamino- Compound of 1 to 99% to 30 to 95% to 50 to 85% to diphenyl sulfone formula (I) 99 to 1% 70 to 5% 50 to 15% p-aminosalicylic compound of the 0.0005 to 20% 0.01 to 4% to 0.15 to 0.77% to acidic Formula (I) 99.9995 to 80% 99.99 to 96% 99.85 to 99.23% streptomycin compound of 0.005 to 33% to 0.05 to 10% to 0.2 up to 2% to formula (I) 99.995 to 67% 99.95 to 90% 99.8 to 98% rifampicin compound of 0.004 to 0.62% to 0.01 to 0.3% to 0.03 to 0.15% to formula (I) 99.996 to 99.38% 99.99 to 99.7% 99.97 to 99.85% Benzaldehyde compound of 0.01 to 33% 0.1 to 10% 0.3 to 1.5% to thiosemicarbazone Formula (I) 99.99 to 67% 99.9 up to 90% 99.7 to 98.5% trimethoprim compound of 11 to 99.99% to 70 to 98% too 89 to 97.5% to formula (I) 89 to 0.01% 30 to 2% 11 to 2.5% isonicotinic acid compound of 0.15 to 3% to 0.2 to 2% to 0.3 to 1.5% to hydrazide formula (I) 99.85 to 97% 99.8 to 98% 99.7 to 98.5% when using drug combinations of the above For a total growth inhibition of mycobacteria, species is already 1/4 for the most part up to lkso the concentration sufficient for a single application of the component (A) would otherwise be necessary. In addition, the well-known development of resistance in mycobacteria against the means available as component (A) and customary for such therapies by their combined use with the halogenated benzylamines in question prevented in the specified proportions. This applies to, among others 4,4'-Diaminodiphenylsulfon as well as streptomycin and especially for rifampicin as well Isonicotinic hydrazide. Allow the medicament combinations according to the invention therefore a considerable reduction in the dose of the combination partner (A) so far used the respective chemotherapeutic agent, which by the well tolerated and only little toxic combination partner (B) is added, and thus a restriction the toxic side effects of the combination partner (A).

With regard to the toxicity of the combination partner (A) corresponding Chemotherapeutics is referred to II. Otten, M. Plempel and W. Siegenthaler, Antibiotic Primer, 4th edition, 1975, Georg Thieme Verlag, Stuttgart, pointed out.

Leave the drug combinations from components (A) and (B) in the form of the free bases of the respective components or, preferably, the acid addition salts use with pharmacologically harmless acids both orally and parenterally, oral administration is preferred. The daily dose to be administered is generally 0.1 to 40 mg / kg, preferably 0.5 to 20 mg / kg and in particular l to 5 mg / kg. A deviation from these daily doses is of course possible, especially since this usually depends on the condition of the patient to be treated and the clinical picture is finally determined by the doctor. So it may in some It is therefore sufficient in cases to manage with less than the aforementioned quantities, while in other cases the indicated dosage ranges are exceeded have to. The daily dose to be consumed in each case is, of course, a total of those in each case Combination partners dependent, so that they are above all with regard to their lower limit can also be significantly below the minimum values given above.

The active ingredients can be formulated in the usual form for oral administration are, for example, in capsules, tablets, coated tablets or even in liquid form Form, such as suspensions or syrups.

By mixing with solid, powdery carriers such as potato starch or corn starch, with additives such as sodium citrate, calcium carbonate or dicalcium phosphate, and binders such as polyvinylpyrrolidone, gelatin or cellulose derivatives, if appropriate with the addition of lubricants such as magnesium stearate, sodium lauryl sulfate or polyethylene glycols, the active ingredient combinations or individual active ingredients can be converted into tablets or dragee cores are processed. Of course, in the case of oral administration forms flavor corrections are also added.

Push-fit capsules, such as capsules, are suitable as further forms of administration made of hard gelatin, or closed soft gelatin capsules with a plasticizer, like glycerin. The push-fit capsules preferably contain the active ingredient as granules, for example in a mixture with fillers such as lactose, sucrose, mannitol or Starches, for example potato starch or amylopectin, cellulose derivatives or highly disperse silicas.

In soft gelatin capsules, the active ingredient is preferably in suitable form Liquids, such as in vegetable oils or liquid polyethylene glycols, dissolved or suspended. In the case of parenteral use, solutions of the active ingredients, for example in sesame oil or olive oil or in physiological saline solution, can be used.

In the drug combinations, the individual components either mixed together or divided so that the individual components do not come into contact with each other. Accordingly, the components of the respective Combination can also be administered separately to achieve the same effect. However, for the sake of simplicity and to avoid dosing errors Administration forms preferred in which all active ingredient components are combined.

The drug combinations can of course also be several Contain representatives from component (A) and / or component (B).

Those contained in the drug combination as component (A) Active ingredients can either be in the form of their free bases or in the form of their usual Salts with pharmacologically acceptable acids are used. It will therefore In the present case, such forms of this are preferably used, as are also already used in the known monotherapy based on compounds according to component (A) for Application.

Those present in the drug combination as component (B) halogen-substituted benzylamines of the general formula (I) containing active ingredients can also be in the form of their free bases or their salts with pharmacological harmless, both organic and inorganic acids are used.

The salts of inorganic acids include, for example, the salts of Hydrohalic acid, sulfuric acid, phosphoric acid, nitric acid or perchloric acid. Salts of organic acids generally include the salts of organic mono-, di- or tricarboxylic acids of the aliphatic, alicyclic, aromatic or heterocyclic acids Series and the sulfonic acids, and individual examples are formic acid, acetic acid, Propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, Ascorbic acid, maleic acid, fumaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, Benzoic acid, antranilic acid, p-hydroxybenzoic acid, salicylic acid, emboxylic acid, methanesulfonic acid, Ethanesulphonic acid, hydroxyethanesulphonic acid, halobenzenesulphonic acids, toluenesulphonic acid, Naphthalenesulfonic acid or sulfanilic acid.

As already stated, the drug combinations contain as Active ingredient according to component (A) at least one of the compounds 4,4'-diaminodiphenyl sulfone, p-aminosalicylic acid, streptomycin, rifampicin, benzal dehydthiosemicarbazone, trimethoprim or isonicotinic acid hydrazide or a pharmacologically acceptable acid addition salt of this. Accordingly, mixtures of two or more such compounds can also be used be present as component (A). The compounds are preferred as component (A) 4,4'-Diaminodiphenylsulfon, p-aminosalicylic acid or streptomycin used, whereby the compounds 4,4'-diaminodiphenylsulfone and / or rifampicin are very particularly preferred are.

These active ingredients according to component (A) show in Middlebrook 7H9 medium and Löwenstein-Jensen medium have the minimum given in Table II below Inhibitory concentrations (MIC values in µg / ml, total growth inhibition) against mycobacterium tuberculosis H37Ra. The inhibitory concentrations for an active ingredient are also compared given according to component (B), namely for N-methyl-3,5-dichlorobenzylamine.

Table II Compound Minimum Inhibitory Concentration (µg / ml) Middlebrook Lowenstein 4,4'-Diaminodiphenylsulfone 32 5.12 p-Aminosalicylic Acid 0.05 0.025 Streptomycin Sulfate 0.1 7.68 Rifampicin 0.01 0.512 Benzaldehyde Thiosemicarbazone 0.1 0.179 Isonicotinic Hydrazide 0 , 1 0.03 N-methyl-3,5-dichlorobenzylamine HC1 16 10.2 Component (B) of the drug combination consists of at least one halogen-substituted benzylamine of the general formula (I) where R is hydrogen or n-alkyl with 1 to 5 carbon atoms and X and Y are identical or different and are hydrogen, fluorine, chlorine or bromine, but X and Y cannot be hydrogen at the same time, or a pharmacologically acceptable acid addition salt thereof, as an active ingredient. Of course, mixtures of two or more of these compounds of this component (B) can also be used. Preferred halogen-substituted benzylamines according to component (B) are N-butyl-3-fluorobenzylamine, N-butyl-3, 5-difluorobenzylamine, N-methyl-3-fluorobenzylamine, N-methyl-3-chlorobenzylamine, N-methyl-3-chloro 5-fluorobenzylamine, N-butyl-3-chloro-5-fluorobenzylamine, N-propyl-3-chlorobenzylamine, N-propyl-3,5-dichlorobenzylamine, N-methyl-3-bromobenzylamine, N-methyl-3,5- dichlorobenzylamine or 3,5-dichlorobenzylamine, the compounds N-butyl-3,5-difluorobenzylamine, N-methyl-3,5-dichlorobenzylamine and N-methyl-3-chlorobenzylamine being very particularly preferred.

Examples of halogenated benzylamines included under those given above general formula (1) fall, emerge from the following table III, in the same time also the minimum inhibitory concentrations (I * g / ml, total growth inhibition) of these Compounds against Mycobacterium tuberculosis H37Ra are indicated.

The testing was carried out on Löwenstein-Jensen medium.

Table III Compound R X Y MIC values No. (/ mi) 1 CH3 F H 19.2 2 CH3 C1 C1 10.2 3 C2Hs CI Cl 17.9 4 n-C3H7 C1 C1 20.4 5 n-C4Hg C1 C1 64.0 6 CH3 F F 32.0 7 QH5 F F 44.8 8 n-C3H7 F F 19.2 9 n-C4H9 F F 6.4 10 n-CsHII F F 32.0 11 H C1 F 32.0 12 CH3 C1 F 19.2 13 C2H5 Cl F 32.0 14 n-C3H7 Cl F 25.6 15 n-C4H9 C1 F 19.2 6 Continuation of compound R X Y MIC values no. (11g / ml) 16 C2115 F H 51.2 17 n-C3H7 F H 25.6 18 n-CsHIJ F H 51.2 19 n-C3H7 Br H 51.2 20 n-C5H11 Cl Cl 128 21 n-C51111 Cl H 51.2 22 H F F 57.6 23 C2Ils C1 H 25.6 24 n-C3H7 C1 H 17.9 25 H Br H 32.0 26 C2H5 Br H 64 27 H F H 51.2 28 H Cl H 17.2 29 CH3 Cl H 10.2 30 CH3 Br H 19.2 31 H Cl Cl 20.4 32 n -C4H9 F H 25.6 33 n -C4Hg Cl H 64.0 34 n -C4H9 Br H 38.4 The compounds with the numbers 1 to 15 correspond to the compounds Examples 1 to 15 which follow later, so that these are new compounds from the general formula (Ia).

The connections 16 to 22 are also new connections from the general formula (Ia).

The compounds 23 to 31 are known compounds that have hitherto been used however, have only been described as intermediates.

The compounds 32 to 34 are also known compounds, for which, however, an antimycobacterial effect has also been described so far (Pharmazie 31 (1976) 6, pages 374 to 381).

The most potent compounds from Table III above are the compounds with the numbers 2, 9 and 29.

The minimum inhibitory concentrations (MIC values in μg / ml, total growth inhibition) these most effective connections to various mycobacteria are derived from the Table IV below. The testing was carried out on Lockemann medium.

Table IV Connection MIC values (11g / ml) No. M. tuber- M. avium M. marinum M. smegmatis culosis H37Rv SN304 SN1254 ATCC 607 2 3 4 4 32 9 4 3 6 32 29 12 16 24 32 The minimum inhibitory concentrations (MIC values in 11g / ml, total growth inhibition) of these most effective connections to Mycobacterium lufu L 209 go out from the following Table V. The testing was carried out on Dubos medium with 5% bovine albumin.

Table V Compound No. MIC values (lg / ml) Mycobacterium lufu L209 2 4 9 8 29 32 to 64 To assess yourself through drug combinations combinations resulting from component (B) are investigated from various compounds according to component (A) and the compound N-methyl-3,5-dichlorobenzylamine hydrochloride (Compound No. 2) as component (B) using the so-called checkerboard method and determination of the so-called FIC index. Combinations that are merely an additive Showing effectiveness is expressed by FIC values of 1.0. All combinations with superadditive and thus synergistic effectiveness show here FIC values of less than 1.0, the synergism naturally being all the more pronounced the lower the respective FIC value.

In these investigations, the following results The combinations shown in Table VI show the FIC values given therein.

Table VI Combination component (A) component (B) FlC value tion no. (Compound No. 2) a Diaminodiphenyl-sulfone N-methyl-3,5-dichlorobenzylamine-0.031 hydrochloride b p-aminosalicylic acid N-methyl-3, 5-dichloro-benzylamine-0.0625 hydrochloride c streptomycin sulfate, N-methyl-3,5-dichlorobenzylamine-0.125 hydrochloride d rifampicin N-methyl-3, 5-dichloro-benzylamine-0.5 hydrochloride e benzaldehyde thiosemicarbazone N-methyl-3,5-dichlorobenzylamine-0.25 hydrochloride f trimethoprim N-methyl-3,5-dichloro enzylamine- 0.5 g hydrochloride isonicotinic acid hydrazide N-methyl-3, 5-dichlorobenzylamine- 1.0 hydrochloride The checkerboard diagrams for the above drug combinations, in which are also entered with the respective FIC values can be found in the attached Fig. 1 to 7 can be taken.

From the above list and the individual chessboard diagrams the data contained shows that combinations of 4,4'-diaminodiphenyl sulfone, p-aminosalicylic acid and streptomycin sulfate as component (A) and from N-methyl-3,5-dichlorobenzylamine hydrochloride as component (B) as an antifungal agent, a highly synergistic one Show effect. There is also a corresponding synergistic effect with combinations from rifampicin, benzaldehyde thiosemicarbazone or trimethoprim as component (A) and N-methyl-3,5-dichlorobenzylamine hydrochloride added as component (B), wherein however, this synergistic antimycobacterial effect is less pronounced than with the first mentioned combinations. Combinations of isonicotinic hydrazide as component (A) and N-methyl-3,5-dichlorobenzylamine hydrochloride as component (B) give little or no synergistic antifungal antifungal Effect, however, are distinguished by the particular advantage that this a comparable effectiveness with a substantial saving in the amount of required Component A can be achieved and that it is otherwise given for component (A) Development of resistance not at all or only after a significantly longer treatment period have such a combination. A comparable superadditive effect results also with combinations that contain other halogen-substituted benzylamines from the general formula (I), the synergistic effect being all the more pronounced is, the lower the minimum inhibitory concentration for the respective compounds are. With the halogen-substituted benzylamines designated as preferred of the general formula (I) therefore also result from such combinations most pronounced synergistic effects.

Combinations with less pronounced synergism or with a practically only additive effect, such as in the case of rifampicin, benzaldehyde thiosemicarbazone, Trimethoprim or especially isonicotinic acid hydrazide are - as already mentioned - Particularly interesting in that, due to the presence of component (B) the usual development of resistance that is otherwise more or less strong for component (A) prevent the bacteria. In addition, such combinations allow a very important one Reduction of the otherwise required dose of the relatively toxic component (A). Both behaviors of such combinations - namely lesser or absent Development of resistance and lower dosage amount for component (A) - let thus, just like the superadditive antimycobacterial effect that is otherwise given to a certain extent subsume again under the term synergism.

To determine the minimum inhibitory concentration for the individual Compounds according to component (A) and the various halogen-substituted benzylamines from the general formula (I) according to component (B) compared to those given above Nutrient media and test methods used for mycobacteria are described below described in more detail, each also citing references in which further details can be found on this. The same also applies to the determination of the individual checkerboard diagrams and determination of the respective FIC values applied Investigation methods.

1. Composition and preparation of the nutrient media a) Middlebrook 7H9 medium (Lenette E. H., Spaulding E. H., Truant J. P., "Manual of Clinical Microbiology", Washington, D. C., 2nd Edition, page 909 (1974)) Monopotassium Phosphate 1,000 g disodium phosphate 2.500 g L-giutamic acid 0.500 g sodium citrate 0.100 g ammonium sulfate 0.500 g pyridoxine 0.001 g ammonium iron III citrate 0.040 g magnesium sulfate 0.050 g zinc sulfate 0.001 g copper sulfate 0.001 g biotin 0.50 mg calcium chloride 0.50 mg water 900 ml after 0.5 ml of sorbimacrogololeate (Tweens 80) and 2 g of dextrose are added to the dissolving of the salts to, adjusts to a pH value of 7.4 with 1N NaOll and autoclaved for 15 min 1210C. A sterile-filtered mixture of is added under sterile conditions 4 ml of 50% dextrose solution, 2 ml of a catalase solution (1 mg / ml) and 94 ml of a Solution of 4 g of beef albumin fraction V in physiological saline solution. b) Löwenstein-Jensen medium (Lenette E. H., Spaulding E. H., Truant J. P., "Manual of Clinical Microbiology", Washington, D.C., 2nd Edition, page 909 (1974)) monopotassium phosphate, 2.40 g magnesium sulfate 7 7 H2O 0.24 g magnesium citrate 0.60 g L (-) - asparagine 3.60 g potato flour 30.00 g glycerine 12.00 ml distilled water 600.00 ml homogenate from whole egg 1000.00 ml malachite green (2% aqueous solution) 20.00 ml Dissolve the salts and the asparagine in water, add glycerin and potato flour and autoclaved. Then eggs become washed in 5% soap solution with 70% ethanol, opened in a sterile bottle, homogenized by shaking and filtered through an annealed sieve. One gives add this egg homogenate to the salt solution and add the malachite green solution. Replenished here 6 ml each is poured into sterile tubes and allowed to coagulate in a drying cabinet at 850C. To check the sterility, incubation is carried out at 37 ° C. for 48 hours. c) Lockemann medium (Zentr. Bakt. Parasitenk., I. Abt. Orig. 142, 79 to 82 (1938) and Z. Hyg. Infectious Diseases 124, 373 to 385 (1942)) disodium hydrogen phosphate 121120 1.5 g potassium dihydrogen phosphate 4.0 g sodium citrate 51 / 2H2O 2.5 g ammonium iron III sulfate 0.01 g asparagine 5.0 g sodium sulfate 5.0 g magnesium chloride 6 61120 0.1 g glycerine 25.0 g = 20 ml distilled Water 1000 ml Dissolve the above ingredients up to and including the magnesium chloride in distilled water and then add the glycerine to the solution. You provide the solution with about 10 ml of 1N NaOH to a pH value of 6.8 and autoclaved at 1080C. d) Dubos-Davis medium (modified Dubos medium) (Lenette E. H., Spaulding E. H., Truant J. P., "Manual of Clinical Microbiology", Washington, D. C., 2nd edition, page 901 (1974)) potassium dihydrogen phosphate 1.0 g disodium hydrogen phosphate 12 H2O 6.5 g ammonium iron e-citrate 0.05 g sodium citrate 1.5 g magnesium sulfate 0.05 g casein hydrolyzate 1.0 g asparagine 1.0 g sorbimacrogoleate (Tweene 80) 0.5 ml of distilled water 900 ml The above ingredients are in distilled water solved. The solution is adjusted to a pH of 6.5 to 6.8 and 15 min autoclaved at 1210C. Then 100 ml of a sterile 2.5% solution of Bovine albumin fraction V in physiological saline solution.

2. Determination of the minimum inhibitory concentrations a) Experiments from Löwenstein-Jensen medium (Wagner W. H., "Infectious diseases and their pathogens", Volume 4 (1975), VEB Gustav Fischer Verlag, Jena) The compounds to be tested are the Löwenstein-Jensen medium in the dissolved state before heat coagulation in a geometric dilution series from 256 t * g / ml added. The test is performed on compounds whose MIC values are below 256 µg / ml are in the range found with the more precise arithmetic Repeated dilution series. Mycobacterium tuberculosis H37Ra used. A standardized inoculum is used by adding the Determines the amount of bacteria at which the MIC value of isonicotinic acid hydrazide is dem in the antibiotic primer (Otten H., Rempel M., Siegenthaler W.

(1975), Georg Thieme Verlag Stuttgart) stated literature value of Corresponds to 0.05 μg / ml. All test tubes with Löwenstein-Jensen medium come with 10 t * l of a bacterial suspension from fresh cultures in physiological saline solution inoculated with the extinction 0.1 (layer thickness 18 mm, filter 546 nm) and 3 to 4 weeks incubated at 370C. This amount of inoculation corresponds to about 105 germs. When evaluating the MIC values determine the smallest concentration at which no growth occurred is. Three tubes are inoculated for each concentration, but not all compounds in water are soluble, methanol is used uniformly as the solvent. b) Turbidity measurements in Middlebrook 7H9 medium. The test tubes provided with screw caps with a 18 mm in diameter also serve as breeding vessels. The measurement of the absorbance is carried out with a photometer Eppendorf 1101 M with a special insert that covers the smooth-walled The test tube. After adding the compounds to be tested to the nutrient medium in the dissolved state (methanol: 0.5 ml in 20 ml medium in a geometric dilution series) is inoculated with Mycobacterium tuberculosis H37Ra. The inoculum corresponds to one Extinction increase of 0.04 (layer thickness 18 mm, filter 546 nm). The incubation takes place at 370 C with constant movement in a rotary shaker (100 revolutions / min) with an incubation hood for a period of 20 to 25 days. The measurements will be Performed once a day. The concentration in test batches, their absorbance according to Is below 0.15 for 21 days is considered the MIC value. c) Determination of the MIC values against different types of mycobacteria The most active compounds, namely the compounds with the numbers 2.9 and 29 (see Tables III and IV) are in Lockemann medium against Mycobacterium tuberculosis H37Ra, Mycobacterium avium, Mycobacterium marinum and Mycobacterium smegmatis and tested in Dubos-Davis medium against Mycobacterium lufu. For this purpose, the compounds are added to the medium in a geometric dilution series. The evaluation takes place every 2 to 3 days over a period of 12 days visual assessment. The concentration at which after the test period no visible cloudiness has occurred is considered the MIC value.

3. Explanation of the checkerboard method (Lorian V., »Antibiotics in Laboratory Medicine ", Williams and Wilkins, Baltimore / London, Chapter 11 (1980)) This is a laboratory technique for the detection of additive, synergistic and antagonistic effects on bacterial growth when using combinations of active ingredients. The chessboard consists of (1st) columns (x-axis) and (2nd) rows (y-axis). the Columns contain a compound (A) in a constant concentration and a second compound (B) in decreasing concentration (geometric dilution series). In the case of the series, the situation is reversed. The concentration of B is constant, while the concentration of A is variable. Each box on the chessboard represents is an experimental approach that has a certain fraction of the MIC value of both the one (A) and the second substance (B) contains. Because of the restricted diffusion in solid media, liquid media such as the Middlebrook 7H9 medium must be used. Because the slow growth of mycobacteria is a test on microtiter plates not possible, so the test is carried out as with the determination of the MIC values in the tube dilution test is carried out.

The presently used and shown in Figs. 1 to 7 of the drawing, modified checkerboard method is limited to a vertical, horizontal one and diagonal test series. The diagonal test series in which the MllK values of the individual components diluted together in a geometric series is most telling. The smaller in the approach, in the last time in the geometric series no Growth can be determined, which are fractions of the MIC values of the individual components (e.g. Fig. 1: 1/64 of the MIC values of both components), the more pronounced it is Synergism. To be able to decide which combination partner for synergism delivers the larger contributions, one also tests the batch series in which half of the MIC value of one substance with the geometric dilution series the second substance is combined and vice versa, which then becomes the vertical and gives the horizontal test series.

The MIC value in turbidity measurements refers to the concentrations of compounds in which there are diagrams showing the duration of growth versus the extinction is plotted, results in a horizontal line or where the absorbance after 3 weeks of growth does not exceed 0.15.

4. Determination of the so-called FIC index (Lorian, V. »Antibiotics in Laboratory Medicine ", Williams and Wilkins, Baltimore / London, Chapter 11 (1980)) The FlC index (Fractional Inhibitory Concentration) is a method to find synergistic To express effects numerically. The FIC index is made up of the lowest concentrations calculated that are sufficient to inhibit growth.

FIClndcx = FICA - = MHKA '. MHKA = MIC of A in an A / B mixture A MHKA 'MHKA = MIC of A alone FICu = MICB,. MICBt = MIC of B in an A / B Mixture B MHKB 'MHKB = MIC of B alone FlC, ndeX <0.5 E synergism (der The smaller the number, the more pronounced the synergism.

= 1 Additive Effects> 2 = Antagonism Instead of the expression MHKA or MHKB in the figures you can directly enter the fractions of the MIC values MHKB MHKB use both substances in the test approach of the diagonal in which just barely no growth occurs.

For example, the FIC index results from FIG. 1: 1 + 1 = 1 = 0.031, 64 64 32 because, for example, the following applies: MIC connection no.2 'in combination = 1 FICA = 64 = 1 MIC compound no. 2 alone = 1 64, 1 F = MI-IK »DS> in combination ~ 64 ~ 1 MHKnns alone - 1 - 64 The halogen-substituted benzylamines of the general formula (1), which are used as component (B) in the drug combination may be present, include, as already indicated, both known and new connections.

The new halogen-substituted benzylamines have the general formula (la) where R 'is hydrogen or n-alkyl having 1 to 5 carbon atoms and X' and Y 'are identical or different and are hydrogen, fluorine, chlorine or bromine, but a) X' and Y 'cannot be hydrogen at the same time, b) X 'and Y' cannot be chlorine at the same time if R 'is hydrogen or n-pentyl, c) X' or Y 'cannot individually be chlorine or bromine if one of the substituents X' or Y is hydrogen and R 'is methyl, ethyl or n-propyl, d) X' or Y 'cannot individually be fluorine, chlorine or bromine if one of the substituents X' or Y 'is hydrogen and R' is n-butyl, and e) X 'or Y' cannot individually be fluorine, chlorine or bromine if one of the substituents X 'or Y' is hydrogen and R 'is hydrogen, or are pharmacologically acceptable acid addition salts thereof.

The substituent R 'can be used in the same way as the substituent R in the general formula (I) any straight-chain alkyl having 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl or pentyl. Methyl and butyl are included preferred.

The new halogen-substituted benzylamines are produced in a manner known per se, namely using methods that correspond to the known Process for the preparation of the known ones falling under the general formula (I) Halogen-substituted benzylamines are analogous.

The process for preparing the halogen-substituted benzylamines of the general formula (Ia) given above and their pharmacologically acceptable acid addition salts therefore consists, for example, in the fact that, in a manner known per se, a benzylideneamine of the general formula (IIa) in which X 'and Y' have the meanings given above and R "is hydroxy or n-alkyl having 1 to 5 carbon atoms, and the compounds obtained are then optionally converted into a pharmacologically acceptable acid addition salt.

The benzylideneamines of the general formula (IIa) are reduced preferably by means of complex metal hydrides, in particular alkali metal hydrides or alkali borohydrides, in an inert solvent at temperatures between 200 ° C. and 1500 ° C., preferably between 300 ° C. and 1000 ° C., in particular between 350C and 650C.

Suitable complex metal hydrides are, for example, lithium aluminum hydride, Sodium bis (2-methoxyethoxy) aluminum dihydride, lithium tri-tert-butoxy aluminum hydride or sodium borohydride.

Suitable solvents are aliphatic and cyclic ethers, such as Diethyl ether, tetrahydrofuran or dioxane, or also lower alcohols.

If R "in the general formula (IIa) represents n-alkyl with 1 to 5 Carbon atoms, then it is a matter of a Schiff's reduction Base. If this reduction is carried out with a complex metal hydride, then used in general, 0.5 times the molar amount of hydride. If necessary, can the amount of reducing agent can also be increased.

The reduction of the Schiff's base can also be carried out on a nickel-diatomite catalyst in lower alcohols at temperatures of generally 200 ° C. to 1000 ° C., preferably 600 C to 850 C, and at an excess hydrogen pressure of generally about 0 to 20 bar, preferably about 5 to 15 bar, can be carried out.

Halogen-substituted benzylamines of the general formula (Ia), in which R "is n-alkyl having 1 to 5 carbon atoms, can also be obtained by hydrogenating a mixture of an aldehyde of the general formula (Illa) wherein X 'and Y' have the meanings given above, with an n-alkylamine having 1 to 5 carbon atoms in the alkyl group at room temperature in a hydrogenation autoclave at an excess pressure of about 50 to 100 bar, preferably about 60 to 80 bar, with Raney Produce nickel in a one-pot reaction.

If R "in the general formula (IIa) stands for a hydroxyl group, then this is the reduction of an oxime. When using a complex metal hydride is expediently the simple one in such a case molar amount of metal hydride applied.

The reduction of such an oxime to the respective primary benzylamine can also be used as active as possible by catalytic hydrogenation Reach catalysts that contain nickel, palladium, platinum, rhodium or aluminum. Examples are Raney nickel, platinum-carbon, palladium-carbon or rhodium-aluminum oxide. To suppress the formation of secondary amines, the reaction temperature is as low as possible worked. Such hydrogenations are normally also carried out at elevated pressure. The solvents used are generally lower alcohols, mixtures of Alcohol and water or glacial acetic acid.

The compounds of the general formula (liga) can also be used directly in halogen-substituted benzylamines of the general formula (Ia), in which R is hydrogen is to be converted by placing them in the presence of excess ammonia and in Presence of a lower alcohol as a solvent at temperatures of 200 ° C up to 1000 ° C., preferably from 400 ° C. to 700 ° C., with Raney nickel under a hydrogen pressure from about 50 to 100 bar, preferably about 80 to 100 bar, of a catalytic hydrogenation undergoes.

The starting materials required in the above processes of the general Formulas (IIa) and (IIIa) are known or can be prepared by processes known per se.

With regard to known processes that are also used in an analogous manner for production the halogen-substituted benzylamines of the general formula (Ia) and the related thereto required starting materials and intermediates of the general formulas (IIa) and (IIIa) can be applied, for the sake of completeness we refer to J. Chem. Soc. 1499 (1953) J. Pharm. Soc. Japan 75, 1161 (1955), Sidgwick, M.V., "Organic Chemistry ofNitrogen '(1937), Clarendon Press, Oxford, Great Britain, and Sven. Kem. Tidskr. 61, 242 (1949) referenced.

Depending on the process conditions and the work-up, one obtains the halogenated benzylamines of the general formula (Ia) either in free form or in the form of their acid addition salts with both organic and inorganic Acids. Such salts can by known conversion of the corresponding free bases can be prepared with the respective acids. Can from the salts if desired, the respective free bases are formed by the Salts treated, for example, with alkali metal bases or ion exchangers. To the Acids suitable for salt formation have already been mentioned above.

Examples (I) Preparation of compounds of the general formula (Ia) by reducing the imines or oximes of the general formula (IIa) with LiAlH4 0.02 mol of imine or 0.01 mol of oxime of the formula (IIa) are dissolved in 30 ml of anhydrous ether dissolved and added dropwise to a suspension of 0.01 mol LiAlH4 in 20 ml of anhydrous ether. After refluxing for 2 hours, cool and carefully pour ice water hydrolyzed. The ether is separated off, dried with sodium sulfate and the precipitate Benzylamine in the form of a common salt, such as the hydrochloride with ethereal hydrogen chloride. After suction, for example, methanol / ether recrystallized. To represent the benzylamines over the oximes is recommended the use of tetrahydrofuran as a solvent before the precipitation of the Salt is expediently replaced by ether. The yields at this stage of the process are on average around 90%.

Preparation of the imine or oxime precursors of the general formula (IIa) a) Preparation of the imines (formula (IIa), R '= n-alkyl with 1 to 5 carbon atoms) 0.025 mol of the respective benzaldehyde of the formula (IIIa) are mixed with 0.03 mol of n-alkylamine offset. The mixture is left to stir at 200 ° C. for 1 hour. In the synthesis of N-methyl-benzylideneamines additional heating to 800C under reflux is recommended.

The imine is then taken up in chloroform and dried with sodium sulfate and, after the solvent has been stripped off, distilled in vacuo. The yields at Imine (Schiff's base) are almost quantitative. b) Manufacturing the oxime (formula (IIa), R '= OH) To an ethanolic solution of 0.1 mol of the 0.1 mol of hydroxylammonium chloride is first added to the respective benzaldehyde of the formula (IIIa) and then 0.05 mol of potassium hydrogen carbonate, each in an aqueous solution. That Oxime formed is extracted with ether, if necessary, after the alcohol was removed in a rotary evaporator. The yields are almost quantitative.

(III) Preparation of the aldehyde of formula (IIIa) wherein X 'is fluorine and Y 'stands for chlorine 3-chloro-5-fluoro-benzaldehyde a) 3-amino-5-nitro-benzyl alcohol The ammonium sulfide solution required for this reaction is prepared by Na2S.9 9 H10 (96.0 g, 0.4 mol) and NH4Cl (85.6 g, 1.6 mol) each in 250 ml of methanol dissolves, combines the solutions and filtered off the precipitated sodium chloride. The ammonium sulfide solution is then allowed to reflux over 30 minutes Flow a boiling solution of 3,5-dinitrobenzyl alcohol (39.6 g, 0.2 mol) in methanol and refluxed for a further 5 hours. The batch is then increased to 200 ml concentrated, cooled, the precipitated sulfur separated off, with 2N hydrochloric acid strongly acidified and stripped off the methanol.

The unreacted 3,5-dinitrobenzyl alcohol can be etherified and be used again. The hydrochloric acid solution is made alkaline and the product etherified. Intense yellow crystals with a melting point of 91.50 ° C. are obtained in a yield of 62%. b) 3-Chloro-5-nitro-benzyl alcohol To form a copper salt solution dissolve CuCl2 (20.2 g, 0.15 mol) and CuCl (0.12 g, 0.0012 mol) in 40 ml of 20% strength Hydrochloric acid and make up to volume with 10% hydrochloric acid from 270 ml.

The 3-amino-5-nitro-benzyl alcohol obtained in step a) above is then made into paste (16.8 g, 0.1 mol) with 35 ml of water and dissolve with 35 ml of 30% hydrochloric acid. It is then diazotized with sodium nitrite (7.25 g, 0.105 mol). The diazonium salt solution is filtered, brought to a volume of 130 ml with 10% hydrochloric acid and slowly added to the 600 C warm copper salt solution with vigorous stirring.

This temperature is maintained for 1 hour. Then lets are allowed to cool overnight, the product crystallizing out. The 3-chloro-5-nitro-benzyl alcohol obtained is separated from the hydrochloric acid solution with ether. The organic phase is with Washed water and 2N sodium hydroxide solution, dried and stripped off. The product is purified by column chromatography, which gives yellowish crystals with a melting point of 78.50C in a yield of 54%. c) 3-amino-5-chlorobenzyl alcohol Add 3-chloro-5-nitro-benzyl alcohol (1.9 g, 0.01 mol), iron powder (2.24 g, 0.04 Mol) and 50 ml of ethanol in a flask equipped with a stirrer, reflux condenser and gas inlet tube is provided, and passes in hydrogen chloride gas until there is no exothermic reaction is observed more. The ethanol is replaced by water.

The acidic, aqueous solution is etherified in order to recover the starting product. The water phase is then made alkaline with 2N sodium hydroxide solution and etherified Product from. This leads to colorless crystals with a melting point of 86.50C in a yield of 81%. d) 3 -Chlor-5-hydroxymethyl-phenyl-diazonium-tetrafluorobe orate Dissolve the 3-amino-5-chlorobenzyl alcohol (15.7 g, 0.1 mol) in 92 ml of 48% strength Tetrafluoroboric acid and cools down to -50C. Then a solution of sodium nitrite (6.9 g, 0.1 mol) was added dropwise in water. After the diazonium salt has precipitated in The refrigerator is suctioned off, washed with cold HBF4, ethanol and ether and dried carefully about P2Os. This is how you get yellow crystals with a Decomposition point of 1000C in a yield of 64%. e) 3-chloro-5-fluoro-benzyl alcohol Small portions of the diazonium tetrafluoroborate salt are heated in an oil bath for so long until there are no more fog from BF3. After adding water, shake with Ether off, the ether washes neutral and the solvent is removed. The cleaning takes place via column chromatography. In this way one arrives at an oil with a boiling point of 2380C in a yield of 25%. fl 3-chloro-5-fluoro-benzaldehyde Active manganese dioxide (21.7 g, 0.25 mol) and 200 ml of benzene are combined and heated under reflux with a water separator for 2 hours. Then you add the benzyl alcohol (0.05 mol) and heated to boiling for 24 hours. The brownstone is filtered off and the benzene carefully distilled off, resulting in colorless Crystals with a melting point of 1400 C reached in a yield of 73%.

The new compounds prepared in the above manner of the general Formula (Ia) are summarized in Table Vil below. The hydrochloride these compounds are colorless crystals. In Table VII is in brackets after the melting point, the solvent indicated for the recrystallization has been used. The yields given therein are based on those used in each case Aldehyde of the formula (IIIa) based.

Table VII Example X Y R Melting Point of Hydro- Yield in No. chloride (solvent% of theory during recrystallization)] F H CH3 2060 C (methanol / ether) 56% 2 Cl C1 CH3 193.50C (methanol / ether) 79% 3 Cl Cl C2H5 2480C (Methanol / ether) 67% 4 Cl Cl n -C3H7 2640C (methanol / ether) 77% 5 Cl Cl n -C4H9 2480C (Methanol / ether) 75% 6 F F CH3 23 10C (methanol / ether) 49% 7 F F C2H5 209-2100C (Methanol / ether) 47% 8 F F n-C3H7 2590 C (methanol / ether) 48% 9 F F n-C4H9 2810 C (methanol / ether) 50% 10 F F n -CsHIl 2770 C (methanol / ether) 45% 11 F Cl H 2110C (Methanol / ether) 41% 12 F Cl CH3 1500C (methanol / ether) 23% 13 F Cl C2Hs 192.50 C (methanol / ether) 45% 14 F Cl n -C3H7 2490 C (methanol / ether) 51% 15 F Cl n -C4H9 2610 C (methanol / ether) 47% - blank page -

Claims (3)

Claims: 1. Medicines for combating mycobacteriosis, in particular tuberculosis and leprosy, in the form of a combination of at least two active ingredient components (A) and (B) and customary pharmacologically acceptable auxiliaries, the active ingredient component (A) consisting of at least one of the compounds 4,4 ~ Diaminodiphenyl sulfone, p-aminosalicylic acid, streptomycin, rifampicin, benzaldehyde thiosemicarbazone, trimethoprim or isonicotinic acid hydrazide or a pharmacologically acceptable acid addition salt thereof is selected, characterized in that the active ingredient component (benzylamine-substituted) of the general formula (B) is selected from where R is hydrogen or n-alkyl having 1 to 5 carbon atoms and X and Y are identical or different and are hydrogen, fluorine, chlorine or bromine, but X and Y cannot be hydrogen at the same time, or there is a pharmacologically acceptable acid addition salt thereof . 2. Medicament according to claim 1, whose active ingredient component (A) from at least one of the compounds 4,4'-diaminodiphenyl sulfone, p-aminosalicylic acid, Streptomycin or rifampicin or a pharmacologically acceptable acid addition salt is selected therefrom, characterized in that the active ingredient component (B) from at least one of the compounds N-butyl-3-fluorobenzylamine, N-butyl-3,5-difluorobenzylamine, N-methyl-3-fluorobenzylamine, N-methyl-3-chlorobenzylamine, N-methyl-3-chloro-5-íluorobenzylamine, N-butyl-3-chloro-5-fluorobenzylamine, N-propyl-3-chlorobenzylamine, N-propyl-3, 5-dichlorobenzylamine, N-methyl-3-bromobenzylamine, N-methyl-3,5-dichlorobenzylamine or 3,5-dichlorobenzylamine consists. 3. Medicament according to claim 1, the active ingredient component (A) of which consists of 4,4'-diaminodiphenylsuffon and / or rifampicin or a pharmacologically acceptable acid addition salt is selected therefrom, characterized in that the active ingredient component (B) from N-butyl-3,5-difluorobenzylamine, N-methyl-3,5-dichlorobenzylamine or N-methyl-3-chlorobenzylamine or a pharmacologically acceptable acid addition salt. The fight against diseases caused by bacteria is a problem that still exists with the previously known antibacterial agents can not be solved satisfactorily and thus not solved in the long term can be. Because there is a multitude of the most diverse bacteria, and this one also have the ability to withstand prolonged treatment with a certain Drugs or a combination of different active substances cause resistance to be able to develop against the respective means. This therefore loses its effectiveness over time certain bacteria more and more and finally loses them practically completely. Alone For this reason alone, new antibacterial agents have to be constantly developed and examined for their effectiveness against a wide variety of bacteria will. The above applies overall and especially for mycobacteria, those for the various grouped under the collective term mycobacteriosis Diseases are causative. Such diseases are for example tuberculosis, as the causative agent Mycobacterium tuberculosis, or leprosy, as the causative agent the Mycobacterium leprae applies. It is not uncommon for several patients to be on the same patient Mycobacteriosis before, so that there are, for example, leprosy patients with tuberculosis or vice versa or that for example leprosy patients or tuberculosis patients suffer from additional mycobacteriosis caused by atypical mycobacteria will. Such atypical mycobacteria include, for example, Mycobacterium avium, Mycobacterium marinum, Mycobacterium smegmatis or Mycobacterium lufu. To the Appropriate antifungal drugs for treating leprosy and / or tuberculosis should therefore not only have a satisfactory effect over the essential show causative mycobacteria, namely against Mycobacterium leprae or Mycobacterium tuberculosis, but also against various other atypical mycobacteria be sufficiently effective. The Mycobacterium leprae, which is primarily responsible for leprosy, leaves unfortunately not yet breed in cultures. For leprosy tests you must therefore used mycobacteria similar to Mycobacterium leprae and cultivated in cultures will. Mycobacterium has been used as such a leprosy test model for years marinum, which is one of the atypical mycobacteria of Runyon group I. (Drug Research 22, 1235 (1972)). Even more than the Mycobacterium marinum is similar to Mycobacterium leprae, but the one - albeit not yet fully classified - Mycobacterium lufu, which is therefore also suitable as a leprosy test model (chemotherapy 29, 58 (1983) and Int. J. Lepr. 48, 330 (1980)).