NO178108B - Salts of hydrazones, pharmaceutical preparations containing the salts and the use of the salts - Google Patents

Abstract

The invention relates to acid addition salts of bases of the formula I <IMAGE> in which A, R1, R2, R3, R4, R5, X and Z have the meanings given in the description, with an acid [PA], which denotes a mono- or polybasic acid selected from carbonic acid, alkanoic acids which are unsubstituted or monosubstituted to polysubstituted, apart from formic acid, unsubstituted acetic acid, lysine and arginine; alkenoic acids which are unsubstituted or substituted, apart from unsubstituted fumaric acid, cycloalkylcarboxylic acids, arylcarboxylic acids, aryl-lower alkylcarboxylic acids in which lower alkyl is unsubstituted or substituted, aryl-lower alkenylcarboxylic acids, heterocyclylcarboxylic acids, alkanesulphonic acids which are unsubstituted or substituted, apart from unsubstituted methanesulphonic acid, aromatic sulphonic acids, alkylsulphuric acids, N-substituted sulphamic acids, organic acids without carboxyl, sulpho, sulphate or phospho groups, and further from pyrophosphoric acid and hydrogen iodide; and tautomers thereof. The acid addition salts are employed for the treatment of disorders which respond to inhibition of S-adenosylmethionine decarboxylase.

Description

The present invention relates to acid addition salts of bases with Formula I

where A stands for a direct bond or -(CE2)-; X represents a residue -C(=Y )-NR 6 R 7 ; Y stands for NR8; Z stands for XRq.; and R 2 independently of one another is hydrogen, lower alkyl or lower alkoxy; the radicals R 3 , R 4 , R 6 , R g and R g stand independently of each other for hydrogen or lower alkyl; and R 5 and R 7 independently represent hydrogen, lower alkyl or hydroxy;

with an acid [PA] , which means a mono- or polyprotic acid selected from alkanoic acids which are unsubstituted or mono- or poly-substituted with hydroxy, with carboxy or with hydroxy and carboxy; besides formic acid, unsubstituted acetic acid, benzoic acid which is unsubstituted or substituted by hydroxy, benzenesulfonic acid, naphthalene-1,5-disulfonic acid and N-substituted cycloalkylsulfamic acids,

pharmaceutical preparations containing these acid addition salts and the use of these acid addition salts for the production of pharmaceutical preparations.

Tautomers can occur when Z stands for XRc and R3 and/or R4 and/or Rg stands for hydrogen.

The corresponding guanyl residue, prepared in Formula I as -N(R3)-C(=Z)-NR4Rg, can then e.g. also exist in the tautomeric forms -N=C(-ZH)-NR4R5, -N(R3)-C(-ZH)=XR5 or -N(R3)-C(-ZH)=NR4.

If e.g. Y stands for NRg and R5 and/or R7 for hydrogen, the corresponding amidine structures which in Formula I are defined as X =-C(=Y^NR^Ry, can also exist in the tautomeric forms -C(-YH)=NR7 or -C(-YH)=NR6. The person skilled in the art is familiar with the existence of such and similar tautomers. All these tautomers are encompassed by the general Formula I.

If A stands for a group -(CH2)- and R2 is different from hydrogen, the substituents corresponding to the residue or residues R2 can also be associated with the carbon atoms in the group -(CE2)#

R2 stands for e.g. for hydrogen or 1 to 4 substituents different from hydrogen, preferably for hydrogen or one to two substituents different from hydrogen, and primarily for hydrogen or a substituent different from hydrogen.

Ri stands for e.g. for hydrogen or one to three substituents other than hydrogen, and preferably for hydrogen or one to two substituents other than hydrogen.

The general terms used above and below preferably have the following meaning within the scope of the present description: The following definitions relate to the residues mentioned in the base with Formula I.

Lower alkyl is e.g. n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably ethyl or methyl, primarily methyl. A substituent other than hydrogen is lower alkyl or lower alkoxy.

The following definitions relate to the acids [PA] ([PA] stands for "Protic Acid"): Alkanoic acids are primarily Ci-C2o-alkanoic acids with the exception of formic acid and unsubstituted acetic acid, such as propionic acid, butyric acid, isobutyric acid, pentanoic acid, hexanoic acid or heptanoic acid, or furthermore octanoic acid, decanoic acid or dodecanoic acid, especially propionic acid or octanoic acid, when these acids are unsubstituted or substituted one to several times, especially one to six times, with hydroxy, either once as glycolic acid, lactic acid or 2-hydroxybutyric acid, or several times e.g. up to five times, as gluconic acid or glucose-monocarboxylic acid ("Glucoheptonic Acid"), with carboxy, e.g. in C2-C2q-alkanedic acid, primarily C2-Cy-alkanedic acid, such as succinic acid, or further adipic acid, pimelic acid, suberic acid or azelaic acid, or with hydroxy and carboxy, such as malic acid, tartaric acid, citric acid, glucaric acid or galactaric acid.

Important acids are octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glucose monocarboxylic acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glutaric acid, galactaric acid, benzoic acid, salicylic acid, 1- or 3-hydroxy-naphthyl-2-carboxylic acid, benzenesulfonic acid, 1,5-naphthalenedisulfonic acid or X-cyclohexylsulfamic acid.

Particularly important acids are octanoic acid, succinic acid, adipic acid, salicylic acid, benzenesulfonic acid, 1,5-naphthalenesulfonic acid or N-cyclohexylsulfamic acid, especially salicylic acid or primarily adipic acid or benzenesulfonic acid.

Very important acids are likewise tartaric acid, especially L-tartaric acid, lactic acid or citric acid.

The mentioned acids can, especially if they contain several acid groups with different acidity which can dissociate protons, also exist as mixed salts with cations, e.g. alkali metal cations, such as sodium or potassium ions, alkali metal salts, such as magnesium salt or zinc salts, where at least one dissociable proton is contained in the acid component for the reaction with the mixed salts, or they may be present in the mixed salts in a form where not all the protons are released, at least one proton is admittedly transferred to the base with Formula I. Thus, for example, carboxylic acids can be used as bicarbonate salts, such as sodium or potassium bicarbonate.

The acid addition salts of a base of Formula I with an acid [PA] can also exist as hydrates. Crystals can also contain other solvents that are used for crystallization.

Depending on the structural conditions, the acid addition salts according to the invention can exist in the form of isomer mixtures or as pure isomers. If e.g. R 2 stands for a substituent different from hydrogen, then the corresponding acid addition salts with Formula I can exist as racemic salts or enantiomeric salts or also as diastereomeric salts, e.g. in the presence of acids with asymmetric centers, such as the aforementioned amino acids, lactic acid or tartaric acid.

The aim of the present invention is to provide new acid addition salts of pharmacologically usable compounds which have a good solubility in physiological fluids and/or fluids which are compatible with physiological fluids, such as physiological sodium chloride solution, mannitol solution or phosphate buffer, and/or show good resorbability by enteral , such as oral delivery, for example by forming ion pairs, such as lipophilic ion pairs.

The acid addition salts of the invention show valuable pharmacological properties. In particular, they show a strong, specific inhibition of the enzyme S-adenosylmethionine decarboxylase (SAMDC). SAMDC plays an important role as a key enzyme in polyamine synthesis, which occurs in virtually all mammalian cells, including humans. Through SAMDC, the polyamine concentration in the cell is regulated. An inhibition of the enzyme SMDC results in a reduction of the polyamine concentration. A reduction of the polyamine concentration results in an inhibition of cell growth, it is possible to inhibit growth in both eukaryotic and prokaryotic cells by delivering SAMDC-inhibiting substances, and even kill cells or inhibit the start of cell differentiation.

The inhibition of the enzyme SAMDC can, for example, be examined by the method according to H.G. Williams-Ashmann and A. Schenone, Biochem. Biophys. Res. Communs. 46, 288 (1972). The acid addition salts according to the invention here show IC5g values of a minimum of 0.005 jjM and less.

A further advantage of the acid addition salts of the invention is that, compared to their strong inhibitory effect on SAMDC, they only slightly inhibit the diamine oxidase and are easily digestible. The inhibition of the diamine oxidase is according to J. Jaenne and D.R. Morris, Biochem. J. 218, 974 (1984) unfavorable, as this may lead to accumulation of putrescine and an indirect SAMDC activation.

Moreover, the acid addition salts of Formula I are e.g. applicable for the treatment of benign and malignant tumours. It can cause tumor regression and also prevent the spread of tumor cells as a result of a metastasis formation as well as the growth of micrometastases. They can also serve e.g. for the treatment of protozoan infection, such as trypanosomiasis, malaria or lung disorders caused by pneumocystis carinii. As selective SAMDC inhibitors, the acid addition salts of bases of Formula I with an acid [PA] can be used alone or also in combination with other pharmacologically active substances. It is conceivable, e.g. a combination with (a) easier of other enzymes of the polyamine biosynthesis, e.g. ornithine decarboxylase inhibitors, (b) protein kinase C inhibitors, (c) tyrosine protein kinase inhibitors, (d) cytokines, (e) negative growth regulators, (f) aromatase inhibitors, (g) antiestrogens or (h) classic cytostatic agents.

The invention relates primarily to the acid addition salts of bases with Formula I where A is a direct bond, X is a residue -C(=NH)-NH2; Z stands for NH; and R 1 , R 2 , R 3 , R 4 and R 5 represent hydrogen; and [PA] is selected from among the above-mentioned acids, or preferably one of the acids defined above as important, for example one defined as very important, e.g. one of the acids selected from N-cyclohexylsulfamic acid, octanoic acid, salicylic acid or benzenesulfonic acid, such as salicylic acid.

The invention primarily also relates to the acid addition salts of bases with Formula I, where A stands for a direct bond, X stands for a residue -C(=NH)-NH2; Z stands for NH; and R 1 , R 2 , R 3 , R 4 and R 5 represent hydrogen; and [PA] is preferably one of the acids defined above as very important, particularly selected from tartaric acid, primarily L-tartaric acid, lactic acid and citric acid.

Most preferred are the acid addition salts of bases of Formula I with an acid [PA] mentioned in the examples.

The acid addition salts of bases with Formula I with an acid [PA] can be prepared according to methods known per se, for example by

a) reacts a base with Formula I

where the residues have the meanings mentioned for the acid addition salts of bases of Formula I, with an acid [PA], where [PA] has the meaning given above, or

b) condense a compound with Formula

wherein the group represents carbonyl, functionally converted carbonyl or protected carbonyl and A, X, and R 2 have the meanings given for the acid addition salts of Formula I, with an amine of Formula where Z, R 3 , R 4 and R 5 have the meanings given for acid addition salts of bases of Formula I, in the presence of an acid [PA] with the aforementioned meanings, or c) with a compound of the Formula

where W3 stands for a residue that can be transferred to a group X

in a base of Formula I and A, Z, R^, R2, R3, R4 and R5 are as defined under Formula I, the residue W3 in the presence of an acid [PA] of the above-mentioned meaning transfers to the group X; or

d) converts a desired acid addition salt of a base of Formula I with an acid, which does not fall within the definition

[PA], to an acid addition salt of a base of Formula I with an acid [PA] as defined above;

and, when desired, converts a desired acid addition salt of a base of Formula I with an acid [PA] into another acid addition salt of a base of Formula I with an acid [PA] , and/or, when desired, purifies the mixture of isomers into ce individual isomers.

In the following detailed description of the methods a) - d), the symbols A, X, Y, Z, R^Rg and [PA] have the indicated meanings for the definitions of acid addition salts of bases of Formula I with acids [PA], unless otherwise stated indicated.

Procedure a)

In the reaction of a base of Formula I with an acid [PA], the corresponding acid addition salt will follow per se known methods for forming acid addition salts of basic compounds.

The conversion to acid addition salt takes place, for example, in solvents, especially in organic solvents, especially in polar organic solvents, primarily in esters, e.g. lower alkanoyl-lower alkyl esters, such as acetic acid ethyl ester, in amides, e.g. N,N-dilower alkyl-lower alkyl amides, such as dimethylformamide, such as alcohols, e.g. hydroxyl lower alkanes, such as methanol, ethanol, ethylene glycol or glycerin, or aryl alcohols, such as phenols, e.g. phenol, or in diethylsulfoxides, in the absence or presence of water, preferably in the absence of water. Particularly preferred is the reaction in alcohols, such as the last mentioned hydroxyl lower alkanes.

The conversion takes place, for example, in free solution, but can also take place on chromatographic columns, e.g. by gel filtration or by ion exchange, or over semipermeable membranes by osmotic process.

The reaction follows at temperatures between the freezing and boiling points of the current solution, preferably between 0 and 50°C, preferably between 20 and 40°C, e.g. at room temperature, in the presence or absence of a shielding gas, such as nitrogen or argon.

The compounds of Formula I and the acid [PA] are added in appropriate molar ratios, or the acid [PA] is added in excess. Preferably, the individual components are added in a molar ratio, when the ratio corresponds to the polarity of the base with Formula I and the acid [PA] in the acid addition salt according to the invention.

The formed salt, for example, falls out by itself, possibly only after cooling, or they are precipitated by the addition of solvents, especially non-polar solvents, e.g. ethers, such as diethyl ether, or of water and/or recovered by partial or complete evaporation.

Procedure b)

As functionally transformed respectively protected carbonyl can be mentioned, for example: dilavereal oxymethyl, C1-C2-alkylenedioxymethyl, dihalomethyl, dilaverealkylthiomethyl or C1-C2-alkylenedithiomethyl.

Preferably, the group CW^W2 is present as free carbonyl in the compound with Formula II.

The condensation reaction according to Method (b) takes place under conditions known per se when forming hydrazones and is carried out in the presence of an acid [PA], which is also catalytically active. [PA] is preferably present in an amount such that the protonation of the reactive amino group in the compound with Formula III occurs only to such a small extent that it is still reactive. Particularly preferred here are the starting compounds added as salts of the acid [PA], as long as it contains salt-forming groups, which are possibly produced in situ, either from the free compound or salts of easily volatile acids, such as hydrohalic acid, e.g. HBr or HC1, formic acid, acetic acid or carboxylic acid (as a carbonate or bicarbonate salt), where the reaction can for example also take place in the presence of a catalytically effective small excess of the acid [PA]. Preferably, one of the solvents that was mentioned under method a) finds use as a solvent, especially an aqueous solvent, such as water, at preferred temperatures from 20° C to the boiling point of the reaction mixture in question, especially at the boiling point of the mixture in question, in presence or absence of a shielding gas, such as nitrogen or argon. For compounds of Formula I such protective carbonyl groups CW^V^ are suitable which, under the conditions of the condensation, convert to free carbonyl.

For the preparation of acid addition salts from a base of Formula I, where R5 is amino, and an acid [PA], it is advisable to add the compound of Formula III in excess.

Procedure c)

In the intermediate products with Formula IV, W3 stands for e.g. for free or functionally converted carboxy, especially halogenocarbonyl, cyano, imino-lower alkyl-thiocarbonyl, imino-lower alkyl-thiocarbonyl or thiocarbamoyl.

The group W3 in a compound with Formula IV can, in the preparation of amidines with Formula I (Y^NRg), e.g. means: an acid addition salt of an imino-lower alkyl ester ("iminola lower alkyl ether") or imino-lower alkyl thioester with one of the mentioned acids, e.g. -C(=KH)-OC2B5•[PA] or -C(=NH) -SC2H5*[PA], besides thiocarbamoyl or cyano.

In the reaction of an imino-lower alkyl ester of Formula IV (as a salt of one of the acids [PA] as defined above) with ammonia or primary resp. secondary amines, the unsubstituted or The mono- or disubstituted acid addition salts of the corresponding amide according to Formula I. Cyano compounds (IV) can e.g. be transferred by the reaction with a primary or secondary (di-)lower alkyl ammonium salt of one of the aforementioned acids [PA] in an optional mono- or disubstituted acid addition salt of an amidine of Formula I.

The carboxylic acid ester agent is obtained, e.g. by acid-catalyzed deposition of alcohols in the nitrile with Formula IV. From the ester imide, the acid addition salts of the amide with Formula I are obtained by means of a Pinner cleavage through thermal cleavage of the ester imide salt with acids [PA] at temperatures above about 80°C.

Acid addition salts of bases of Formula I, where X stands for a residue -C(=NH)-NRfcR7 with acids [PA] , can also be obtained by reacting compounds of Formula IV or their acid addition salts with one of the above-mentioned acids [PA ], where W3 is the residue-C(=S)-NH2, during S-alkylation, e.g. with trilower alkyloxonium tetrafluoroborate, and then reaction with an ammonia salt of one of the aforementioned acids [PA] or the corresponding acid addition salt of an amine of Formula XHR5R7 and the aforementioned acids [PA].

The reactions specified under c) can be carried out under known reaction conditions, unless otherwise specified, in the absence or usually in the presence of a solvent or diluent, preferably such as are inert to the reagents used and dissolve these, in or the presence of catalysts, catalyst agents or neutralizing substances, depending on the type of reaction and/or the reactants at lowered, normal or elevated temperature, e.g. in the temperature range from about -70°C to about 190°C, preferably from about -20°C to about 150°C, e.g. at room temperature or at the boiling point of the solvent used in the solvent mixture, under atmospheric pressure or in a closed vessel, optionally under pressure, and/or in an inert atmosphere, e.g. under nitrogen atmosphere.

Procedure d)

The reaction of the desired acid addition salt from a base of Formula I with an acid, which does not fall within the definition of

[PA], is carried out according to usual methods for the conversion of salts.

Acids that do not fall under the definition of [PA] include all further protonic acids, for example organic acids that do not fall under the definition of [PA], such as formic acid, acetic acid, methanesulfonic acid, or inorganic acids, such as sulfuric acid, halogen hydrogen acids, such as HF, HC1, HBr or HI, besides hydrogen nitrous or phosphoric acid. Particularly preferred are salts of hydrohalic acid.

The conversion of these salts of acids that do not fall under the definition of [PA] to acid addition salts of an acid [PA] takes place, for example, in solvents, especially in organic solvents, preferably in polar organic solvents, primarily esters, e.g. lower alkanoyl-lower alkyl esters, such as ethyl acetate, in amides, e.g. N,N-dilower alkyl lower alkyl amides, such as dimethylformamide, in alcohols, e.g. hydroxyl lower alkanes, such as methanol, ethanol, ethylene glycol or glycerin, or aryl alcohols, such as phenols, e.g. phenol, or dimethyl sulfoxide, in the absence or presence of water, preferably in the absence of water. Particularly preferred is the reaction in alcohols, such as the last-mentioned hydroxyl lower alkanes.

The reaction can also take place over the free radicals in Formula I, which are, for example, produced by transferring the acid salt of a base of Formula I with an acid that does not fall under the definition of [PA], which is used as the starting material, by means of a base, e.g. a hydroxy base, such as an alkali hydroxide, e.g. NaOH or KOH, in aqueous solution in the presence or absence of an organic solvent, as defined under a), to the free base; the following transformation of the free base follows, for example, as described under Method a).

The compound of Formula I and the acid [PA] were added in the aforementioned reaction in suitable molar ratios, or the acid [PA] was added in excess. Preferably, the individual components were added in the molar ratio which corresponds to the ratio in molarity of the base with Formula I and the acid [PA] in the acid addition salts according to the invention.

The reaction takes place at temperatures between the freezing and boiling points of the solution used, preferably between 0 and 50°C, preferably between 20 and 40°C, e.g. at room temperature, in the presence or absence of a shielding gas, such as nitrogen or argon.

The formed salts precipitate themselves, for example possibly after cooling, or they are precipitated by the addition of a solvent, especially non-polar solvents, e.g. ether, such as diethyl ether, or water and/or recovered by partial or complete evaporation.

Additional procedures - precautions.

Acid addition salts of a base of Formula I with an acid [PA] can be transferred to acid addition salts of other bases of Formula I and/or other acids [PA], whereby known methods find application.

This can happen, for example, by converting the acid [PA] , the base with Formula I or both components in the acid addition salt.

For example, the acid component [PA] can be extracted, either directly by transfer in the presence of an acid [PA] to be introduced, such as e.g. can be added in excess, or by direct transfer of the acid addition salt, which is used as starting material, which contains base with Formula I, to the free base, for example by reacting the acid addition salt of the base with Formula I, which was used as starting material, with a base, preferably a hydroxy base, such as an alkali hydroxide, such as e.g. NaOH or KOH, in aqueous solution in the near, or preferably absence, of an organic solvent as defined under a), in the free base and then converting the free base according to method a) into another acid addition salt with Formula I, besides via dialysis, using ion exchange or gel chromatography.

Also the base of Formula I in an acid addition salt consisting of a base of Formula I and an acid [PA] can be transferred to another base according to Formula I.

A base of Formula I in an acid addition salt with an acid [PA] , where X is a residue of Formula -C(=XH)-XH-OH, can be transferred by reaction in the presence of a base, such as triethylamine, and an oxidizable reagent, such as iron pentacarbonyl, in an organic solvent, such as tetrahydrofuran, at an elevated temperature, preferably the boiling point of the reaction mixture, and subsequent reaction of the product formed with the same acid [PA] to the acid addition salt of a base of Formula I, where the residue X represents -C(=NH)-XH2• where [PA] is unchanged compared to the starting salt.

Mixtures of isomers formed according to the invention can be purified in a known manner into the individual isomers, racemates, e.g. by forming salts with optically pure salt-binding reagents and by separating the diastereomer mixtures thus formed, e.g. by means of fractional crystallization or by chromatography on optically active column material.

In the methods according to the present invention, such starting materials were preferably used which lead to the acid addition salts described above as particularly valuable.

The invention also relates to any embodiment of the methods where one starts from a desired process step from intermediates and performs the missing process steps, or where starting substances are used which under the reaction conditions form or are in the form of a derivative, e.g. a salt.

Pharmaceutical preparations.

The present invention also relates to pharmaceutical preparations which contain one of the pharmacologically active acid addition salts from a base of Formula I with an acid [PA] as active ingredient. Particularly preferred are preparations for enteral, especially oral, as well as parenteral delivery. The preparations contain active substances alone or preferably together with at least one pharmaceutically usable carrier material. The dosage of the active substance depends on the disease to be treated, as well as on the species, age, weight and individual condition, as well as the method of application.

The pharmaceutical preparations contain from about 0.1% to about 95% of the active ingredient, where single-dose application forms preferably contain from about 1% to about 90% and non-single-dose application forms preferably contain 0.1 to about 20% active ingredient. Unit dose forms, such as dragees, tablets or capsules contain from about 1 mg to about 500 mg of the active ingredient.

The pharmaceutical preparations according to the invention are prepared in a known manner, e.g. using conventional mixing, granulating, coating, dissolving or lyophilizing methods. Pharmaceutical compositions for oral use can thus be prepared by mixing the active substance with one or more solid carriers, possibly granulating a formed mixture and processing the mixture respectively. the granulate when desired, possibly with the addition of additional excipients, into tablets or dragon cores.

Suitable carriers are especially fillers, such as sugar, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphate, e.g. tricalcium phosphate or calcium hydrogen phosphate, besides binders, such as starch, e.g. corn, wheat, rice or potato starch, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and/or polyvinyl pyrrolidone, and/or when desired, explosives, such as the above-mentioned starches, besides carboxymethyl starch, cross-linked polyvinyl pyrrolidone, alginic acid or a salt thereof, such as sodium alginate.

Further additives are primarily flow-regulating and lubricating agents, e.g. silicic acid, talc, stearic acid and salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol or derivatives thereof.

Dragon cores can be equipped with suitable, possibly gastric juice-resistant, coatings, where concentrated sugar solutions are used, which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, varnish solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. The tablets or dragon coatings can have dyes or pigments added, e.g. for identification or characterization of different active ingredient doses.

Stingable capsules of gelatin, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerin or sorbitol, are also orally usable compositions. The stick capsules may contain active substances in the form of a granule, e.g. in a mixture with fillers, such as corn starch, binders and/or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycol, where stabilizers may also be added.

Further oral forms of application are e.g. syrups prepared in the usual way, which contain active ingredients, e.g. in suspended form and a concentration of approx. 0.1 to approx. 10%, preferably approx. 1% or another dose such as with measuring spoons of 5 or 10 ml gives a suitable dose. In addition, e.g. powdered or liquid concentrates for making shakes, e.g. in milk, topical. Similar concentrates can also be packaged in single-dose quantities.

Current as rectally usable pharmaceutical preparations are e.g. suppositories, which consist of a combination of the active ingredient with a suppository base. Suitable as a suppository base material is e.g. natural or synthetic triglycerides, paraffin hydrocarbon, polyethylene glycol or higher alkanol.

For parenteral delivery, primarily aqueous solutions of an active substance in water-insoluble form are suitable, e.g. a water-soluble salt, or an aqueous injection suspension, containing viscosity-increasing substances, e.g. sodium carboxymethyl cellulose, sorbitol and/or dextran and any stabilizers. Here, the active substance can be present, possibly together with excipients, also in the form of lyophilisates and is brought into solution for parental delivery by adding suitable solvents. An isotonic solution for infusion can preferably be prepared by adding suitable salts, such as NaCl, buffers, such as phosphate buffer, e.g. with sodium as an excipient, and/or sugar alcohols, such as mannitol, to which further of the auxiliaries mentioned may also be added.

Solutions such as those used for parenteral delivery may also be used as infusion solutions. The invention also relates to a method for treating the above-mentioned disease states which are particularly conditioned by a lack of S-adenosylmethionine decarboxylase inhibition, which is affected by treatment with an inhibitor of S-adenosylmethionine decarboxylase. The acid addition salts according to the invention can be given prophylactically or therapeutically, preferably in amounts suitable for inhibiting the S-adenosylmethionine decarboxylase, if it is used preferably in the form of a pharmaceutical preparation. Thus, for a body weight of about 70 kg, a daily dose of about 1 mg to about 1000 mg, preferably from about 25 mg to 100 mg orally, is given especially against the aforementioned diseases, respectively. 2 to 50 mg parenterally, of an acid addition salt of the present invention, e.g. to a warm-blooded animal such as a human, which needs such treatment, e.g. as it suffers from a protozoan infection or from tumors.

The invention also relates to a pharmaceutical composition suitable for delivery to a mammal, e.g. human for the prevention or treatment of a disease affected by a treatment with an inhibitor of S-adenosylmethionine decarboxylase, in particular a tumor disease or protozoan infection, comprising an amount of an acid addition salt of Formula I or tautomers thereof effective for inhibition of S-adenosylmethionine decarboxylase and a pharmaceutically usable carrier.

Output connections.

The protonic acids [PA] are known, can be prepared by known methods or are also commercially available.

The starting compounds of Formula I are prepared according to known methods by (i) condensing a compound of Formula II, as defined under method a), with an amine of Formula III, as defined under method a), or (ii) a compound of Formula IV, as defined under method c), and transfers the residue W3 to a group X,

and, if desired, converts a formed compound of Formula I into another compound of Formula I, and/or, when desired, converts a formed salt into the free compound or another salt, and/or, when desired, converts a formed free compound of Formula I with salt-binding properties of a salt.

In the following detailed description of the processes i)-ii), the symbols appearing in the formulas A, X, Y, Z and R-^-Ra as well as [PA] have the meaning indicated for the acid addition salts of the base of Formula I with acids [PA], unless otherwise stated.

Procedure (i) :

As functionally transformed respectively protected carbonyl CW-j^» can be mentioned, for example: dilavereal oxymethyl, C1-C2-alkylenedioxymethyl, dihalomethyl, dilaverealkylthiomethyl or C1-C2-alkylenedithiomethyl.

The group CW-]^ is preferably present in the compound with Formula II as free carbonyl.

The condensation reaction according to Method (a) follows under the aforementioned conditions with the formation of hydrazones. They are preferably catalyzed by acid. In the compound of Formula II, such protective carbonyl groups CW3W2 are suitable which, under the conditions of the condensation, turn into free carbonyl. For the preparation of compounds of Formula I, where R5 is amino, it pays to add the compound of Formula III in excess.

The intermediates with Formula I, where Y in the residue X means NH, were e.g. formed by transferring a compound of Formula V

first by treatment with hydrogen sulphide to the corresponding thiocarboxamide [-C(=S )-NH2] . The latter can also be prepared in another way starting from the analogous carboxamide [-C(=0)-NH2], e.g. by reaction with Lawesson's Reagent [2, 4-bis-(4-metosyphenyl)-2, 4-dithioxo-1,3,2,4-dithiadiphos-phetane]. The thiocarboxamide becomes e.g. S-alkylated by lower-alkyl iodide or tri-lower alkyl oxonium tetrafluoroborate and thereby transferred to imino-lower alkyl thioester hydroiodide [-C(=NH)S-alkyl*HI] resp. -tetrafluoroborate, which can easily be transferred by reaction with ammonia or amines of Formula NHRfcRy in the presence of carboximidamide of Formula I [see S. Patai (Ed.), The Chemistry of Amidines and Imidates, Wiley, London etc. 1975, pp. 303-304].

The preparation of the carboxamide of Formula II from the cyano compound of Formula V is analogous to the preparation of carboxamides of Formula I from the cyano compound of Formula IV as described under Method (ii), and is described in detail there.

A further possibility for preparing compounds with Formula II consists in treating a compound with Formula

V, where the group CW1W2 is as defined under Formula II, e.g. with methanol and hydrochloric acid in e.g. chloroform or diethyl ether, whereby the corresponding iminoethyl ester hydrochloride was formed, as e.g. by reaction with ammonia or a primary or secondary amine with Formula XHR6R7 and e.g. methanol, can be converted to the desired carboximidamide of Formula II. Admittedly, these methods can in some cases fail due to steric hindrance by the group A or

The starting compounds of Formula V are known or can be prepared analogously to known compounds.

The connections with Formula V are obvious. e.g. prepared by intramolecular Friedel-Craft acetylation of u-phenyl lower alkanoic acid with Formula VI,

where W 4 is cyano or a cyano precursor, e.g. halogen, especially bromine, or protected amino, e.g. acetylamino.

After the cyclization step, the intermediate cyano step can then be transferred in a known manner to cyano, e.g. bromine by reaction with copper(I) cyanide or acetylamino by removal of acetyl protecting groups, diazotization and reaction with copper(I) cyanide.

Compounds with Formula V, where groups. CV-^ is carbonyl, can be further prepared, e.g. through oxidation, e.g. with chromium trioxide (CrO 3 ), from the corresponding non-carbonyl compound of Formula VII where W 4 is cyano or a cyano intermediate as defined above. If a cyan intermediate step is used, this can be further transferred after oxidation to cyano, e.g. as stated above.

A further possibility for preparing compounds with Formula V, where the group CW^W2 is carbonyl, consists in starting from a compound with Formula II, where X is hydrogen, and introducing the cyano group, for example, through a reaction sequence analogous to US-PS 3,956 .363, Example 10, which consists of nitration, reduction of the nitro group to amino, diazotination and reaction with copper (I) cyanide (Sardmeyer reaction).

The preparation of aminoguanidine, -ureas and -thiourines of Formula III is known. Amino(thio)ureas ["semi(thio)carbazide] are, for example, prepared in an analogous manner to corresponding simple (thio)ureas. There, for example, the corresponding hydrazine with Formula H2X-XEE3 is used instead of amines and for example reacted with an isocyanate of Formula R4N=C=0 or R5N=C=0, an isothiocyanate of Formula R4N=C=S or R5N=C=S, a carbamoyl chloride of Formula R4R5N-COCI or a thiocarbamoyl chloride of Formula R4R5X- CSCI Furthermore, for example, the reaction between a hydrazine of Formula H 2 N-NHR 3 with an acyl isothiocyanate, for example acetyl isocyanate, and subsequent acid hydrolysis is also possible.

Aminoguanidine of Formula III, where Z stands for NRg and R3, R4, R5 and R9 are defined as under Formula I, are known and can be e.g. prepared from corresponding aminothioureas with Formula III, by transferring the latter through alkylation, such as with an alkyl thiosylate or -halide, to the corresponding S-alkylisothiuronium salt and reacting this with an amine of Formula XHR^Rg.

Procedure ( i i) :

In the intermediate products with Formula VI, V3 means e.g. free or functionally converted carboxy, especially halogenocarbonyl, cyano, imino-lower alkylcarbonyl, imino-lower alkylthiocarbonyl or thiocarbamoyl.

The group W3 in a compound with Formula IV can, in the preparation of amidines with Formula II (Y~N~Rg), e.g. mean: an acid addition salt of an imino-lower alkyl ester (~ imino-lower alkyl ether) or imino-lower alkyl thioester, e.g. -C(=NH)-OC2H5-HC1 or -C(=NH)-SC2H5-EI or cyano.

In the reaction of an imino-lower alkyl ester of Formula IV (as salt) with ammonia or primary resp. secondary amines, the unsubstituted or The mono- or disubstituted amidines of formula I. The cyano compounds of formula IV can be transferred e.g. through reaction with an alkali metal amide, e.g. KNE2, or by reaction with a primary or secondary (di )-lower alkylammonium halide, e.g. "'"M^CB^Cl- to an optionally mono- or di-substituted amidine of Formula I.

The carboxylic acid ester imide is formed e.g. by acid-catalyzed deposition of alcohols with the nitrile of Formula IV. From the ester amide, the amide is obtained by a Pinner cleavage by thermal cleavage of the ester imide salt at temperatures above about S0<=>C.

Compounds with Formula IV, where W3 is cyano, can e.g. be produced by reacting a compound of Formula V with a compound of Formula III according to method ii). From compounds of Formula IV, where V/3 is cyano, other compounds of Formula IV, where V/3 is free or otherwise functionally converted carboxy, can be prepared in a known manner or as described above.

Compounds of Formula I, where X is a residue -C(=NH)-NRfcR7, can also be formed by reacting compounds of Formula IV, where V/3 is a residue -C(=S)-NH2 during S-alkylation , e.g. with trilower alkyl oxonium tetrafluoroborate and subsequent reaction with ammonia or an amine of Formula NHR^R7 or a corresponding ammonium salt, e.g. the chloride.

Compounds of Formula I can be transferred to other compounds of Formula I.

Thus, e.g. compounds of Formula I where X is a residue -C(=S)-KH2 be converted by S-alkylation, e.g. with trilower alkyl oxonium tetrafluoroborate, and subsequent reaction with ammonia or an amine of Formula NHR5R7 or preferably a corresponding ammonium salt thereof, to compounds of Formula I, where X stands for a residue -C(=NH)-NR6R7.

Compounds with Formula I, where X stands for an N-hydroxy-amidino residue -C(=NRg)-NHOH, can be converted e.g. by reaction with iron pentacarbonyl[Fe(CO)g] to other compounds of Formula I, where X stands for an analogous amidino residue-C(=NRg)-NH2 (see e.g. B.J. Chem.Soc.Chem.Commun. 1975, 761).

High compounds of Formula I formed according to the invention with salt-forming properties can be transferred to their salts in a known manner, compounds with basic properties e.g. by treatment with acids, either the same protonic acids [PA], or preferably with other protonic acids, for example with organic acids that do not fall under the definition [PA], such as formic acid, acetic acid, methanesulfonic acid, or inorganic acids, such as sulfuric acid, hydrohalic acid , such as HF, HC1, HBr or HI, besides nitric or phosphoric acid. Halohydrogen acid is particularly preferred. The reaction takes place, for example, analogously to method a) for producing acid addition salts of bases with Formula I with acids [PA]. The acid addition salts of bases of Formula I, especially those with protonic acids other than [PA], can also be transferred to the free compounds. This can happen e.g. by transfer to the free base, for example by reacting salts of a compound of Formula I which was used as starting material, with a hydroxy base, such as an alkali hydroxide, e.g. NaOH or KOH, in aqueous solution in the near or, preferably absence, of an organic solvent, as defined under a) in the free base, besides through dialysis, by means of ion exchange or gel chromatography.

The preparation of starting compounds of Formula II, III and IV was prepared according to the description of methods i) and i i).

Due to the close relationship between the compounds of Formula I, II, III, IV and also V, VI and VII in free form and provided that the said compounds contain salt-binding groups in the form of their salts, above and below free compounds respectively their salts also mean the corresponding salts, e.g. acid addition salts or also salts with bases, resp. the free connections.

The preparation of salts, for example of the compounds of Formula II, III and IV with salt-forming groups, is done analogously to the preparation of salts of bases of Formula I (Procedure a).

The compounds, including their salts, may also be formed in the form of hydrate, or their crystals may comprise e.g. the solvent used for crystallization.

Mixtures of isomers formed according to methods i) or ii) can also be separated in a known manner into their individual isomers, racemates e.g. through formation of salts with optically pure salt-forming reagents and separation of the diastereomer mixture thus obtained, e.g. by means of fractional crystallization.

The above-mentioned reactions under method i) or ii) can be carried out under known reaction conditions, in the absence or usually the presence of the solvent or diluent, preferably those which are inert to the reagents used and dissolve them, in the absence or presence of catalysts, condensing agents or neutralizing substances, depending on the type of reaction and/or the reactants at lowered, normal or elevated temperature, e.g. in the temperature range from about 70°C to about 190°C, preferably from about -20°C to about 150°C, for example at room temperature or at the boiling point of the solvent used in the reaction mixture, under atmospheric pressure or in a closed vessel, optionally under pressure, and/or in an inert atmosphere, e.g. under a nitrogen atmosphere.

Below, the preparation of some starting compounds of Formula I is described for purely illustrative purposes. Temperatures are given in degrees Celsius. The following abbreviations are used: abs. = absolute (anhydrous); D20 = deuterated water; DMF = N,N-dimethylformamide; DMSO-d^ = perdeuterated dimethylsulfoxide; ether = diethyl ether; acetic ester = acetic acid ethyl ester; IR = infrared spectroscopy; Temp. = melting point; THF = tetrahydrofuran; MS(FAB) = mass spectrum ("Fast Atom Bombardment"). 1) Output connection A:

4-Amino-1-indanone-2'-amidinohydrazone dihydrochloride

A solution of 3.8 g (27.9 mmol) of aminoguanidine hydrogen carbonate in 200 ml of water and 14.7 ml of 2N hydrochloric acid was heated to 60 °C and, with stirring for half an hour, a solution of 5.85 g (27.8 mmol) of 4-amidino-l- indanone-hydroclofid in 200 ml of methanol. The reaction mixture was refluxed for 24 hours and after cooling evaporated to dryness. The residue was suspended in 50 ml of ethanol, filtered, washed with ethanol and ether and dried. The title compound was obtained which contained one mole of crystal water, mp >330°; SM(FAB): (M+H)<+>=231; ^-H-lvMR (D2O): S=8.08 (d, 1H); 7.75 (d, 1H) ; 7.58 (t.lH); 3.35 (m, 2H); 2.96 (m, 2E).

The intermediate steps were produced as follows:

(a) 4- thiocarbamoyl-l-indanone

A solution of 12.1 g (77 mmol) of 4-cyano-1-indanone [Coll. Czechoslovak. Chem. Commun. 43, 3227 (1978)] in 220 ml of pyridine and 10.6 ml (77 mmol) of triethylamine was saturated at 40° for 3 hours with hydrogen sulphide and further stirred at the same temperature for 16 hours. After cooling to dryness, the reaction mixture was evaporated and 300 ml of water was added to the residue. The crystallized yellow product was suctioned off, washed with water, dried and recrystallized from acetic acid. It thus obtained the title compound, m.p. 197<=>C (under degradation).

(b) 4-amidino-l-indanone hydrochloride

A solution of 9.8 g (51.3 mmol) of 4-thiocarbamoyl-1-indanone in 500 ml of abs. methylene chloride was added at room temperature under argon with 10.8 g (54 mmol) of triethyloxonium tetrafluoroborate. After 16 hours, a mixture of 4.2 g of potassium carbonate and 4.2 ml of water was added to the reaction solution. It was stirred for a short time, filtered and the filtrate was washed in water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The crude ethyl thioiminoether thus formed was dissolved in 160 ml of absolute ethanol, 3.3 g (60 mmol) of ammonium chloride was added and heated for 20 hours with reflux. After cooling, the reaction mixture was evaporated to dryness. The title compound was purified by chromatography on 1000 ml Amberlite® ER-180 resin (water as eluent) and recrystallized from ethanol/ether, mp 215 - 218°C (during degradation). 2) Starting compound B: 4-amidino-1-indanone-2' - (N- hydroxyamidino)-hydrazone-dihydro-chloride

A solution of 316 mg (1.5 mmol) 4-amidino-l-indanone hydrochloride (see intermediate 1b) under starting compound A) in 7 ml of methanol was added to a solution of 394 mg (1.5 mmol) 1-amino-3-hydroxyguanidine- 4-toluenesulfonate in 6 ml water and 0.75 ml (1.5 mmol) 2N hydrochloric acid, heated for 2 hours under reflux and stirred for 16 hours at room temperature. The reaction mixture was evaporated and the residue was purified by chromatography (Pharmacia column SR-28-100) on silica gel 0PTI-UP C12 ® (water as eluent, 5 ml fractions, flow rate 27.5 ml/hour). The contents of fractions 58-78 were combined, evaporated and the residue crystallized from ethanol. The title compound was obtained as waxy crystals, MS(FAB): (M+H)<+> = 247; -^E-XME (D 2 O): S=8.06 (d, 1H); 7.73 (d, 1H); 7.58 (h, 1E); 3.36 (m, 2H); 2.98 (m, 2H). 3) Output connection C:

5-amidino-1-tetralone-2'-amidinohydrazone dihydrochloride

A solution of 0.41 g (3 mmol) aminoguanidine bicarbonate in 31.5 ml 0.1 N hydrochloric acid was added to 0.675 g (3 mmol) 5-amidino-1-tetralone hydrochloride and heated for 72 hours with reflux. After cooling, it was evaporated to dryness and the title compound was recrystallized from methanol/ether, m.p. >250°; MS(FAB): (M+H)<+>=245; <i>H-XMR (DMS0-d6): S=11.3 (s, 1H); 9.5 (m, 4H); 8.65 (d, 1E); 7.92 (m, 3H); 7.52 (d, 1H); 7.46 (t, 1H); 2.7 - 2.85 (m, 4E); 1.9 (m, 4H).

The intermediate steps were produced as follows:

(a) 5-cvano-l-tetralone

A solution of 1.0 g (4.4 mmol) of 5-bromo-1-tetralone [J.Org. Chem. 49, 4226 (1984)] in 1.3 ml of DMF was added 0.41 g (4.5 mmol) of copper (I) cyanide and stirred for 6 h at 160<=.> The reaction mixture was then cooled to SO<:> and a solution was added of 1.6 g of iron (III) chloride hexahydrate in 2.5 ml of water and 0.44 ml of concentrated hydrochloric acid. It was stirred for 45 minutes, cooled the reaction mixture diluted with water and extracted with toluene. The organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated. It obtained the title compound as yellow-orange crystals, IR (CE 2 Cl 2 ): 2220, 1690 cm"1; ifl-XMR (CDC 13 ): δ=08.26 (q, 1H); 7.81 (q, 1E); 7.43 (t, 1H); 3.21 (t, 2H); 2.72 (t, 2H); 2.23 (m, 2H).

(b) 5-thiocarbamoyl-1-tetralone

Analogous to the procedure described for the starting compound A under 1 a), 10.6 g (62 mmol) of 5-cyano-1-tetralone in 200 ml of pyridine and 8.6 ml of triethylamine were treated and processed with hydrogen sulphide. The title compound was obtained as yellow crystals, m.p. 200 - 205".

(c) 5-amidino-1-tetralone hydrochloride

Analogous to the procedure described for starting compound A under 1 b), 8.6 g (42 mmol) of 5-thiocarbamoyl-1-tetralone was treated with 8.8 g (44 mmol) of triethyloxonium tetrafluoroborate and 2.6 g (49 mmol) of ammonium chloride. The title compound was obtained as light pink crystals, MS(FAB): (M+H)<+>=189. 4) Starting compound E: 4 - (N-hydroxyamidino)-1-indanone-2*-amidinohydrazone dihydrochloride 0.2 g (3 mmol) of hydroxylamine hydrochloride was suspended in 1 ml of abs. ethanol and added 2 ml of a 1N sodium ethoxide ethanol solution. This mixture was stirred for 1 hour and filtered. To the filtrate was added a solution of 0.26 g (1 mmol) 4-cyano-1-indanone-2'-amidinohydrazone hydrochloride (see under 18 a); in 2 ml of water, and it was heated for 6 hours under reflux. After cooling, the reaction mixture was evaporated and the title compound was crystallized from water, m.p. >250a; 1 H-NMR (DMSO-d 6 + D 2 O): S=8.12 (m, 1H); 7.55 (m, 2E); 3.22 (m, 2H); 2.83 (m, 2H). 5) Starting compound F: 4-amidino-2-methyl-1-indanone-2'-amidinohydrazone dihydrochloride

A solution of 1.0 g (5.0 mmol) of 4-amidino-2-methyl-1-indanone hydrochloride and 0.68 g (5.0 mmol) of aminoguanidine hydrogen carbonate was stirred in 10 ml of 0.5 N hydrochloric acid for 120 h at 25°. The crystallized product was filtered off, washed with a little water and dried. One thus obtained the compound in the title, m.p. >250°; MS(FAB): (M+H)<+> = 245; <1>-H-NMR (D 2 O): S=7.95 (d, 1H); 7.66 (d, 1H); 7.48 (t, 1H); 3.45 (m, 2H)-; 2.85 (d, 1H); 1.12 (d, 3H).

The intermediate steps were produced as follows:

(a) 4- Thiocarbamoyl-2-methyl-1-indanone

Analogous to the procedure described for starting compound A under 1 a), 11.1 g (65 mmol) of 4-cyano-2-methyl-1-indanone [p. "US-PS 3,956,363] in 200 ml of pyridine and 9.7 ml of triethylamine treated and worked up with hydrogen sulphide. The title compound was thus obtained as yellow crystals, m.p. 195 - 198° (during degradation); <1>H-NMR ( DMS0-d6): S=9.61 (s, 1H); 7.71 (m, 2H); 7.48 (m, 1H); 3.48 (m, 1H); 2.81 (m, 2H); 1.23 (s, 3H); 1.19 (p, 3H).

(b) 4-amidino-2-methyl-1-indanone hydrochloride

Analogously to the procedure described for starting compound A under 1 b), 10.2 g (50 mmol) of 4-thiocarbamoyl-2-methyl-1-indanone was treated with 11.0 g (55 mmol) of triethyloxonium tetrafluoroborate and 3.2 g (60 mmol) of ammonium chloride. The title compound was obtained as pink crystals. These were directly sold on. 6) Starting compound G: 5-amidino-6-methoxy-1-tetralone-2*-amidinohydrazone-dlhydrochloride

Analogous to starting compound A under 1), the compound in the title was prepared starting from 5-cyano-6-methoxy-1-tetralone [Chem.Pharm.Bul1. 31, 2329 (1983)]. 7) Starting compound H: 4-amidino-6-methoxy-7-methyl-1-indanone-2'-amidinohydrazone dihydrochloride

Analogous to starting compound C, the compound in the title was prepared starting from 4-bromo-6-methoxy-7-methyl-1-indanone (J.Chem.Soc.Perkin Trans. 1 1974, 1911). 8) Starting compound I: 4-amidino-6,7-dimethyl-1-indanone-2'-ainidinonydrazone dihydrochloride

Analogous to starting compound A under 1), the compound in the title was prepared starting from 4-amidino-6,7-dimethyl-1-indanone hydrochloride, m.p. >240°C; MS(FAB): (M+H)<+> = 259; <1>H-NMR (D 2 O): S: 7.43 (s, 1H); 3.12 (m, 2B); 2.75 (m, 2H); 2.43 (p, 3E); 2.24 (p, 3H).

The intermediate steps were produced as follows:

(a) 4-cyano-6,7-dimethyl-1-indanone

A mixture of 17.8 g (74.5 mmol) of 4-bromo-6,7-dimethyl-1-indanone [J.Het.Chem. 24, 677 (1987 )] and 7.3 g (82 mmol) of cupric (I) cyanide in 18 ml of DMF were stirred for 6 hours at 170°. The reaction mixture was then cooled and 200 ml of toluene and a solution of 31.2 g of iron(III) chloride hexahydrate in 47 ml of water and 8.2 ml of concentrated hydrochloric acid were added in succession. It was stirred for 20 minutes at 70°, cooled and the reaction mixture was diluted with toluene and water. The organic phase was separated, washed with water, a half-saturated sodium hydrogen carbonate solution and again with water, dried and evaporated. The residue was crystallized from acetate and ether and corresponded to the title compound. Beige crystals were obtained. Temp. 160 - 163°; IR (CH 2 Cl 2 ): 2220, 1710 cm -1 .

(b) 4-thiocarbamoyl-6.7-dimethyl-1-indanone

Analogous to the procedure described for starting compound A under 1 a), 10 g (54.1 mmol) of 4-cyano-6,7-dimethyl-1-indanone in 200 ml of pyridine and 7.5 ml of triethylamine were treated and treated with hydrogen sulphide. The title compound was thus obtained in the form of yellow crystals, m.p. 207 - 20S:; <i>H-NMR (DMS0-d6): S = 10.03 (s, 1H); 9.49 (p, 1H); 7.49 (p, 1H); 3.12 (m, 2H); 2.61 (m, 2E); 2.54 (p, 3H); 2.29 (p, 3H).

(c) 4-amidino-6.7-dimethyl-1-indanone hydrochloride

Analogously to the procedure described for starting compound A under 1 b), 4.4 g (20 mmol) of 4-thiocarbamoyl-6,7-dimethyl-l-indanone was treated with 4.26 g (21 mmol) of triethyloxonium tetrafluoroborate and 1.2 g (24 mmol) ammonium chloride. The title compound was obtained as beige crystals. 9) Starting compound J: 4-amidino-7-hydroxy-3-methyl-1-indanone-2'-amidinohydrazone dihydrochloride

Analogous to starting compound C, the compound in the title was prepared starting from 4-bromo-7-hydroxy-3-methyl-1-indanone [Indian J. Chem.Sect. B 24B, 1061 (1985)].

10) Starting compound L: 4-amidino-6,7-dimethoxy-1-indanone-2'-amidinohydrazone dihydrochloride

A solution of 0.4 g (3 mmol) aminoguanidine hydrogen carbonate in 6 ml 0.5 N hydrochloric acid was added to 0.73 g (2.7 mmol) 4-amidino-6,7-dimethoxy-1-indanone hydrochloride and stirred for 24 hours at 50°. After cooling, the crystallized product was suctioned off, washed with a little water and dried to give the title compound, m.p. >220°; MS(FAB): (M+H) + = 291; 1-H-NMR (D 2 O); 5=7.45 (s, 1H); 3.97 (p, 6H); 3.27 (m, 2H); 2.98 (m, 2H).

The intermediate steps were produced as follows:

(a) 4-cyano-6.7-dimethoxy-1-indanone

A mixture of 6.57 g (24.2 mmol) of 4-bromo-6,7-dimethoxy-1-indanone [Can. J. Chem. 57, 1603 (1979 )] and 2.5 g (28 mmol) of copper (I) cyanide in 7 ml of DMF were stirred for 5.75 hours at 170°. The reaction mixture was then cooled to 100° and 70 ml of toluene and a solution of 9.7 g (36 mmol) of iron(III) chloride hexahydrate in 15.6 ml of water and 3.5 ml of concentrated hydrochloric acid were added one after the other. The mixture was stirred for 30 minutes at 80°, cooled and diluted with toluene and water. The organic phase was separated, washed with water, semi-saturated sodium hydrogen carbonate solution and again with water, dried and evaporated. The residue was distilled at 150-160°/0.1 mbar in a ball tube column and corresponded to the compound in the title, m.p. 150°; IR(CH 2 Cl 2 ): 2220, 1710 cm-<1>, 1H-XMR (CDCl 3 ): δ=7.33 (s, 1H), 4.12 (s, 3H), 3.90 (s, 3H); 3.19 (m, 2H); 2.76 (m, 2H).

(b ) 4- Thiocarbamo. yl- 6. 7- dimethoxy-l- indanone

Analogously to the procedure described for starting compound A under 1 a), 3.7 g (17 mmol) of 4-cyano-6„7-dimethoxy-1-indanone in 100 ml of pyridine and 2.4 ml of triethylamine were treated and treated with hydrogen sulphide. The title compound was thus obtained in the form of pale yellow crystals, m.p. 196-199°!<i>H-NMR (DMS0-d6): δ = 10.06 (s, 1E); 9.50 (p, 1E); 7.41 (p, 1H); 3.84 (p, 6H); 3.13 (m, 2H); 2.63 (m, 2H).

(c) 4- amidino- 6. 7- dimethoxy- 1- indanone- hydrochloride

Analogous to the procedure described for Starting compound A under 1 b), 3.3 g (13 mmol) of 4-thiocarbamoyl-6,7-dimethoxy-1-indanone was treated with 2.8 g (14 mmol) of triethyloxonium tetrafluoroborate and 0.8 g (15 mmol) ammonium chloride. The title compound was obtained as beige crystals, m.p. 188° (during degradation); 1 H-NMR (DMSO-d 1 ): δ = 9.4 (s, 3H); 7.63 (p, 1E); 3.92 (p, 3H); 3.89 (p, 3H); 3.18 (m, 2H); 2.68 (m, 2H). 11) Starting compound M: 4-amidino-6-methyl-1-indanone-2'-ainidinohydrazone dihydrochloride

Analogous to the starting compound C, the compound in the title was prepared starting from 4-bromo-6-methyl-1-indanone (Bull.Soc.Chim. France 1964, 3103), m.p. >250°C; MS(FAB): (M+H)<+>=245; 1 H NMR (D 2 O): δ = 7.89 (s, 1H); 7.62 (p, 1E); 3.34 (t, 2H); 2.96 (t, 2H); 2.45 (p, 3H). 12) Starting compound N: 4-amidino-3-methyl-1-indanone-2'-amidinohydrazone dihydrochloride

A solution of 300 mg (1.3 mmol) of -4-amidino-3-methyl-1-indanone hydrochloride in 6 ml of water was added to 300 mg (2.3 mmol) of aminoguanidine hydrogen carbonate in 4 ml of 0.5 X hydrochloric acid and stirred for 24 hours at 80°. The reaction mixture was cooled, evaporated and the residue was purified by chromatography on 180 ml of Amberlite® ER-180 resin with water as eluent. The title compound was recrystallized from methanol/ether, m.p. >250°; Rf=0.18 (Silica gel, methylene chloride/methanol/concentrated ammonia 5:3:1); MS(FAB): (M+H)<+>=245; 3-E-NMR (D 2 O): δ=7.97 (d, 1H); 7.64 (d, 1H); 7.49 (h, 1E); 3.86 (m, 1E); 3.17 (q, 1H); 2.49 (d, 1H); 1.24 (d, 3H).

The intermediate steps were produced as follows:

(a) 4-cvano-3-methyl-1-indanone

A mixture of 2.6 g (11.5 mmol) of 4-bromo-3-methyl-1-indanone [J.Org.Chem. 22, 1019 (1957] and 1.14 g (12.7 mmol) of copper(I) cyanide in 2.5 ml of DMF were stirred for 6 hours at 170°. The reaction mixture was then cooled to 100° and successively added 50 ml of toluene and a solution of 4.5 g (16.5 mmol) of ferric chloride hexahydrate in 7 ml of water and 1.7 ml of concentrated hydrochloric acid. It was stirred for 20 minutes at 70°, cooled and the reaction mixture was diluted with toluene and water. the organic phase was separated, washed with water, a half-saturated sodium hydrogen carbonate solution and again with water, dried and evaporated. IR (CE 2 Cl 2 ): 2220, 1710 cm-<1>, 1E-XMR (CDC 13 ): δ=7.92 (m, 2E); 7.52 (t, 1H); 3.73 (m, 1H); 3.03 (q, 1H); 1.55 (d, 3H).

(b) 4- Thiocarbamoyl- 3- methyl- 1- indanone

Analogous to the procedure described for starting compound A under 1 a), 1.45 g (8.47 mmol) of 4-cyano-3-methyl-1-indanone in 25 ml of pyridine and 1.2 ml of triethylamine were treated and treated with hydrogen sulphide. The title compound was obtained in the form of pale yellow crystals, m.p. 198 - 200°; 3-H-NMR (DMSO-d 6 ): ~ S = 9.78 (s, 1H); 7.65 (m, 2H); 7.46 (m, 1H); 3.98 (m, 1E), 2.95 (q, 1E); 2.26 (q, 1E); 1.25 (d, 3H).

(c) 4-amidino-3-methyl-1-indanone hydrochloride

Analogous to the procedure described for starting compound A under 1 b), 0.96 g (4.68 mmol) of 4-thiocarbamoyl-3-methyl-1-indanone was treated with 1.0 g (4.93 mmol) of triethyloxonium tetrafluoroborate and 0.3 g (6 mmol) of ammonium chloride. The title compound was obtained as beige crystals, <1>E-NMR (DMS0-d6): S = 9.59 (s, 4H); 7.65 (m, 2E); 7.46 (m, 1E); 3.98 (m, 1E); 2.95 (q, 1E); 2.26 (q, 1E); 1.25 (d, 3H). 13) Starting compound 0: 4-amidino-2-ethyl-1-indanone-2'-amidinohydrazone dihydrochloride 3-(2-bromophenyl)-2-ethyl-propionic acid (DS-PS 2,733,868) was cyclized with polyphosphoric acid under heating to the corresponding 1-indanone and converted to the title compound analogously to the procedure described for starting compound C. Mp.>250°C; SM(FAB): (M+H)<+> = 259, %-NMR (D 2 O): δ=7.96 (d, 1E); 7.65 (d, 1H); 7.48 (h, 1E); 2.95 - 3.48 (m, 3E); 1.3-1.8 (m, 2E); 0.83 (t, 3E). 14) Starting compound P: 4-amidino-2-n-butyl-1-indanone-2'-amidinohydrazone dihydrochloride

3-(2-Bromophenyl)-2-n-butyl-propionic acid (DS-PS 2,733,868) was cyclized under heating with polyphosphoric acid to the corresponding 1-indanone and converted to the compound in the title analogously to the procedure described for Starting compound C.

Additional methods for preparing starting compound A)

(4-amidino-1-indanone-2'-amidinohydrazone dihydrochloride):

15) Analogous to the procedure described for Starting compound A under 1 b), 4-thiocarbamoyl-1-indanone-2'-amidinohydrazone hydrochloride (Starting compound D) was reacted with triethyloxonium tetrafluoroborate and ammonium chloride, whereby starting compound A was obtained, m.p. >330°; MS(FAB): (M+H)<+>=231; <1>H-NMR (D 2 O): S=S.0S (d, 1H); 7.75 (d, 1H); 7.58 (t, 1H); 3.35 (m, 2H); 2.96 (m, 2E) . 16) A solution of 0.26 g (1 mmol) 4-cyano-1-indanone-2'-amidinohydrazone hydrochloride in 5 ni abs. methanol was added to 1.2 ml of 1N sodium methoxide solution in methanol and heated for 16 hours under reflux. After cooling, 0.16 g (3 mmol) of solid ammonium chloride was added to the reaction mixture and stirred for 1 hour at 60<=.> The reaction mixture was then evaporated and the residue crystallized from dilute ethanol. Starting compound A was thus obtained, m.p.>330°.

The intermediate steps were produced as follows:

(a) 4-cyano-1-indanone-2'-amidinohydrazone hydrochloride

Analogously to the procedure mentioned for the starting compound A line 1), 314 mg (2 mmol) of 4-cyano-l-lndanone was dissolved in 20 ml of methanol, a solution of 272 mg (2 mmol) of aminoguanidine bicarbonate in 9 ml of water and 1 ml of 2N hydrochloric acid and stirred for 4 days under reflux. After cooling, the reaction mixture was evaporated to dryness and the residue crystallized from water. Thus the compound in the title was obtained, m.p. >230°; - 1 H-NMR (DMSO-d 6 /D 2 O): S: 8.16 (d, 1H); 7.9 ~(d, 1E); 7.55 (t, 1H); 3.28 (m, 2E); 2.9 (m, 2H); IR (Xujol (Paraffin)): 2190 cm"<1> (CN). 17) A solution of 6.12 g (45 mmol) aminoguanidine hydrogen carbonate in 100 ml water and 46 ml IN hydrochloric acid added 9.45 g (44.9 mmol) 4- amidino-1-indanone hydrochloride (see under Compound A, lb)) and stirred at 24" for 24 hours. The crystallized product was sucked off, washed with a little water and recrystallized from 300 ml of water. Starting compound A was thus obtained, which contained 1 mol of crystal water, m.p.

>330°; SM(FAB): (M+H)<+> = 231; %-NMR (D 2 O); 5=8.08 (d, 1E); 7.75 (d, 1H); 7.58 (t, 1H); 3.35 (m, 2H); 2.96 (m, 2E).

IS) A mixture of 0.32 g (1 mmol) 4-(N-hydroxyamidino)-1-indanone-2'-amidino-hydrazone dihydrochloride (Starting compound E), 0.36 ml (2 mmol) triethylamine and 0.2 g (1 mmol) iron pentacarbonyl in 10 ml of abs. THF was boiled for 16 h with reflux. The reaction mixture was then evaporated and the residue crystallized from dilute hydrochloric acid, whereby starting compound A was obtained, m.p. >330°. 19) Starting compound Q: 4-amidino-2-propyl-indanone-1-amidinohydrazone dihydrochloride

The compound in the title was prepared analogously to starting compound 0 starting from 2-bromobenzyl bromide and malonic acid diethyl ester, m.p. >250°C; MS(FAB): (M+H)<+>=273; 3 H-NMR

(D20): S=7.98 (d, 1H); 7.67 (m, 1H); 7.49 (t, 1H); 3.44 (m, 2H); 3.01 (m, 1H); 1.1 - 1.75 (m, 4H); 0.81 (t, 3H).

Examples

The following examples serve to illustrate the invention, but in no way limit its scope.

Temperatures are indicated in degrees Celsius (°C). If there is no temperature indication, the reactions are carried out at room temperature. When evaporation takes place with a rotary evaporator unless otherwise specified.

Proton nuclear resonance spectroscopy values are given in ppm ("Parts Per Million") with reference to tetramethylsilane (S=0) as internal standard. d=doublet, s=singlet, t=triplet, m=multiplet.

For elemental analyses, the sum formulas, molecular weight, calculated and found analysis values are indicated.

The abbreviations used have the following meaning:

Example 1: 4-amidino-1-indanone-2'-amidonohvdrazone-dicyclamate

To a solution of 460 mg (2 mmol) of 4-amlidinoindanone-1-amidinohydrazone in 80 ml of methanol was added a solution of 717 mg (4 mmol) of N-cyclohexylsulfamic acid in 20 ml of methanol and evaporated to dryness. The residue was dissolved in ethanol and crystallized by adding diethyl ether. Thus the compound in the title was obtained, m.p. 210° (Zers.); 1 H-NMR (D 2 O): δ 7.97 (d, 1H); 7.64 (d, 1H); 7.47 (t, 1H); 3.25 (m„ 2H); 2.9 (m, 4H); 1 - 2 (m, 20H);

Analysis for C23<H>40<N>806S2 (588.75):

Calculated: 46.92$ C, 6.85$ H, 19.03$ N,

Found: 46.5$ C, 6.9$ H, 19.0$ N.

The starting material was prepared as follows:

a) 4-amidino-1-indanone-2'-amidinohvdrazone

9.63 g (30 mmol) of 4-amidino-1-indanone-2'-amidinohydrazone dihydrochloride (Starting compound A, prepared according to one of the methods described under "Starting compounds", e.g. according to 16)) was dissolved in 900 ml of distilled water and heated to 70 - 80°C and cooled to 10°C. This solution was then added dropwise with stirring to 30 ml of 2N caustic soda. The separated product was sucked off, washed with a little water and dried. This was the compound in the title, mp. 250°

(Zers.).

Example 2:

4- amidino-1- indanone- 2'- amidinohvdrazone- dioctanoate

To a solution of 460 mg (2 mmol) of 4-amidinoindanone-1-amidinohydrazone (Example 1a)) in 80 ml of methanol was added 631 µl (4 mmol) of octanoic acid and evaporated to dryness. The residue was dissolved in ethanol and crystallized by adding diethyl ether. One thus obtained the compound in the title, m.p. 190°

(Zers.); 1 H-NMR (DMS0-d6): S 8.03 (d, 1H); 7.52 (d, 1H); 7.47

(t, 1H); 3.19 (m, 2H); 2.85 (m, 2E); 1.98 (t, 4H); 1.42 (m, 4H); 1.19 (p, 24E); 0.81 (t, 6E);

Analysis for C27<H>46<N>604 (518.70):

calculated: 62.52$ C, 8.94$ E, 16.20$ X,

found: 62.3$ C, 8.9$ E, 16.2$ X.

Example 3: 4-amidlino-1-indanone-2'-amidinohydrazone-di salicylate

A solution of 690 mg (3 mmol) of 4-amidinoindanone-1-amidinohydrazone (Example 1a)) in 100 ml of methanol was added to a solution of 830 mg (6 mmol) of salicylic acid in 50 ml of ethanol and the reaction mixture was evaporated to half. To this solution was added 70 ml of water, whereupon the compound in the title crystallized, m.p. 206-9<:> (Zers.);

Analysis for C25H26<X>606 (507.1);

calculated: 59.13$ C, 5.19$ E, 16.55$ X, found: 59.3$ C, 5.2$ E, 16.8$ X.

Example 4: 4-amidino-1-indanone-2'-amidinohydrazone-dibenzene-sulfonate

A solution of 690 mg (3 mmol) of 4-amidinoindanone-1-amidinohydrazone (Example 1a)) in 100 ml of methanol was added to a solution of 975 mg (3 mmol) of benzenesulfonic acid in 50 ml of methanol and evaporated to dryness. The residue was crystallized from ethanol. One thus obtained the compound in the title, m.p. >250<6> (Zers.); <i>fl-NMR (D20): § 7.38 - 7.95 (m, 16H); 3.21 (m, 2E); 2.78 (m, 2E);

Analysis for C23E26N60(,S2 (546.63 ):

calculated: 50.54$ C, 4.79$ H, 15.37$ X, found: 50.4$ C, 4.8$ H, 15.6$ X.

Example 5: Additional salts.

Example 5a: 4-amidino-1-indanone-2'-amidinohydrazone succinate

A solution of 920 mg (4 mmol) of 4-amidino-1-indanone-2'-amidinohydrazone in 120 ml of methanol was added to a solution of 472 mg (4 mmol) of succinic acid in 120 ml of methanol. The crystallized product was suctioned off, washed with a little methanol and dried and this was the title compound, m.p. 200°

(Zers. );

Analysis for C15<E>20<N>604•1.04 E20 (367.10):

calculated: 49.08$ C, 6.06$ E, 22.89$ N,

found: 49.13$ C, 6.07$ E, 23.04$ N.

Example 5b: 4-amidino-1-indanone-2'-amidinohydrazone-adipate

A solution of 230 mg (1 mmol) of 4-amicino-1-indanone-2'-amidinohydrazone in 30 ml of methanol was added to a solution of 146 mg (1 mmol) of adipic acid in 25 ml of ethanol. The crystallized product was suctioned off, washed with a little ethanol and dried to give the title compound, m.p. 200 = (Zers.);

Analysis for C17E24N604•0.25 E20 (380.92);

calculated: 53.60$ C, 6.48$ E, 22.06$ N,

found: 53.79$ C, 6.73$ E, 21.93$ N.

Example 5c: 4-amidino-1-incanone-2'-amidinohydrazone-1.5-naphthalene disulfonate

A solution of 920 mg (4 mmol) of 4-amicino-1-indanone-2'-amidinohydrazone in 120 ml of methanol was added to a solution of 1.49 g (4 mmol) of 1,5-naphthalenedisulfonic acid in 100 ml of methanol. The crystallized product was filtered off with suction, washed with a little methanol and dried to give the title compound, m.p.

>250°;

Analysis for C21<E>22<N>606S2-2.36 H2O (561.09): calcd.; 44.95$ C, 4.80$ E, 14.98$ N, found: 45.06$ C, 4.98$ E, 15.21$ N.

Example 5d: 4-amidino-l-indanone-2'-amidinohydrazone-L-tartrate

A solution of 920 mg (4 mmol) of -4-amidino-1-indanone-2'-amidinohydrazone in 120 ml of methanol was added to a solution of 600 mg (4 mmol) of L-(+)-tartaric acid in 100 ml of methanol. The crystallized product was filtered off with suction, washed with a little methanol and dried to give the title compound, m.p. 190°

(Zers. );

Analysis for C15E20N6<0>6•0.26 E20 (385.04): calcd: 46.79$ C, 5.37$ E, 21.83$ N, found: 46.83$ C, 5.37$ E, 21.87$ N.

Example 5e: 4-amidino-1-indanone-2'-amidinohydrazone citrate

A solution of 230 mg (1 mmol) of 4-amidino-1-indanone-2'-amidinohydrazone in 30 ml of methanol was added to a solution of 210 mg (1 mmol) of citric acid in 10 ml. The crystallized product was filtered off with suction, washed with a little methanol and dried to give the title compound, m.p. >220<:> (Zers.);

Analysis for C17<E>22<N>607 (422.40):

calculated: 48.34$ C, 5.25$ E, 19.90$ N, found: 48.23$ C, 5.33$ E, 2 0.07$ N.

Example 6:

Analogous to the above-mentioned examples, the following starting compounds can be transferred to the acid addition salts of octanoic acid, succinic acid, adipic acid, salicylic acid, cyclohexylsulfamic acid, benzenesulfonic acid, citric acid, tartaric acid or 1,5-naphthalenedisulfonic acid: a) 4-amidino-l-indanone- 2'-(N-hydroxyamidino)-hydrazone dihydrochloride (Starting compound B); b) 5-amidino-1-tetralone-2'-amidinohydrazone dihydrochloride (Starting compound C); c) 4-(N-hydroxyamidino)-1-indanone-2'-amidinohydrazone dihydrochloride (Starting compound E); d) 4-amidino-2-methyl-1-indanone-2'-amidinohydrazone dihydrochloride (Starting compound F); e) 5-amidino-6-methoxy-1-tetralone-2'-amidinohydrazone dihydrochloride (Starting compound G); f) 4-amidino-6-methoxy-7-methyl-1-indanone-2'-amidinohydrazone dihydrochloride (Starting compound E); g) 4-amidino-6,7-dimethyl-1-indanone-2'-amidinohydrazone dihydrochloride (Starting compound I); h) 4-amidino-7-hydroxy-3-methyl-1-indanone-2'-amidinohydrazone dihydrochloride (Starting compound J); i) 4-amidino-6,7-dimethoxy-1-indanone-2'-aminohydrazone dihydrochloride (Starting compound L); j ) 4-amidino-6-methyl-1-indanone-2'-amidinohydrazone dihydrochloride (Starting compound M); k) 4-amidino-3-methyl-1-indanone-2'-amidinohydrazone dihydrochloride (Starting compound N); 1) 4-amidino-2-ethyl-1-indanone-2'-amidinohydrazone dihydrochloride (Starting compound 0);

m) 4-amidino-2-n-butyl-1-indanone-2'-amidinohydrazone-dihydro-chloride (Starting compound P).

n) 4-amidino-2-n-propyl-indanone-1-amidinohydrazone (Starting compound Q).

Example 7:

Capsules containing 0.25 g of active ingredient, e.g. one of the acid addition salts from Examples 1-6 can be prepared as follows:

Composition (for 5000 capsules)

The powdery substances are passed through a sieve with a mesh size of 0.6 mm and mixed. Portions each of 0.33 g of the mixture were filled into gelatin capsules using a capsule filling machine.

Example 8:

10,000 tablets were produced, each containing 5 mg of active ingredient, e.g. one of the acid addition salts prepared in Examples 1-6:

Composition:

Procedure: All powdery components were sieved through a sieve with a mesh size of 0.6 mm. Then the active substance, milk sugar, magnesium stearate and half of the starch were mixed in a suitable mixer. The other half of the starch was suspended in 65 ml of water and to the resulting suspension added a boiling solution of polyethylene glycol in 260 ml of water. The resulting paste was added to the powder mixture and granulated if necessary with the addition of more water. The granulate was dried overnight at 35°C, passed through a sieve with a mesh size of 1.2 mm and pressed to

tablets with a dividing line.

Claims (7)

1. Acid addition salt, characterized in that it is formed from bases with Formula I where A stands for a direct bond or -(CH2)-; X represents a residue -C(=Y)-NR 6 R 7 ; Y stands for NRg; Z stands for NRg; R 2 and R 2 stand independently of each other for hydrogen, lower alkyl or lower alkoxy; the radicals R 3 , R 4 , R 4 , R 8 and R 9 independently represent hydrogen or lower alkyl; and R 5 and R 7 independently represent hydrogen, lower alkyl or hydroxy; with an acid [PA] , which means a mono- or polyprotic acid selected from alkanoic acids which are unsubstituted or mono- or poly-substituted with hydroxy, with carboxy or with hydroxy and carboxy; besides formic acid, unsubstituted acetic acid, benzoic acid which is unsubstituted or substituted by hydroxy, benzenesulfonic acid, naphthalene-1,5-disulfonic acid and N-substituted cycloalkylsulfamic acids. 2. Acid addition salt according to claim 1, characterized in that it is formed from a base with Formula I, where A is a direct bond, X stands for a residue -C(=NH)-NH2; Z stands for NH; and , R2, R3. R3. R 4 and R 5 stand for hydrogen; with an acid [PA], which stands for N-cyclohexylsulfamic acid, octanoic acid, salicylic acid or benzenesulfonic acid. 3. Acid addition salt according to claim 1, characterized in that it is formed from a base with Formula I, where A stands for a direct bond, X stands for a residue -C(=XH)-NH2; z stands for NH; and R 1 , R 2 , R 3 , R 4 and R 5 represent hydrogen; with an acid [PA], which is selected from citric acid, lactic acid and tartaric acid. 4. Acid addition salt according to claim 1, characterized in that it is formed from a base with Formula I where A is a direct bond, X stands for a residue -C(=NH)-NH2; Z stands for NH; R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen, with an acid [PA] that is succinic acid, adipic acid, or 1,5-naphthalene disulfonic acid. 5 . Acid addition salt according to claim 1, characterized in that it is formed from a base of Formula I, where A is a direct bond, X stands for a residue -C(=XH)-XH2; Z stands for NH; and R 1 , R 2 , R 3 , R 4 and R 5 represent hydrogen; with the acid [PA], which is selected from adipic acid and benzenesulfonic acid. 6. Pharmaceutical preparation, characterized in that it contains an acid addition salt according to any one of claims 1-5 together with pharmaceutically usable carrier materials. 7. Use of an acid addition salt according to one of claims 1-5 for the production of pharmaceutical preparations when used for the treatment of diseases which are improved by an inhibition of the enzyme S-adenosylmethionine decarboxylase.