SK315292A3 - Hydrazone 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

Technical field

MM - - * 0 D 50 XJ r ~ > o o <c- ro <-> m >> n -c m N - <

cn ·, x

CO ro o j cn> oo CO o

CO “Ί

CH

The present invention relates to acid addition salts derived from a base of formula I < 9b &gt;

R, (I) 'N'

I

R in which

A represents a direct bond or a group of formula - (CH ₂ ) _n -, wherein n is 1, 2 or 3,

X is -C (= Y) -NR ₈ R ₇ ,

Y is NR 8, O or S,

Z is a group of formula NR _g, O or S,

R 1 and R ₂ independently of one another represent a hydrogen atom or one or more substituents other than a hydrogen atom,

R ₄ , R g, R g and R g are independently of each other a lower alkyl group and a single hydrogen atom

R ₅ and R ₇ mean! independently of one another a hydrogen atom, a lower alkyl group, a hydroxy group, an etherified or esterified hydroxy group, an unsubstituted, monosubstituted or disubstituted amino group, with a (PA) acid which is one or more protonated acid selected from carbonic acid, alkanoic acids which are unsubstituted or singly or multiply substituted, except formic acid, unsubstituted acetic acid, lysine and arginine, alkenoic acids which are not or are substituted, except unsubstituted fumaric acid, cycloalkylcarboxylic acids, arylcarboxylic acids, aryl (lower alkyl) carboxylic acids, where lower alkyl is not or is substituted, aryl (lower alkenyl) carboxylic acids, heterocyclocarboxylic acids, alkanesulfonic acids which are not or are substituted, with the exception of unsubstituted methanesulfonic acid, aromatic sulfonic acids, alkylsulfuric acids, N-substituted sulfamic acids, organic acids not containing carboxy, sulfo, sulfate or phospho groups, and also pyrophosphoric and hydroiodic acids, and their tautomers, and processes for the preparation of these acid addition salts, pharmaceutical compositions, acid addition salts include, and the use of such acid addition salts for the therapeutic treatment of the human or animal body or for the manufacture of a pharmaceutical composition.

Tautomers may occur, for example, when

Z is a group of formula NR _g, and R ₃ and / or _R4 and / or _R5 represents a hydrogen atom:

The corresponding guanyl residue in the general formula

I is -N (R ₃ ) -C (= Z) -NR ₄ R ₅ , and can then also be, for example, in tautomeric forms -N = C (-ZH) -NR ₄ R ₅ , -N (R ₃ ) -C (-ZH) = NR ₅ or -N (R ₃ ) -C (-ZH) = NR ₄ .

For example, when Y is NR 8 and R ₆ and / or R ₇ is hydrogen, the corresponding amidine structure, defined as X representing -C (= Y) -NR ₈ R ₇ in formula I, may also be present. occur in tautomeric forms -C (-YH) = NR ₇ or -C (-YH) = NR 8. Those of ordinary skill in the art are those described or similar tautomers. All these tautomers are included! under general formula I.

When A is - (CH ₂ ) _n - and R ₂ is different from hydrogen, the substituent or substituents corresponding to R ₂ may also be bonded to the carbon atoms of - (CH ₂ ) _n - .

R ₂ is for example a hydrogen atom or 1 to 4 substituents other than a hydrogen atom, a separate represents a hydrogen atom or 1 or 2 substituents other than hydrogen, and above all represents a hydrogen atom or a substituent which is other than hydrogen.

R f represents, for example, a hydrogen atom or 1 to 3 substituents other than a hydrogen atom, and in particular represents a hydrogen atom or 1 or 2 substituents which are different from a hydrogen atom.

The general terms used hereinbefore and hereinafter have the following meanings within the scope of the present invention:

The following definitions apply to the residues listed for the base of Formula I.

Lower alkyl is, for example, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl , preferably an ethyl or methyl group, and in particular a methyl group.

A substituent other than a hydrogen atom is, for example, lower alkyl, trifluoromethyl, cycloalkyl, aryl (lower alkyl), hydroxy, lower alkoxy, aryl (lower alkoxy), aryloxy, acyloxy, e.g. lower alkanoyloxy, halogen, N-, amino, amino, (lower alkyl) amino, N, N-di (lower alkyl) amino, acylamino, for example lower alkanoylamino, nitro, lower alkanoyl, arylcarbonyl, carboxy, (lower alkoxy) carbonyl, carbamoyl (formula -CONH ₂ ), N- (lower alkyl) carbamoyl, N, N-di (lower alkyl) carbamoyl, N-arylcarbamoyl, cyano, mercapto, lower alkylthio, lower alkylsulfonyl, sulfamoyl (formulas -SO ₂ NH ₂ ), N- (lower alkyl) sulfamoyl or N, N-di (lower alkyl) sulfamoyl.

Aryl is, for example, phenyl or naphthyl, such as 1-naphthyl or 2-naphthyl. The phenyl or naphthyl radical may be unsubstituted or substituted, especially if it is a phenyl group. The aryl group is preferably a phenyl group which is unsubstituted or which is substituted by one or more substituents, in particular by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, nitro, amino, halogen, trifluoromethyl, carboxy, (lower alkoxy) carbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di (lower alkyl) carbamoyl, cyano, lower alkanoyl, arylcarbonyl, lower alkylsulfonyl, sulfamoyl a N- (lower alkyl) sulfamoyl group and an N, N-di (lower alkyl) sulfamoyl group. Firstly, an aryl group represents a phenyl group which is unsubstituted or which is substituted by a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen atom or a trifluoromethyl group, in particular a phenyl group.

An arylcarbonyl group is, for example, a benzoyl group which is unsubstituted or substituted by a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen atom or a trifluoromethyl group, in particular a benzoyl group.

An aryl (lower alkyl) group is, for example, a phenyl (lower alkyl) group, especially a benzyl group.

Halogen is especially chlorine and bromine, but may also be fluorine or iodine.

Lower alkanoyl is, for example, formyl, acetyl, propionyl or pivaloyl.

The cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, in particular a cycloalkyl group having 5 or 6 carbon atoms, which means that it contains from 3 to 8 or 5 to 6 carbon atoms in the ring.

However, the cycloalkyl group may also be substituted, for example by a lower alkyl group.

An etherified hydroxy group is, for example, a lower alkoxy group. Esterified hydroxy is, for example, lower alkanoyloxy. Monosubstituted amino is, for example, lower alkylamino. Disubstituted amino is, for example, di (lower alkyl) amino, (lower alkylene) amino, for example alkylene amino of 4 to 7 carbon atoms and especially 4 or 5 carbon atoms, for example piperidino, oxa (lower alkylene) amino, thia (lower alkylene) amino or an aza (lower alkylene) amino group, for example, morpholino, thiomorpholino, piperidino or 4- (lower alkyl) piperazino.

The following definition applies to (PA) acids (the designation (PA) refers to protic or protonic acids):

Alkanic acids introduce! especially alkanoic acids of 1 to 20 carbon atoms with the exception of formic acid and unsubstituted acetic acid, preferably alkanoic acids of 2 to 7 carbon atoms such as propionic acid, butyric acid, isobutyric acid, pentanoic acid, hexanoic acid or heptanoic acid, or further octanoic acid, decanoic acid or dodecanoic acid, in particular propionic acid or octanoic acid, these acids being unsubstituted or substituted by one or more substituents, in particular by one to six substituents, preferably a hydroxy group, either simply as in the case glycolic acid, lactic acid or 2-hydroxybutyric acid, or multiple, for example up to 5-fold, as in the case of gluconic acid, or

Ί monocarboxylic acids derived from glucose (glucoheptonic acid), a carboxy group, for example in alkanedicarboxylic acids having 2 to 20 carbon atoms in the alkane moiety, especially in alkanedicarboxylic acids having 2 to 7 carbon atoms such as succinic acid or further adipic acid, pimelic acid , suberic acid or azelaic acid, hydroxy and carboxy, such as in the case of malic acid, tartaric acid, citric acid, glucaric acid or galactaric acid, amino or amino and carboxy and / or one or two radicals selected independently of one another from the group consisting of mercapto, methylmercapto, hydroxy, phenyl, 4-hydroxyphenyl, naphthyl, cyclohexyl, imidazolyl or indolyl, as in the case of amino acids, with lysine and arginine being excluded, especially gl acid utamic or aspartic acid in (D) -, (L) - or (D, L) -form, preferably in (D) - or (L) -form, substituted amino or substituted amino and carboxy and / or one or two radicals selected independently of one another from the group consisting of mercapto (also in oxidized form as the corresponding disulfide from two molecules of the corresponding mercaptan), methylmercapto, hydroxy, phenyl, 4-hydroxyphenyl, naphthyl, cyclohexyl, imidazole, or indolyl amino groups such as N-mono (lower alkyl) amino acids or N, N-di (lower alkyl) amino acids such as N-methylglycine or N- (lower alkanoyl) amino acids such as acetylaminoacetic acid (N-acetylgylcin) ), N-acetylasparagine or N-acetylcystine, by an oxo group such as pyruvic acid or acetic acid, a phosphono group and an amino group, as in the case of e phosphoserine, or a phospho group and a hydroxy group, as in the case of an acid

2-glycerophosphoric acid, 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1-phosphoric acid or fructose-1,6-diphosphoric acid. Amino acids are primarily α-amino acids which are in the (D) -, (L) - or (D, L) -form, preferably in the (L) - or (D) -form, and in the case of other asymmetric centers may be present as other isomers selected from, for example, glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-Val-OH), norvaline (α-aminovaleric acid), leucine (H-Leu) -OH), isoleucine (H-Ile-OH), norleucine (α-aminohexanoic acid, H-Nle-OH), serine (H-Ser-OH), homoserine (α-amino-T-hydroxybutyric acid), threonine ( H-Thr-OH), methionine (H-Met-OH), cysteine (H-Cys-OH) (which can also be presented as cystine in oxidized form), phenylalanine (H-Phe-OH), tyrosine (H- Tyr-OH), β-phenylserine (β-hydroxyphenylalanine), phenylglycine, α-naphthylalanine (H-Nal-OH), cyclohexylalanine (H-Cha-OH), cyclohexylglycine, tryptophan (H-Trp-OH), aspartic acid ( H-Asp-OH), asparagine (H-Asn-OH), aminomalonic acid, glutamic acid (H-Glu-OH), glutamine (H-Gln-OH), histidine ( H-His-OH), S-hydroxylysine, ornithine (α, δ-diaminovaleric acid), α, τ-diaminobutyric acid and α, β-diaminopropionic acid and, unless otherwise specified, arginine (H-Arg-OH) and lysine (H-Lys-OH). Particularly preferred amino acids are glycine, serine, cystine, aspartic acid and glutamic acid, particularly aspartic acid and glutamic acid. Amino acids may be omitted in defining substituted alkanoic acids.

Alkenoic acids are, for example, alkene dicarboxylic acids having 2 to 10 carbon atoms which are unsubstituted, such as maleic acid, or which are substituted, preferably by a hydroxyl group, such as in the case of hydroxymaleic acid (tautomeric form: oxaleacetic acid) or lower alkyl group, e.g. methyl group, such as in the case of methylmaleic acid.

Unsubstituted fumaric acid is excluded from the options included.

Cycloalkylcarboxylic acids are preferably C 4 -C 12 cycloalkylcarboxylic acids in which the cycloalkyl radical is monocyclic, bicyclic or tricyclic, preferably monocyclic or tricyclic, exemplified by cyclopentyl, cyclohexyl, cycloheptyl or adamantyl and for example o unsubstituted groups such as cyclohexanecarboxylic acid or adamantanecarboxylic acid.

In arylcarboxylic acids, the aryl moiety contains 6 to 20 carbon atoms, preferably 6 to 14 carbon atoms, and is, for example, selected from the group consisting of phenyl,

A 1-naphthyl group, a 2-naphthyl group and an indane radical which are unsubstituted, such as in the case of benzoic acid, or are substituted, preferably with 1 to 3 independently selected substituents from the group consisting of lower alkyl such as methyl, halogen, such as fluorine, chlorine or bromine, hydroxy, lower alkoxy such as methoxy, phenoxy, lower alkanoyloxy such as acetoxy, amino and carboxy such as salicylic acid, 1-hydroxynaphthyl-2-carboxylic acid, 3-carboxylic acid, 3-carboxylic acid, 2-carboxylic acids

3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, acid

2-acetoxybenzoic acid, 4-aminosalicylic acid or phthalic acid.

In aryl (lower alkyl) carboxylic acids, the aryl group is similar to the last defined arylcarboxylic acids and is unsubstituted or substituted as defined herein, the lower alkyl group preferably being a methyl or ethyl group, the lower alkyl group being unsubstituted, as in the case of phenylacetic acid or substituted, for example by hydroxy, as in the case of mandelic acid.

In aryl (lower alkenyl) carboxylic acids, the aryl group is as defined hereinabove for arylcarboxylic acids and the lower alkenyl group preferably contains 2 to 4 carbon atoms, as in the case of cinnamic acid.

Heterocyclocarboxylic acids contain, for example, a heterocyclic group comprising one to three rings, preferably one or two rings, which are saturated or partially or fully unsaturated, preferably saturated or unsaturated, with 5 to 12 ring atoms, preferably 5 to 7 ring atoms, which are selected from carbon atoms and one to three heteroatoms, preferably containing one or two heteroatoms, in particular an oxygen atom, a nitrogen atom and / or a sulfur atom, in particular an oxygen atom and a nitrogen atom, the heterocyclic group being, for example, pyrrolyl, imidazolyl , pyrazolyl, oxazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl or quinoxalinyl, or wholly or partially saturated derivatives derived therefrom or further pyranyl or furanyl and also unsubstituted, such as or nicotinic acid or isonicotinic acid, or one to five times substituted, preferably with hydroxy and / or hydroxy (lower alkyl), for example hydroxy or hydroxymethyl, such as in the case of glucuronic acid or galacturonic acid.

The alkanesulfonic acids are preferably alkane sulfonic acids having 2 to 20 carbon atoms, preferably alkanesulfonic acids having 2 to 7 carbon atoms, such as ethanesulfonic acid, which are unsubstituted or are preferably substituted by one or two radicals selected from hydroxy and sulfo, such as in the case of 2-hydroxyethanesulfonic acid or alkanedisulfonic acids, for example lower alkanedisulfonic acids, such as ethane-1,2-disulfonic acid. Methanesulfonic acid is excluded.

In aromatic sulfonic acids, the aromatic moiety is, for example, an aryl group as defined for arylcarboxylic acids and is unsubstituted as in the case of benzenesulfonic acid or an acid.

2-naphthalenesulfonic acid, or substituted as mentioned above, in particular by a lower alkyl group, for example methyl, such as in the case of 2-, 3- or 4-methylbenzenesulfonic acid or another sulfonyl group, such as in the case of 1,3-benzenesulfonic acid, or of 1,5-naphthalenedisulfonic acid, particularly as in 1,5-naphthalenedisulfonic acid.

Alkylsulphuric acids represent! in particular alkylsulphuric acids having 1 to 20 carbon atoms, especially lower alkylsulphuric acids such as methylsulphuric acid, ethylsulphuric acid and dodecylsulphuric acid.

N-substituted sulfamic acids are, for example, N-cycloalkylsulfamic acids in which the cycloalkyl radical is preferably a C 4 -C 12 cycloalkyl group and the cycloalkyl radical is a monocyclic, bicyclic or tricyclic group, such as cyclopentyl, cyclohexyl, cycloheptyl or adamantyl preferably a monocyclic radical such as cyclohexylsulfamic acid or N-alkylsulfamic acids, preferably N- (lower alkyl) sulfamic acids, such as methylsulfamic acid, ethylsulfamic acid or propylsulfamic acid.

Organic acids without carboxy, sulfo, sulfate or phospho groups contain, for example, acidic hydroxy groups such as ascorbic acid.

Important acids are carbonic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glucosomonocarboxylic acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, glutamic acid, aspartic acid, N-methylglycine, acetylaminoacetic acid, N-acetylasparagine, N-acetylcystine, pyruvic acid, acetic acid, phosphoserine, 2-glycerophosphoric acid, 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1-phosphoric acid, fructose-1,6-diphosphoric acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicyloic acid 1-hydroxynaphthyl-2-carboxylic acid, 3-hydroxynaphthyl-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, nicotinic acid, isonicotinic acid, glucuronic acid, galacturonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2-methylbenzenesulfonic acid, acid

3-methylbenzenesulfonic acid, 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, methylsulfamic acid, ethylsulfamic acid, propylsulfamic acid or ascorbic acid.

Very important acids are octanoic acid, succinic acid, adipic acid, salicylic acid, benzenesulphonic acid, 1,5-naphthalenesulphonic acid and N-cyclohexylsulphamic acid, of particular importance being salicylic acid and, first of all, adipic acid and benzenesulphonic acid.

Also very important acids are tartaric acid, especially L-tartaric acid, lactic acid and citric acid.

Said acids, especially if they contain more acidic groups of different acidity which can dissociate protons, can also be presented as mixed salts with cations, for example alkali metal cations such as sodium or potassium cations, alkaline earth salts such as magnesium or zinc salts, wherein at least one dissociable proton per acid moiety is present in said salts prior to the reaction or may be present in the form of a salt which is not completely free of protons and wherein at least one proton is transferred to the base of formula (I).

For example, carbonic acid may be used in the form of a bicarbonate salt, such as sodium bicarbonate or potassium bicarbonate.

The acid addition salts of the compounds of formula I with (PA) acid may also be in the form of a hydrate. The crystals may also include other solvents that have been used for crystallization.

In each case, based on the actual structure of the legs, the acid addition salts of the present invention may be in the form of isomeric mixtures or pure isomers. This means, if for example R ₂ substituents other than hydrogen and are the corresponding acid addition salt of formula I with acids are as racemic salt or a salt of enantiomeric or as the diastereomeric salts, e.g., in the presence of the asymmetric centers, such as the listed amino acid lactic or tartaric acid.

It is an object of the present invention to provide novel acid addition salts of pharmacologically useful compounds which have good solubility in physiological fluids and / or fluids similar to physiological fluids such as sodium chloride solution, mannitol solution or phosphate buffer and / or exhibit good resorbability in enteral administration, such as oral administration, for example by the formation of ion pairs, such as lipophilic ion pairs.

The acid addition salts of the present invention exhibit valuable pharmacologically useful properties. These salts exhibit a particularly potent, specific S-adenosyl methionine decarboxylase (SAMDC) inhibitory effect. SAMDC plays an important role as a key enzyme in polyamine synthesis that occurs in virtually all mammalian cells, including human. Polyamine concentrations are regulated in the cells by SAMDC. Inhibition of the SAMDC enzyme results in a decrease in the polyamine concentration. Since decreasing the concentration of polyamines causes suppression of cell growth, it is possible to suppress both eukaryotic and prokaryotic cell growth by administering a SAMDC suppressant and essentially kill the cells or trigger a mechanism to stop cell differentiation.

SAMDC inhibition can be demonstrated, for example, by the method of H. G. Williams-Ashmann and A. Schenone in Biochem. Biophys. Res. Conmuns., 46, 288 (1972). The acid addition salts of the present invention have an IC50 of at least 0.005 μιηοΐ and less.

A further advantage of the acid addition salts of the present invention is that, when compared to their strong SAMDC depressant, they only inhibit the diaminooxidase to a small extent and are well tolerated. Suppression of diaminooxidase is inappropriate as described by J. Jaenne and D. R. Morris in Biochem. J., 218, 974 (1984), since it may lead to accumulation of putrescine and indirect activation of SAMDC.

The acid addition salts of formula I are therefore useful in the treatment of benign and malignant tumors. These agents can cause tumor regression and further prevent the proliferation of tumor cells with subsequent metastasis, as well as the growth of micrometastases. They may further serve to treat protozoal infections such as trypanosomiasis, malaria or pneumonia caused by Pneumocystis carinii.

As a selective SAMDC suppressant, the base addition salts of the formula I with (PA) acids can be used alone or also in combination with other pharmacologically active substances. In this context, it is necessary to mention, for example, a combination with

(a) inhibitors of other polyamine biosynthesis enzymes, such as an ornithine decarboxylase inhibitor;

(b) protein kinase C inhibitors;

(c) tyrosine protenkinase inhibitors;

d) cytokines,

(e) negative growth regulators;

(f) aromatase inhibitors;

(g) anti --osterogenic products; or

(h) classical cytostatically active substances.

The invention preferably relates to acid addition salts of the formula I wherein A is a direct bond or a group of the formula - (CH ₂ ) _n -, wherein n is 1 or 2, X is the radical of formula -C (= Y) -NR 8 R _7, Y represents NR _g, O or S, Z is a group of formula NR _g, O or S, R and _R2 are! independently of one another hydrogen atom or one or two substituents selected from the group consisting of lower alkyl, trifluoromethyl, cycloalkyl, aryl (lower alkyl), hydroxy, lower alkoxy, aryl (lower alkoxy), aryloxy, lower alkanoyloxy, halogen, amino, N- (lower alkyl) amino, N, N-di (lower alkyl) amino, lower alkanoylamino, nitro, lower alkanoyl, arylcarbonyl, carboxy, (lower alkoxy) carbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di (lower alkyl) carbamoyl, N-arylcarbamoyl, cyano, mercapto, lower alkylthio, lower alkylsulfonyl, sulfamoyl, N- (lower alkyl) sulfamoyl or N, N -di (lower alkyl) sulfamoyl, wherein the aryl group denotes a phenyl group which; is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl, R _3, R _4, R g, R _g and R _g are independently hydrogen or lower alkyl and R ₅ and R ₇ zhamenají independently of one another hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, amino, lower alkylamino, di (lower alkyl) amino, (lower alkylene) amino, or oxa (lower alkylene) amino, thia (lower alkylene) amino or an aza (lower alkylene) amino, with (PA) acid, wherein the one or more protonated acid is selected from carbonic acid, alkanoic acids which are unsubstituted or are singly or multiply substituted, except formic acid, unsubstituted acetic acid, lysine and arginine, alkenic acids which are not or are su substituted, with the exception of unsubstituted fumaric acid, cycloalkylcarboxylic acids, arylcarboxylic acids, aryl (lower alkyl) carboxylic acids where lower alkyl is not or is substituted, aryl (lower alkenyl) carboxylic acids, heterocyclocarboxylic acids, alkanesulfonic acids which are not or are substituted, with the exception of unsubstituted methanesulfonic acid, aromatic sulfonic acids, alkylsulfuric acids, N-substituted sulfamic acids, non-carboxylic acid organic acids, sulfo group, sulfate group or phosphine group, and also pyrophosphoric acid and hydroiodic acid, for example one of the aforementioned acids for example, one of the acids defined as very important, and their tautomers.

Particularly preferred are acid addition salts, base of the formula I, wherein A is a direct bond or a group - (CH _{2) n} -, wherein n is 1 or 2,

X is a radical -C (= Y) _-NRgR? , Y is NH, O or S, Z is NH, O or S, R 1 and R ₂ independently of one another are hydrogen or one or two substituents selected from the group consisting of lower alkyl, trifluoromethyl , phenyl (lower alkyl), hydroxy, lower alkoxy, and halogen, R ₃ , R ₄ and R 8 are alkyl; a hydrogen atom and R and _R? independently of one another are hydrogen, lower alkyl, hydroxy or amino, with (PA) acid, wherein the one or more protonated acid is selected from carbonic acid, alkanoic acids which are unsubstituted or are singly or multiply substituted, except formic acid , unsubstituted acetic acid, lysine and arginine, alkenic acids which are not or are substituted, with the exception of unsubstituted fumaric acid, cycloalkylcarboxylic acids, arylcarboxylic acids, aryl (lower alkyl) carboxylic acids where lower alkyl is not or substituted, aryl (lower alkenyl) ) carboxylic acids, heterocyclocarboxylic acids, alkanesulfonic acids which are not or are substituted, with the exception of methanesulfonic acid, aromatic sulfonic acids, alkylsulfuric acids, N-substituted sulfamic acids, organic acids neo containing a carboxy, sulfo, sulfate or phospho group; and pyrophosphoric acid and hydroiodic acid, for example one of the aforementioned important acids, such as one of the ones defined as particularly important, or tautomers thereof.

In the first instance, acid addition salts of the base of formula I are preferred, wherein A represents a direct bond or a group of formula -CH ₂ ', X represents a radical of formula -C (= Y) -NR ₈ R ₇ ,

Y is NH or S, Z is NH, R _T is hydrogen or one or two substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy and halogen, R ₂ is hydrogen or lower alkyl R ₃ , R ₄ and R 8 are hydrogen and R ₅ and R ₇ are hydrogen; independently of one another a hydrogen atom, a lower alkyl group or a hydroxy group with a (PA) acid having the meanings given above, for example one of the acids defined as important, in particular one of the acids defined as particularly important, or tautomers thereof.

Particularly preferred are acid addition salts of the base of formula I wherein A is a direct bond, X is a radical of formula -C (= NH) -NH ₂ , Z is a group of formula NH, R 6 represents a hydrogen atom or one or two substituents selected from the group consisting of lower alkyl, hydroxy and lower alkoxy, R _2, R ₃ , R ₄ and R 8 are hydrogen and R ₅ is hydrogen or hydroxy with (PA) an acid as defined above, for example one of the acids defined as important, in particular one of the acids defined as particularly important, or tautomers thereof.

As a subgroup of the set of acid addition salts of the formula I with (PA) acids, it is useful to highlight:

(a) acid addition salts, a base of formula (I) wherein A is a direct bond;

b) acid addition salts, a base of formula I wherein X is -C (= NH) -NH ₂ ,

c) acid addition salts, base of the formula I, wherein Z is a radical of formula -NH-, R ₄ is H and R ₅ is H or OH and

d) acid addition salts, a base of the formula I, wherein R, and _R2 is a r a hydrogen atom; the other groups have the already mentioned meanings, with (PA) acids selected from the above files, such as one of the acids defined as being very important , or tautomers thereof.

The invention also relates, in the first place, to acid addition salts of the base of formula I, wherein A represents a direct bond, X represents a radical of formula -C (= NH) -NH ₂ , Z represents a group of the formula NH and R p R ₂ , R ₃ , R ₄ and R ₅ are each hydrogen, with (PA) acids defined above or preferably marked as important above, for example those defined as very important, for example an acid selected from N-cyclohexylsulfamic acid, octanoic acid, salicylic acid or benzenesulfonic acid , such as salicylic acid.

The invention also relates primarily to acid addition salts of the base of formula I, wherein A represents a direct bond, X represents a radical of formula -C (= NH) -NH ₂ , Z represents a group of the formula NH and R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each hydrogen, with the (PA) acids defined above as very important, especially selected from tartaric acid, especially L-tartaric acid, lactic acid and citric acid.

Most preferred are the acid addition salts of 21, the base of formula (I) with the (PA) acids described in the examples.

The base addition salts of the formula I with (PA) acids are prepared in a manner known per se, for example by:

(a) a base of formula (I)

(I) ITL ₃ R ₄ in which the radicals are as defined for acid addition salts of bases of formula I with an acid, is reacted with (PA) an acid, wherein (PA) is as defined above,

b) a compound of formula II

X

v / v v ₂ in which the group CW- _L W ₂ represents a carbonyl group, a functional modified carbonyl group or a protected carbonyl group, and

A, X, R and _R2 are as defined for acid addition salts of bases of formula I with an acid, is condensed with an amine of the formula III

R ₃ R ₄ (H 1) wherein

Z, R ₃ , R ₄ and R _{5 have the} meanings given for the acid addition salts of the formula I in the presence of (PA) an acid, wherein (PA) has the meanings given above,

c) in a compound of formula IV

(IV), i

R ₃ Ŕ ₄ in which

W ₃ represents a residue which can be converted into a group

X in the base of formula I and

A, Z, R 1, R ₂ / ^R 3 / ^R 4 ^{and R} 5 have the meanings given under the general formula I, the residue W _{3 is} converted to the group X in the presence of (PA) acid, wherein (PA) has the above meanings, the sky

(d) any acid addition salt of formula (I) not falling under definition (PA) is converted to an acid addition salt of formula (I) with (PA) acid, wherein (PA) has the above meanings and, if desired, the obtained base addition salt of formula (I) with (PA) acid is converted to another base addition salt of formula (I) with (PA) acid and / or, if desired, the isomeric mixture is separated into individual isomers.

, In the following description available processes a) to d), the symbols A, X, Y, Z, R and _G, and (PA) is defined as in the definition of base addition salts of formula I with (PA) acids unless otherwise indicated.

Method a)

The reaction of the base of formula I with (PA) acid to the corresponding acid addition salt is carried out in a manner known per se which leads to the formation of acid addition salts of basic compounds.

The reactions for the preparation of acid addition salts are carried out, for example, in solvents, in particular in organic solvents, in particular polar organic solvents, in ethers, for example (lower alkanoyl) (lower alkyl) ethers, such as ethyl ether, amides, for example in N, N-di (lower alkyl) (lower alkanoyl) amides such as dimethylformamide, in alcohols such as hydroxy (lower alkanes) such as methanol, ethanol, ethylene glycol or glycerin, or in aryl alcohols such as phenols, e.g. phenol, or in dimethylsulfoxide, in the absence or presence of water, preferably in the absence of water. Especially preferred is the reaction in the alcohols, such as the hydroxy (lower alkanes) mentioned in this paragraph.

The reaction takes place, for example, in free solution, but can also be carried out on a chromatographic column, for example using gel filtration or ion exchange or semipermeable membranes using osmotic pressure.

The reaction is carried out at a temperature from the freezing point to the boiling point of the solvent, preferably from 0 to 50 ° C, in particular from 20 to 40 ° C, for example at room temperature, in the presence or absence of a protective gas such as nitrogen or argon.

The compounds of formula (I) and (PA) acid are used in suitable molar ratios or (PA) acid is used in excess. Preferably, the individual components are used in a molar ratio that corresponds to the molarity ratio of the base of formula (I) and the (PA) acid in the acid addition salts of the invention.

The salts formed precipitate on their own, or only after cooling, or by the addition of a solvent, a special non-polar solvent, for example an ether such as diethyl ether or water, and / or are obtained by partial or complete evaporation.

Method b)

As a functional modified or protected CW ₁ W ₂ carbonyl group, there is exemplified a di (lower alkoxy) methyl group, an alkylenedioxymethyl group having 1 or 2 carbon atoms in an alkylene moiety, a dihalomethyl group, a di (lower alkyl) thiomethyl group or an alkylenedithiomethyl group with 1; 2 carbon atoms in the alkylene moiety.

Preferably, CW ₁ W ₂ in the compound of formula (II) represents a free carbonyl group.

The condensation reactions according to process b) are carried out under known conditions for the formation of hydrazones and in the presence of (PA) acid which is presently catalytically active. The (PA) acid is preferably present in an amount that protonates the reacting amino group in the compound of formula III only to a small extent so that the compound is still reactive. Particularly preferred for this are the starting compounds if they contain salt-forming groups such as salt (PA) acids, which may optionally be produced in situ, either from free compounds or salts of slightly volatile acids such as hydrohalic acids, for example hydrobromic acid or hydrochloric acid, acid formic acid, acetic acid or carbonic acid (such as carbonate or bicarbonate), whereby the reaction can also be carried out, for example, in the presence of a catalytically effective small excess (PA) of the acid. As the solvent, use is made of the solvent mentioned under process (a), in particular aqueous solvents such as water, at preferred temperatures from 20 ° C to the boiling point of the respective reaction mixture, in particular at the boiling point of the respective mixture, in the presence or absence of a shielding gas such as nitrogen; argon. Suitable compounds of formula (II) are those protected carbonyl groups CW ₁ W ₂ which, under condensation conditions, convert to a free carbonyl group.

For the production of acid addition salts from bases of formula I wherein R ₅ is amino, and (PA) acids it is recommended to use the compound of formula III in excess.

Method c)

In the intermediates of formula (IV), W _{3 is,} for example, a free or functional substituted carboxy group, in particular a halocarbonyl group, a cyano group, an imino (lower alkoxy) carbonyl group, an imino (lower alkyl) thiolcarbonyl group or a thiocarbamoyl group.

The group W _{3 of the} compound of the formula IV in the preparation of the amidine of the formula I (Y represents a group of the formula NR _g ) can for example be imino (lower alkyl ester) or imino (lower alkyl) sulfide addition salts with one of the abovementioned compounds. S-acids, for example -C (= NH) -OC ₂ H ₅ (PA) or -C (= NH) -SC ₂ H ₅ (PA), furthermore a thiocarbamoyl group or a cyano group.

Reaction of the imino (lower alkyl) ester of formula IV (as an acid (PA) salt as defined above) with ammonia or primary or secondary amines affords unsubstituted, monosubstituted or disubstituted acid addition salts corresponding to the amidine of formula I. Cyano compounds of formula IV can be converted by reaction with a primary or secondary (di) - (lower alkyl) amine salt of said acid (PA) to an optionally monosubstituted or disubstituted amidine addition salt of the formula I with an acid.

In the preparation of the compound of formula (IV), W ₃ in the preparation of a carbamoyl-substituted base of formula I (Y is oxygen) as an acid addition salt (PA) component may be carboxy, halocarbonyl (e.g. -COC1) or lower alkanoyloxy . Manufacture optionally carbamoyl group mono- or di-substituted bases of formula I as components of acid addition salts (PA) an acid, is carried out from a corresponding intermediate of the formula IV, wherein R ₃ is carboxy, halocarbonyl or lower alkanoyloxy group, by reaction with ammonia, primary or secondary amines in a manner known per se. The corresponding acid addition salts of the base I can be obtained directly from the reaction mixture by precipitation, but also by acidification, for example of an alcoholic or neutral reaction mixture, with the abovementioned (PA) acids.

In the preparation of the addition salts of carbamoyl-substituted bases of the formula I (Y represents an oxygen atom) with an acid, for example, the group W ₃ in the compound of the formula IV can be cyano. Intermediates of formula IV in which W ₃ is cyano may be converted, for example, by partial hydrolysis, according to the Graf-Ritter reaction or through salts of carboxylic acid esterimide with the corresponding (PA) acids to the optionally carbamoyl monosubstituted or disubstituted base of formula I. acid addition salts. The conditions for the hydrolysis of the cyano-containing intermediates can be selected by interrupting the reaction at the amide stage. Suitable acids for this purpose are acid hydrolysis (PA) as defined above, in particular the strong acids mentioned above and having a pH of less than or equal to 5, at room temperature or during heating, for example to boiling point or up to 150 ° C. C, in the presence of an anhydrous solvent or a solvent that contains a stoichiometric amount of water.

The acid addition salt of the N-substituted amide of formula (I) from the nitrile of formula (IV) also succeeds in the Graf-Ritter reaction. To this end, the nitrile is reacted in the presence of an (PA) acid, preferably a stronger acid (pK 2 less than or equal to 5), with a compound which can form carbenium ions in an acidic environment, for example olefins such as propylene or alcohols such as ethanol.

The carboxylic acid esters are obtained, for example, by the acid-catalyzed rearrangement of the alcohols into the nitriles of formula IV. The esterimides obtain the acid addition salts of the amide (I) using Pinner cleavage, by thermal decomposition of the esterimide salt with (PA) acid at a temperature above about 80 ° C.

Base addition salts of formula I wherein X is -C (= NH) -NRgR ₂ with (PA) acids may also be prepared by reacting compounds of formula IV or its addition salts with the above (PA) acids, wherein W ₃ is a radical of formula -C (= S) -NH 2, under S-alkylation with, for example, tri (lower alkyl) oxonium tetrafluoroborate and then reaction with the ammonium salt of the above (PA) acid or the corresponding amine addition salt of the formula NHR 8 R? with one of the already mentioned (PA) acids.

The reaction of (c) may be carried out, unless otherwise indicated, under the reaction conditions known per se in the absence or usually in the presence of a solvent or diluent, preferably a solvent or diluent against which the reagents used are inert and which are dissolved, in the absence or presence of a catalyst, condensation agents or neutralizing agents, depending on the type of reaction and / or the components involved in such reaction at reduced, normal or elevated temperatures, for example in a temperature range of about -70 to about 190 Preferably from about -20 to about 150 ° C, for example at room temperature or the boiling point of the solvent used in the reaction mixture at atmospheric pressure or in a closed vessel, optionally under pressure and / or in an inert atmosphere, for example under a nitrogen atmosphere.

Method d)

The reaction of any base addition salt of formula (I) with an acid that does not fall under the acids defined as (PA) acids is accomplished by conventional salt conversion methods.

Acids that do not fall under the definition of (PA) acids include all other protonic acids, for example organic acids such as formic acid, acetic acid or methanesulfonic acid, or inorganic acids such as sulfuric acid, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, followed by azidic acid or phosphoric acid. Particularly preferred are the salts of hydrohalic acids.

Reactions of such acid salts that do not fall! under the definition of (PA) acids, the addition salts with (PA) acids are carried out, for example, in a solvent, in particular an organic solvent, in particular polar organic solvents, first in esters such as (lower alkanoyl) (lower alkyl) esters, such as ethyl acetate, amides such as N, N-di (lower alkyl) (lower alkanoyl) amides such as dimethylformamide in alcohols such as hydroxy (lower alkanes) such as methanol, ethanol, ethylene glycol or glycerin, or aryl alcohols phenols, such as phenol, or in dimethylsulfoxide, in the absence or presence of water, preferably in the absence of water. Particular preference is given to reaction in alcohols such as the above-mentioned hydroxy (lower alkanes).

However, the reaction may also be carried out with the free base of the formula I, for example produced when the base salts of the formula I with acids not falling under the definition of (PA) acids used as starting materials are converted by a base, e.g. a hydroxide, such as an alkali metal hydroxide, for example with sodium hydroxide or potassium hydroxide, in an aqueous solvent in the absence or presence of an organic solvent as defined under a), to the free base, and then treating the free base as described, for example under a).

The compounds of the formula I with (PA) acids are used in suitable molar ratios in the reactions described above or (PA) acid is used in excess. The individual components are preferably used in a molar ratio which corresponds to the molarity base of the formula I and the (PA) acid in the acid addition salts of the invention.

The reaction is carried out at a temperature from the freezing point to the boiling point of the solvent, preferably at a temperature of 0 to 50 ° C, in particular from 20 to 40 ° C, for example at room temperature, in the presence or absence of a shielding gas such as nitrogen or argon. .

For example, the salts formed precipitate, optionally after cooling, by themselves or with the addition of a solvent, a particular non-polar solvent, for example an ether such as diethyl ether or water, and / or are obtained by partial or complete evaporation.

Additional measures

The acid addition salts of the formula I with (PA) acids can be converted into the acid addition salts and / or other (PA) acids of the other bases of the formula I using a method known per se.

This process can be carried out by converting (PA) an acid, a base of the formula I or both components of an acid addition salt.

For example, the (PA) acid component may be exchanged, either directly by the presence in the presence of (PA) the acid to be introduced, which may be used, for example, in excess, or indirectly by the acid addition salt containing the base of formula I used as starting material. , to the free form, for example by reacting an acid addition salt of a base of formula I with a base, a particular base formed with a hydroxide such as an alkali metal hydroxide, for example sodium hydroxide or potassium hydroxide, in aqueous solution in the presence or preferably in the absence of an organic solvent as defined in process a), followed by conversion to the free base and finally reacting the free base of process a) to another acid addition salt of formula I with dialysis, ion exchange or gel chromatography.

The bases of the formula I in acid addition salts, which consist of the bases of the formula I and the (PA) acid, can also be converted to other bases of the formula I.

For example, bases of formula I wherein X is -C (= S) -NH ₂ may be converted by S -alkylation, for example tri (lower alkyl) oxonium tetrafluoroborate, followed by reaction with the ammonium salt of (PA) acid contained in in the original acid addition salt and ammonia or amine alone of the formula NHRgR ₇ on another base of formula I wherein X is a radical of formula -C (= NH) -NRgR ₇ , wherein in the acid addition salts obtained the acid component itself above.

The base of formula (I) in addition salts with (PA) acids where X is -C (= NH) -NH-OH can be converted by reaction in the presence of a base such as triethylamine and an oxidizing agent such as iron pentacarbonyl, in an organic solvent, such as tetrahydrofuran, at an elevated temperature, preferably at the boiling point of the reaction mixture, and then reacting the obtained product with the appropriate (PA) acid to form a base addition salt of formula I with an acid wherein X is -C (= NH) -NH ₂ , wherein (PA) acid does not change from the starting salt.

The isomer mixtures obtainable according to the invention can be separated in a manner known per se into the individual isomers, racemates, for example by preparing salts with optically pure salt-forming agents and separating the diastereomeric mixtures thus obtained, for example by fractional crystallization or column chromatography of optically active materials.

In the process according to the invention, it is advantageous to use: those starting compounds which lead to acid addition salts which have already been described as being particularly valuable.

The invention also relates to such process embodiments starting from a compound obtained as an intermediate in any or any of the manufacturing steps or steps and missing process steps, or wherein the starting material is formed under the reaction conditions or the starting material is used in the form of a derivative, for example in the form of its salt.

Pharmaceutical preparations

The present invention also relates to pharmaceutical compositions comprising: as active ingredient, a pharmacologically active addition salt of the formula I with (PA) acid. Especially preferred are compositions for enteral, especially oral, as well as parenteral administration. Contain! the active ingredient alone or preferably together with at least one pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the disease to be treated, as well as the species of the individual, its age, weight and individual condition as well as the mode of use.

The pharmaceutical compositions contain from about 0.1 to about 95% of the active ingredient, wherein the unit dosage forms preferably contain from about 1 to about 90% and the non-unit dosage forms preferably contain from about 0.1 to about 20%. active ingredients. Unit dosage forms such as dragees, tablets, or capsules contain from about 1 to about 500 mg of the active ingredient.

The pharmaceutical compositions of the present invention can be prepared in a manner known per se, for example by means of conventional mixing, granulating, dragee, solvent or lyophilization processes. Thus, pharmaceutical compositions for oral administration can be obtained when the active ingredient is contacted with one or more carriers, the mixture obtained is optionally granulated and, if necessary, the mixture or granulate is formulated into tablets with the addition of additional excipients. or dragee cores.

Suitable carriers are special fillers such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example calcium phosphate or dibasic phosphate, as well as binders such as starches, for example corn, wheat, rice or potato starch. methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and / or, if desired, disintegrants such as the aforementioned starches, further carboxymethylated starches, cross-linked polyvinylpyrrolidone, alginic acid or its salts such as sodium alginate.

Supplementary excipients are, first of all, flow control agents and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium salts of stearic acid, and / or polyethylene glycol or derivatives thereof.

Dragee cores may be provided with a suitable coating which is optionally resistant to gastric juice, which may include, but is not limited to, concentrated sugar solutions, optionally containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents. or mixtures of solvents or for making gastric juice-resistant coatings, solutions of suitable cellulosic preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyestuffs or pigments may be added to the tablets or dragee core, for example, to recognize or indicate different doses of the active ingredient.

Pharmaceutical compositions for oral use are also insertable gelatin capsules as well as soft, sealed gelatin capsules and plasticizers such as glycerin or sorbitol. The push-fit capsules may contain the active ingredient in the form of a granulate, for example in admixture with a filler such as corn starch, a binder and / or a glidant such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is dissolved or suspended, preferably in a suitable liquid excipient, such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilizers may optionally be added to the ingredients.

Other dosage forms for oral use are, for example, syrups obtainable by conventional means in which the active ingredient is, for example, in suspended form and is present in a concentration of about 0.1 to 10%, preferably about 1%, or a similar concentration such as measuring 5 or 10 ml of syrup provides a suitable unit dose.

Powder or liquid concentrates for the preparation of cocktails, for example in milk, are also suitable. Such concentrates may also be packaged in an amount appropriate to the unit dose.

Suitable rectal pharmaceutical compositions are, for example, suppositories which consist of a combination of the active ingredient and a suppository base. Suitable lace bases are, for example, naturally occurring or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alcohols.

Particularly suitable for parenteral use are aqueous solutions of the active ingredient which are in water-soluble form, for example water-soluble salts, or aqueous suspensions for injection which contain water. viscosity enhancers, for example sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally stabilizers. The active ingredient, if desired together with the excipients, can also be in the form of a lipophilisate and can be used for parenteral use by adding a suitable solvent in solution. Isotonic solutions for infusion may be prepared by the addition of suitable salts such as sodium chloride, buffers such as phosphate buffer, for example with sodium as the counter ion and / or sugar alcohols such as mannitol, and optionally additional excipients may also be added.

Solutions such as are used, for example, for parenteral use can also be used as infusion solutions.

usability

The invention also relates to a method for the treatment of the aforementioned disease states, in particular conditional on the suppression of S-adenosyl methionine decarboxylase, which react to treatment with inhibition of S-adenosyl methionine decarboxylase. The acid addition salts of the present invention can be administered prophylactically or therapeutically, particularly in an amount suitable for the suppression of S-adenosyl methionine decarboxylase, and are preferably used in the form of a pharmaceutical composition. The acid addition salts of the present invention are administered. warm-blooded individuals, including bees, who require! such treatment, because it suffers from a protozoal infection or tumor, at a body weight of about 70 kg, at a daily dose effective against said diseases, from about 1 to about 1000 g, preferably from about 25 to 100 mg orally or from 2 to 50 mg parenterally.

The invention also relates to pharmaceutical compositions which are also suitable for administration to a mammal, for example a human, in order to avoid or treat a disease which responds to a S-adenosylmethionine decarboxylase suppressant treatment, particularly in the case of cancer or protozoal infections. Such pharmaceutical compositions include acid addition salts of a compound of Formula I or tautomers thereof in an amount effective to inhibit S-adenosyl methionine decarboxylase, and a pharmaceutically acceptable carrier material.

Starting compounds

Protic acids ((PA) acids) are known, are obtainable according to known methods and are commercially available.

The starting compounds of the formula (I) are prepared according to methods which are known per se, as follows

i) a compound of formula II as defined for process a), condensed, and an amine of the formula III, as defined in process a), or ii) the compound of formula IV, as defined for Process c), the residue W ₃ and transfered to the group X and, if desired, the obtained compound of formula I is converted to another compound of formula I and / or, if desired, the obtained salt is converted to a free compound or to another salt and / or, if desired, obtained free the compound of formula I having salt-forming properties is converted to salt.

In the following description of methods (i) and (ii), the formulas A, X, Y, Z and R @ 1 to R @ 8 are suitable in the formulas as well as (PA) for the addition salts of the base of formula I with (PA). ) acids, unless otherwise stated.

Method i)

As a functionally modified or protected CW ₁ W ₂ carbonyl group, there is exemplified a di (lower alkoxy) methyl group, an alkylenedioxymethyl group having 1 or 2 carbon atoms in the alkylene moiety, a dihalomethyl group, a di (lower alkyl) thiomethyl group or an alkylenedithiomethyl group with 1; 2 carbon atoms in the alkylene moiety.

Preferably, the group CW-W ₂ in the compound of formula II represents a free carbonyl group.

The condensation reaction according to process i) is carried out under known conditions for the formation of hydrazones and is preferably acid catalyzed. In the compounds of formula (II), suitable protected carbonyl groups C 1 -W ₂ W _{2 are} converted to a free carbonyl group under condensation conditions.

For the preparation of compounds of formula I, wherein R ₅ is amino, it is recommended to use a compound of the formula III in excess.

Intermediates of formula I wherein Y in X is NH are obtained, for example, by compound of formula V

(V) is first converted by treatment with hydrogen sulfide to the corresponding thiocarboxamide (-C (= S) -NH ₂ ). This compound can also be obtained in another way when starting from an analogous carboxamide (-C (= O) -NH ₂ ), for example by reaction with Lawesson's reagent (2,4-bis- (4-methoxyphenyl) -2,4-dithioxo). -l, 3,2,4-dithiadifosfetanem). The thiocarboxamide is S-alkylated with, for example, a lower alkyl iodide or tri (lower alkyl) oxonium tetrafluoroborate, thereby converting the hydroiodide or tetrafluoroborate to an imino (lower alkyl) sulfide (-C (= NH) S-alkyl.Hl), which can readily be converted with ammonia. or an amine of formula NHR ₆ R ₇ to the desired carboximidamide of formula I (cf. S. Patai (ed.), The Chemistry of Amidines and Imidates, Wiley, London, etc., pp. 303 and 304 (1975)).

The preparation of the carboxamide of the formula II from the cyano compounds of the formula V takes place analogously to the preparation of the carboxamide of the formula I from the cyano compounds of the formula IV described in process ii) and is also described in detail herein.

Another possibility for preparing compounds of Formula II is characterized in that the compound of formula V, wherein the group CW ^ W ₂ is as defined in formula II, is treated for example with ethanol and hydrochloric acid, for example, chloroform or diethyl ether, producing the corresponding iminoethyl ester hydrochloride, which can be converted, for example, by reaction with an aminoac or a primary or secondary amine of the formula NHR ₆ R ₇ and, for example, methanol to the desired carboximidamide of the formula II. However, this process may fail in some cases on steric hindrance by the A group or the R 1 group.

The starting compounds of the formula (V) are known per se or can be prepared analogously to known compounds.

Compounds of formula V may be prepared, for example, by intramolecular Friedel-Crafts acylation of o-phenyl (lower alkanoic acid) (omega-phenyl (lower alkanoic)) of formula VI

in which

W ₄ represents a cyano group or a cyano precursor, or a derivative thereof, for example an acid chloride or an acid anhydride. The catalysts used may be free acids, for example polyphosphoric acids and acid chlorides or anhydrides, for example aluminum chloride.

Preferably, compounds of formula VI are used in this reaction wherein W ₄ is a cyano group or a cyano precursor, for example, a halogen atom, a particular bromine atom, or a protected amino group, for example, acetylamino. After the cyclization step, the cyano precursor can be carried out to the cyano group in a manner known per se, for example in the case of a bromine atom by reaction with copper cyanide or in the case of acetylamino by cleavage of the acetyl protecting group, diazotization and reaction with copper cyanide.

Compounds of formula V in which the group CW ₁ W ₂ is a carbonyl group can be prepared, for example, by oxidation, for example with chromium oxide, from the corresponding compounds not containing a carbonyl group of the formula VII

in which

W ₄ represents a cyano group or a cyano precursor as defined above.

If a cyano precursor is used, the precursor is again converted to the cyano group following subsequent oxidation, for example as described above.

Another possibility for the preparation of compounds of formula V in which W ₄ is a carbonyl group is by starting from a compound of formula II in which X is a hydrogen atom and introducing a cyano group, for example by a reaction sequence analogous to that described in U.S. Pat. U.S. Patent No. 5,201,516; No. 3,956,363, Example 10, by nitration, reduction of the nitro group to the amino group, diazotization, and reaction with copper cyanide (Sandmeyer reaction).

The preparation of the aminoguanidines, amino ureas and aminothioureas of formula III is known per se. Amino (thio) ureas (semi (thio) carbazides) are produced, for example, in an analogous manner to the corresponding simple (thio) ureas. For example, the corresponding hydrazines H ₂ N-NHR _{3 are used} instead of amines and reacted, for example, with an isocyanate R ₄ N = C = O or R ₈ N = C = O, an isocyanate R ₄ N = C = S or R ₅ N = C = S, carbamoyl chloride of formula R ₄ R ₅ N ₄ -COC 1 or thiocarbamoyl chloride of formula R ₈ R ₂ N-CSCl. In addition, it is also possible to react the hydrazine H ₂ N-NHR ₃ with an acyl isothiocyanate, for example acetyl isothiocyanate and subsequent hydrolysis under acidic conditions.

The aminoguanidines of the formula III, in which Z represents a group of the formulas NR _g and R ₃ , R ₄ , R ₅ and R _{g have the} meanings given under the formula I, are identical and can be prepared, for example, from the corresponding aminothioureas III. aminothioureas by alkylation, for example alkyl tosylate or alkyl halide, are converted to the corresponding S-alkylisothiuronium salts and reacted with an amine of the formula NHR ₄ Rg.

Method ii)

In the intermediates of formula (IV), W _{3 is,} for example, a free or functional substituted carboxy group, in particular a halocarbonyl group, a cyano group, an imino (lower alkoxy) carbonyl group, an imino (lower alkyl) thiolcarbonyl group or a thiocarbamoyl group.

For example, the group W ₃ in the compound of formula (IV) may be an acid addition salt of imino (lower alkyl (ester (imino (lower alkyl) ether)) or imino (lower alkyl) sulfide, e.g. -C (= NH) -OC ₂ H ₅ .HCl or

-C (= NH) -SO ₂ Hg.HI, or cyano.

Reaction of the imino (lower alkyl) ester of formula IV (in the form of a salt) with ammonia or primary or secondary amines yields unsubstituted, monosubstituted or disubstituted amidines of formula I. Cyano compounds of formula IV may be reacted with, for example, an alkali metal amide such as KNH ₂ or by reaction with a primary or secondary (di) - (lower alkyl) ammonium halide, for example with ⁺ NH ₃ CH ₃ Cl ', to convert a monosubstituted or disubstituted amidine of the formula I, if appropriate.

In the preparation of carbamoyl compounds of formula I (Y is O), the group W ₃ in the compound of formula IV may for example be carboxy, halocarbonyl (e.g. chlorocarbonyl), lower alkanoyloxy or cyano. Form an optionally mono- or di-substituted carbamoyl compounds of formula I from corresponding intermediates of formula IV, wherein W ₃ is carboxy, halocarbonyl or lower alkanoyloxy, reacting with ammonia or primary or secondary amines is known. Intermediates of formula IV in which W ₃ is cyano may be converted by partial hydrolysis according to the Graf-Ritter reaction, or via the carboxylic acid esterimide salt of the monosubstituted or disubstituted carbamoyl compound of formula I. The hydrolysis conditions of the cyano compound may be selected as such. The reaction is carried out by interrupting the reaction in the amide step. Suitable for this purpose are hydrolysis with acids, for example 80% sulfuric acid (with heating), polyphosphoric acid (at 110 to 150 ° C), mixtures of hydrobromic acid and glacial acetic acid (at room temperature, in the presence of formic acid or without further solvent) or hydrogen chloride gas in an ethereal solution carried out with the addition of water or aqueous hydrochloric acid, or a reaction with boron halide.

The N-substituted amides or nitriles of formula (IV) have also been produced by the Graf-Ritter reaction.

Let it go! react nitriles in the presence of a strong acid, in particular 85 to 90% sulfuric acid, or also polyphosphoric acid, formic acid, boron trifluoride or other Lewis acid but not aluminum chloride, with compounds which may form carbenium ions in an acidic environment, with olefins such as propylene and alcohols such as ethanol.

The carboxylic acid esters are obtained. for example, acid catalyzed alcohol rearrangement to nitriles of formula IV. From esterimide, amides are obtained by Pinner cleavage by thermal cleavage of esterimide salts at temperatures above about 80 ° C.

Compounds of formula IV in which W ₃ is cyano can be prepared, for example, by reacting a compound of formula V with a compound of formula III according to process ii). From the compound of formula IV, wherein W ₃ is CN, may be prepared other compounds of formula IV, wherein W ₃ represents a free or functionally modified carboxy, in a conventional manner or as above.

The compounds of formula I, wherein X is a radical of formula -C (= NH) -NRgR ?, can also be obtained by reacting a compound of formula IV, wherein W ₃ is -C (= S) _-NH2 in S alkylation conditions, for example, tri (lower alkyl) oxoniumtetrafluorborátem, followed by reaction with ammonia or an amine of formula NHR _{6 R?} or the corresponding ammonium salt, for example chloride.

Compounds of formula I may be converted to other compounds of formula I.

For example, compounds of formula I wherein X is -C (= S) -NH ₂ , S-alkylation, for example tri (lower alkyl) oxonium tetrafluoroborate, followed by reaction with ammonia or an amine of formula NHR ₆ R ₇ or in particular the corresponding ammonium salt, can be converted to a compound of formula I wherein X is -C (= NH) -NR 8 R 8.

The compounds of formula I, wherein X is a radical N-hydroxyamidine of the formula -C (R _g) -NHOH, may be converted for example by treatment with iron pentakarbonylem (formula Fe (CO) ₅₎ to a different compound of formula I, wherein X represents an analogous amidine moiety of the formula -C (= NR 8) -NH ₂ (see, for example, J. Chem. Soc. Chem. Commun.

1975, 761).

The free compounds of the formula I obtainable according to the invention with salt-forming properties can be converted into salts in a manner known per se, namely those with basic properties, for example by treatment with acids, either with protonic (PA) acids or preferably with other protonic acids, for example, organic acids not falling under the definition of (PA) acids such as formic acid, acetic acid or methanesulfonic acid, or inorganic acids such as sulfuric acid, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid; azidic acid or phosphoric acid. Particularly preferred are hydrohalic acids. The reaction is carried out analogously to process a) for the preparation of acid addition salts of the formula I with (PA) acids.

The base addition salts of the formula I with acids, in particular protonic acids other than (PA) acids, can be converted to the free compounds. This can be done, for example, by converting to the free base, for example by reacting a salt of a compound of formula I used as a starting material, with a base hydroxide such as an alkali metal hydroxide, for example sodium or potassium hydroxide, in aqueous solution in the absence or preferably in the presence of organic. solvents as defined in process a) to form the free base, further by dialysis, ion exchange or gel chromatography.

The preparation of the starting compounds of the formulas II, III and IV is carried out as explained in the detailed description of the process

(i) and (ii).

As a result of the close relationship between the compounds of the formulas I, II, III, IV and also V, VI and VII in the free form and, if these compounds contain salt-forming groups, in the form of salts, salts according to the meaning and purpose also include, if appropriate, the corresponding salts, for example acid addition salts or else salts with bases or free compounds.

The preparation of salts, for example compounds of formulas II, III and IV, containing salt-forming groups, is carried out analogously to the preparation of salts of the base of formula I (process a).

The compounds, including their salts, may also be obtained in the form of a hydrate, or their crystals may contain, for example, the solvent used for crystallization.

Mixtures of isomers obtainable according to process i) or ii) can also be separated into the individual isomers, racemates, for example by forming a salt with optically pure salt forming agents and separating the diastereomers thus obtained, for example by fractional crystallization.

The above reaction according to process i) or ii) can be carried out under reaction conditions known per se in the absence or usually in the presence of a solvent or diluent, preferably a solvent or diluent which is inert to the reactants used and these components. solvent, in the absence or presence of catalysts, condensing agents, or heutralizing agents, depending on the nature of the reaction and / or the reactants involved in such reaction at a reduced, normal or elevated temperature, for example in a temperature range of about -70 to about 190 ° C, preferably from about -20 to about 150 ° C, for example at room temperature or the boiling point of the solvent used in the reaction mixture, at atmospheric pressure or in a sealed vessel, optionally under elevated pressure and / or under an inert atmosphere, e.g. atmosphere.

DETAILED DESCRIPTION OF THE INVENTION

In the following examples, the preparation of the starting compounds of formula I is described for purely illustrative reasons. As is usual, temperatures are given in degrees Celsius.

It is noted that the term absolute has the same meaning as anhydrous, the compound represented by formula D ₂ O represents deuterated water, DMSO-d ₆ denotes perdeuterated dimethylsulfoxide, ether is abbreviated for diethyl ether, ethyl acetate is equivalent to ethyl acetate, IR abbreviated denotes infrared spectroscopy and MS (FAB) are used to denote the mass spectrum using fast atom bombardment techniques.

1) Starting compound A:

dihydrochloride ^{4-amino-2-indanone-1} -amidinohydrazonu

A solution of 3.8 g (27.9 mmol) of aminoguanidine bicarbonate in 200 ml of water and 14.7 ml of 2-normal hydrochloric acid was heated to 60 DEG C. and stirred with a solution of 5.85 g (30 minutes) with stirring. 27.8 mmol) of 4-amidino-1-indanone hydrochloride in 200 ml of methanol. The reaction mixture was refluxed for 24 hours and evaporated to dryness after cooling. The residue is suspended in 50 ml of ethanol, filtered, washed with ethanol and ether and dried. This gives the title compound which contains 1 mole of crystal water and has a melting point above 330 ° C.

MS (FAB method): (M + H) &lt; ^{+ &gt}; = 231.

¹ H-NMR analysis (D ₂ O): δ = 8.08 (d, 1H), 7.75 (d, 1H), 7.58 (t, 1H), 3.35 (m, 2H), 2 96 (m, 2H) ppm.

In the preparation steps, the compounds are prepared as follows:

(a) 4-Thiocarbamoyl-1-indanone

A solution of 12.1 g (77 mmol) of 4-cyan-1-indanone (Coll. Czechoslov. Chem. Commun., 43, 3227 (1978)) in 220 ml of pyridine and 10.6 ml (77 mmol) of triethylamine is saturated with The reaction mixture was stirred at the same temperature for 16 hours. After cooling, the reaction mixture was evaporated to dryness and 300 ml of water were added to the residue.

The crystallized yellow material is filtered off with suction, washed with water, dried and recrystallized from ethyl acetate. This gives the title compound having a melting point of 197 ° C (decomposition).

b) 4-Amidino-1-indanone hydrochloride

A solution of 9.8 g (51.3 mmol) of 4-thiocarbamoyl-1-indanone in 500 absolute methylene chloride was contacted 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. After stirring briefly, the reaction mixture is filtered and the filtrate is washed with water. The organic phase was dried (MgSO4), filtered and evaporated. The crude ethylthioimino ether thus obtained is dissolved in 160 ml of absolute ethanol, treated with 3.3 g (60 mmol) of ammonium chloride and refluxed for 20 hours. After cooling, the reaction mixture was evaporated to dryness. The title compound is purified by chromatography on 1000 mL of Amberlite ^R ER-180 resin using water as the eluent, and recrystallized from a mixture of ethanol and ether. M.p. 215 DEG-218 DEG C. (dec.).

2) Starting compound B:

4-amidino-1-indanone-2 '- (N-hydroxyamidino) hydrazone dihydrochloride

A solution of 316 mg (1.5 mmol) of 4-amidino-1-indanone hydrochloride (see the compound from Preparation Step 1b), described under Starting Compound A) in 7 mL of methanol, was contacted with a solution of 394 mg (1.5 mmol). of 1-amino-3-hydroxyguanidine-4-toluenesulfonate in 6 ml of water and 0.75 ml (1.5 mmol) of 2-normal hydrochloric acid and refluxed for 2 hours and then stirred at room temperature for 2 hours. 16 hours. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel (Pharmacia SR-28-100 column, OPTI-UP C ₁₂ ^R silica gel), eluting with water. Capture! a 5 ml fraction at a flow rate of 27.5 ml / h. Fractions 58-78 were combined, evaporated and the residue crystallized from ethanol. This gives the title compound as a crystal.

MS (FAB method): (M + H) &lt; ^{+ &gt}; = 247.

^ • H-NMR (D ₂ 0): δ = 8.06 (d, 1H), 7.73 (d, 1H), 7.58 (t, 1H), 3.36 (m, 2H); 2.98 (m, 2H) ppm.

3) Starting compound C:

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

A solution of aminoguanidine bicarbonate (0.41 g, 3 mmol) in 0.1 N hydrochloric acid (31.5 ml) was treated with 5-amidino-1-tetralone hydrochloride (0.675 g, 3 mmol) and the reaction mixture was heated to reflux. for 72 hours. After cooling, the reaction mixture was evaporated to dryness and the title compound crystallized from a mixture of methanol and ether. The compound obtained has a melting point greater than 250 ° C.

MS (FAB method): (M + H) ⁺ = 245.

¹ H-NMR analysis (DMSO-d ₆ ): δ = 11.3 (s, 1H), 9.5 (m, 4H), 8.65 (d, 1H), 7.92 (m, 3H), 7.52 (d, 1H), 7.46 (t, 1H), 2.7-2.85 (m, 4H), 1.9 (m, 4H) ppm.

I

In the preparation steps, the compounds are prepared as follows:

(a) 5-Cyano-1-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 dimethylformamide was treated with 0.41 g ( (5 mmol) of copper cyanide and stirred at 160 ° C for 6 hours. The reaction mixture is then cooled to 80 ° C and a solution of 1.6 g of ferric chloride hexahydrate in 2.5 ml of water and 0.44 ml of concentrated hydrochloric acid is added. After stirring for 45 minutes, the reaction mixture was diluted with water and extracted with toluene. The organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated. There was thus obtained the title compound as yellow-orange crystals.

IR (CH ₂ Cl ₂ ): 2220, 1690 cm ^-1 .

¹ H-NMR analysis (CDCl ₃ ): δ = 8.26 (q, 1H), 7.81 (q,

1H), 7.43 (t, 1H), 3.21 (t, 2H), 2.72 (t, 2H), 2.23 (m, 2H) ppm.

b) 5-Thiocarbamoyl-1-tetralone

In an analogous manner to that described for the starting compound A under 1a), 10.6 g (62 mmol) of 5-cyan-1-tetralone in 200 ml of pyridine and 8.6 ml of triethylamine with hydrogen sulfide were treated. The title compound is thus obtained in the form of yellow crystals, m.p. 200-205 ° C.

c) 5-Aminido-1-tetralone hydrochloride

In an analogous manner to that described for starting compound A under 1b), 8.6 g (42 mmol) of 5-thiocarbamoyl-1-tetralone were treated with 8.8 g (44 mmol) of triethyloxonium tetrafluoroborate and 2.6 g (49 mmol). ammonium chloride. This yields the title compound, which is light pink colored crystals.

MS (FAB method): (M + H) &lt; ^{+ &gt}; = 189.

4) Starting compound D:

4-thiocarbamoyl-1-indanone-2'-amidinohydrazone hydrochloride

A solution of 1.9 g (10 mmol) of 4-thiocarbamoyl-1-indanone (prepared as described under Starting Compound A, 1a) in 50 ml of ethanol is treated with 1.36 g (10 mmol) of aminoguanidine bicarbonate and 10 ml. 2-normal hydrochloric acid and refluxed for 24 hours. The reaction mixture was evaporated to dryness upon cooling to give the title compound.

5) Starting compound E:

4- (N-hydroxyamidino) -1-indanone-2'-amidinohydrazone dihydrochloride

0.2 g (3 mmol) of hydroxylamine hydrochloride is suspended in 1 ml of absolute ethanol and treated with 2 ml of a 1-N solution of sodium ethoxide in ethanol. The mixture was stirred for 1 hour and then filtered. To the filtrate was added a solution of 0.26 g (1 mmol) of 4-cyano-1-indanone-2'-amidinohydarazone hydrochloride (see below, under 18a) in 2 mL of water and refluxed for 6 hours. After cooling, the reaction mixture was evaporated and the title compound crystallized from water. This compound has a melting point greater than 250 ° C.

¹ H-NMR _(DMSO-dg + D ₂ 0): & = 8.12 (m, 1 H);

7.55 (m, 2H); 3.22 (m, 2H); 2.83 (m, 2H) ppm.

6) 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 bicarbonate in 10 ml of 0.5N hydrochloric acid was stirred at temperature. 25 ° C for 120 hours. The crystallized compound is filtered off with suction, washed with a little water and dried. This yields the title compound having a melting point greater than 250 ° C.

MS (FAB method): (M + H) ⁺ = 245.

- ^ H-NMR (D ₂ 0): S = 7.95 (d, 1H), 7.66 (d, 1H), 7.48 (t, 1H), 3.45 (m, 2H); 2.85 (d, 1 H), 1.12 (d, 3 H) ppm.

In the preparation steps, the compounds are prepared as follows:

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

In a manner analogous to that described for starting compound A under 1a), it was contacted and further treated with 11.1 g (65 mmol) of 4-cyano-2-methyl-1-indanone (U.S. Pat.

956,363) in 200 ml of pyridine and 9.7 ml of triethylamine with hydrogen sulfide. This affords the title compound as yellow crystals having a melting point of 195-198 ° C (decomposition).

¹ H-NMR analysis (DMSO-d ₆ ): δ = 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 (s, 3H) ppm.

b) 4-Amidino-2-methyl-1-indanone hydrochloride

In a manner analogous to that described for starting compound A under 1b), 10.2 g (50 mmol) of 4-thiocarbamoyl-2-methyl-1-indanone are treated with 11.0 g (55 mmol) of triethyloxonium tetrafluoroborate and 3.2 g (60 mmol). mmol) of ammonium chloride. The title compound is obtained as pink crystals and is reacted directly.

7) Starting compound G:

5-amidino-6-methoxy-1-tetralon-2'-amidinohydrazone dihydrochloride

The title compound was prepared analogously to the starting compound A as described under 1) starting from 5-cyano-6-methoxy-1-tetralone (Chem. Pharm. Bull., 31, 2329 (1983)).

8) Starting compound H:

4-Amino-6-methoxy-7-methyl-1-indanone-2'-amidinohydrazone dihydrochloride

The title compound was prepared in analogy to the starting compound C, starting from 4-bromo-6-methoxy-7-methyl-1-indanone (J. Chem. Soc. Perkin Trans., 1, 1974, 1911).

9) Starting compound I:

dihydrochloride ^{4-amidino-6,7-dimethyl-2-indanone-1} -amidinohydrazonu

The title compound was prepared in analogy to the starting compound A, as described under 1), starting from 4-amidino-6,7-dimethyl-1-indanone hydrochloride. The compound produced has a melting point greater than 240 ° C.

MS (FAB technique): (M + H) ⁺ = 259.

1 H-NMR analysis (D ₂ O): δ = 7.43 (s, 1H), 3.12 (m, 2H), 2.75 (m, 2H), 2.43 (s, 3H), 2 .24 (s, 3H) ppm.

In the preparation steps, the compounds are prepared 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., TA, 677 (1987)) and 7.3 g (82 mmol) of medium cyanide The reaction mixture was stirred in 170 ml of dimethylformamide and stirred at 170 ° C for 6 hours. The reaction mixture was then cooled to 100 ° C and 200 ml of toluene and a solution of 31.2 g of ferric chloride hexahydrate in 47 ml of water and 8.2 ml of concentrated hydrochloric acid were gradually added. The reaction mixture was then stirred at 70 ° C for 20 minutes, cooled and diluted with toluene and water. The organic phase was separated, washed with water, half-saturated sodium bicarbonate solution and again with water, dried and evaporated. The residue was crystallized from a mixture of ethyl acetate and ether to give the title compound. Beige crystals having a melting point of 160-163 ° C are obtained.

IR (CH ₂ Cl ₂ ): 2220, 1710 cm @ -1.

b) 4-Thiocarbamoyl-6,7-dimethyl-1-indanone

In a similar manner as described for starting compound A under 1), 10 g (54.1 mmol) of 4-cyano-6,7-dimethyl-1-indanone in 200 ml of pyridine and 7.5 ml of triethylamine are contacted and further treated with hydrogen sulfide. This gives the title compound which is in the form of yellow crystals having a melting point of 207-208 ° C.

¹ H-NMR analysis (DMSO-d ₆ ): δ = 10.03 (s, 1H), 9.49 (s, 1H), 7.49 (s, 1H), 3.12 (m, 2H), 2.61 (m, 2H), 2.54 (s, 3H), 2.29 (s, 3H) ppm.

c) 4-Amidino-6,7-dimethyl-1-indanone hydrochloride

In a similar manner to that described for starting compound A under 1b), 4.4 g (20 mmol) of 4-thiocarbamoyl-6,7-dimethyl-1-indanone were treated with 4.26 g (21 mmol) of triethyloxonium tetrafluoroborate and 1.2 g. g (24 mmol) of ammonium chloride. The title compound is obtained in the form of beige crystals.

10) Starting compound J:

4-amidino-7-hydroxy-3-methyl-1-indanone-2'-amidinohydrazone dihydrochloride

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

11) Starting compound K:

of 4- (methylamidino) ^-L-2-one indanún -amidinohydrazonu

In an analogous manner to that described for starting compound A under 1), 4-thiocarbamoyl-1-indanone-2'-amidinohydrazone hydrochloride (starting compound D) is reacted with triethyloxonium tetrafluoroborate and methylammonium chloride to give the title compound.

12) Starting compound L:

4-amidino-6,7-dimethoxy-1-indanone-2'-amidinohydrazone dihydrochloride

A solution of 0.4 g (3 mmol) of aminoguanidine bicarbonate in 6 ml of 0.5N hydrochloric acid was treated with 0.73 g (2.7 mmol) of hydrochloride.

Of 4-amidino-6,7-dimethoxy-1-indanone and stirred at 50 ° C for 24 hours. After cooling, the crystallized substance is filtered off with suction, washed with a small amount of water and dried. This affords the title compound having a melting point greater than 220 ° C.

MS (FAB method): (M + H) &lt; ^{+ &gt}; = 291.

¹ H-NMR (D ₂ 0): & 7.45 (s, 1H), 3.97 (s, 6H), 3.27 (m, 2H), 2.98 (m, 2H).

In the preparation steps, the compounds are prepared 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 cyanide in DMF (7 mL) was stirred at 170 ° C for 5.75 hours. The reaction mixture was cooled to 100 ° C and then washed with 70 ml of toluene, and a solution of 9.7 g (36 mmol) of ferric chloride hexahydrate in 15.6 ml of water and 3.5 ml of concentrated hydrochloric acid was added. Stir at 80 ° C for 30 minutes, then cool the reaction mixture and dilute with toluene and water. The organic phase was separated, washed with water, half-saturated sodium bicarbonate solution and again with water, dried and evaporated. The residue is distilled using a collar flask at a temperature of 150-160 ° C and a pressure of 10 Pa. This gives the title compound having a melting point of 150 ° C.

IR (CH ₂ Cl ₂ ): 2220, 1710 cm ^-1 .

¹ H-NMR analysis (CDCl ₃ ): δ = 7.33 (s, 1H), 4.12 (s,

3Η), 3.90 (s, 3H), 3.19 (m, 2H), 2.76 (m, 2H) ppm.

b) 4-Thiocarbamoyl-6,7-dimethoxy-1-indanone

In a similar manner to that described for starting compound A under 1a), 3.7 g (17 mmol) of 4-cyano-6,7-dimethoxy-1-indanone in 100 ml of pyridine and 2.4 ml of triethylamine are contacted and further treated with hydrogen sulfide. This gives the title compound which is in the form of pale yellow crystals, m.p. 196-199 ° C.

¹ H-NMR (DMSO-d₆) = 10.06 (s, 1H), 9.50 (s 1H), 7.41 (s, 1H), 3.84 (m, 6H), 3, 13 (m, 2H); 2.63 (m, 2H) ppm.

c) 4-Amidino-6,7-dimethoxy-1-indanohydrochloride

In a similar manner to that described for starting compound A under (1b), 3.3 g (13 mmol) of 4-thiocarbamoyl-6,7-dimethoxy-1-indanone were treated with 2.8 g (14 mmol) of triethyloxonium tetrafluoroborate and 0.8 g. g (15 mmol) of ammonium chloride. The title compound is obtained in the form of a beige crystal, m.p. 188 DEG C. (dec.).

¹ H-NMR analysis (DMSO-d ₆ ): δ = 9.4 (s, 3H), 7.63 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.18 (m, 2H); 2.68 (m, 2H) ppm.

13) Starting compound M:

4-amidino-6-methyl-1-indanone-2'-amidinohydra dihydrochloride zone

The title compound was prepared in analogy to the starting compound C, starting from 4-bromo-6-methyl-1-indanone (Bull. Soc. Chim. France, 1964, 3103). The compound produced has a melting point greater than 250 ° C.

MS (FAB method): (M + H) ⁺ = 245.

¹ H-NMR analysis (D ₂ O): δ = 7.89 (s, 1H), 7.62 (s, 1H), 3.34 (t, 2H), 2.96 (t, 2H), 2 .45 (s, 3H) ppm.

14) 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 treated with 300 mg (2.3 mmol) of aminoguanidine bicarbonate in 4 mL of 0.5N hydrochloric acid. and stirred at 80 ° C for 24 hours. The reaction mixture was cooled, evaporated and the residue purified by chromatography on Amberlite ^R ER-180 resin using water as eluent. The title compound is obtained, which is recrystallized from a mixture of methanol and ether. This compound has a melting point greater than 250 ° C.

Rf = 0.18 (silica gel, methylene chloride / methanol / concentrated ammonia = 5: 3: 1).

MS (FAB method): (M + H) ⁺ = 245.

¹ H-NMR analysis (D ₂ O): δ = 7.97 (d, 1H), 7.64 (d, 1H), 7.49 (t, 1H), 3.86 (m, 1H), 3 17 (q, 1H); 2.49 (d, 1H); 1.24 (d, 3H) ppm.

In the preparation steps, the compounds are prepared as follows:

(a) 4-Cyano-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 cyanide The reaction mixture was stirred at 170 ° C for 6 hours. The reaction mixture was then cooled to 100 ° C and then washed with 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 was added. After stirring at 70 ° C for 20 minutes, the reaction mixture was cooled and diluted with toluene and water. The organic phase was separated, washed with water, half-saturated sodium bicarbonate solution and again with water, dried and evaporated. The residue is distilled using a limestone flask at a temperature of 100 to 120 ° C and a pressure of 5 Pa. This gives the title compound having a melting point of 109-111 ° C.

IR spectroscopy (CI @ + Cl3): 2220, 1710 cm @ ^-1 .

¹ H-NMR analysis (CDCl ₃ ): δ = 7.92 (m, 2H), 7.52 (t, 1H), 3.73 (m, 1H), 3.03 (q, 1H), 2, 40 (q, 1 H), 1.55 (d, 3 H) ppm.

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

In a similar manner to that described for starting compound A under 1a), 1.45 g (8.47 mmol) of 4-cyano-3-methyl-1-indanone in 25 ml of pyridine and 1.2 ml of triethylamine are contacted and further treated with hydrogen sulfide. This gives the title compound which is in the form of light yellow crystals, m.p. 198-200 ° C.

1 H-NMR analysis (DMSO-d ₆ ): δ = 9.78 (s, 1H), 7.65 (m, 2H), 7.46 (m, 1H), 3.98 (m, 1H), 2.95 (q, 1H), 2.26 (q, 1H), 1.25 (d, 3H) ppm.

c) 4-Amidino-3-methyl-1-indanone hydrochloride

In a similar manner to that described for starting compound A under 1b), 0.96 g (4.68 mmol) of 4-thiocarbamoyl-3-methyl-1-indanone is treated with 1.0 g (4.93 mmol) of triethyloxonium tetrafluoroborate and 0. 3 g (6 mmol) of ammonium chloride. This gives the title compound as beige crystals.

¹ H-NMR _(DMSO-d6): 5 = 9.59 (s, 4 H), 7.65 (m, 2H), 7.46 (m, 1H), 3.98 (m, 1 H); 2.95 (q, 1H), 2.26 (q, 1H), 1.25 (d, 3H) ppm.

15) Starting compound 0:

4-amidino-2-ethyl-1-indanone-2'-amidinohydrazone dihydrochloride

3- (2-Bromo-phenyl) -2-ethyl-propionic acid (German Patent No. 2,733,868) is cyclized by heat treatment with polyphosphoric acid and the corresponding 1-indanone to convert the title compound in a similar manner to that described for the starting compound. C. The compound produced has a melting point greater than 250 ° C.

MS (FAB technique): (M + H) ⁺ = 259.

¹ H-NMR analysis (D ₂ O): δ = 7.96 (d, 1H), 7.65 (d, 1H), 7.48 (t, 1H), 2.95-3.48 (m, 3H), 1.3-1.8 (m, 2H), 0.83 (t,

3H) ppm.

16) Starting compound P:

4-amidino-2-n-butyl-1-indanone-2'-amidinohydrazone dihydrochloride

3- (2-Bromo-phenyl) -2-n-butyl-propionic acid (German Patent No. 2,733,868) is cyclized by heat treatment with polyphosphoric acid having the corresponding 1-indanone and converting it to the title compound in a similar manner as described for starting compound C.

Other production methods for starting compound A:

4-amidino-1-indanone-2'-amidinohydrazone hydrochloride

17)

In a similar manner to that described for starting compound A under 1b), 4-thiocarbamoyl-1-indanone-2'-amidinohydrazone hydrochloride (starting compound D) is reacted with triethyloxonium tetrafluoroborate and ammonium chloride to give starting compound A having a temperature of mp &gt; 330 ° C.

MS (FAB method): (M + H) &lt; ^{+ &gt}; = 231.

^ • H-NMR (D ₂ O): δ = 8.08 (d, 1H), 7.75 (d, 1H), 7.58 (t, 1H), 3.35 (m, 2H); 2.96 (m, 2H) ppm.

18)

A solution of 0.26 g (1 mmol) of ^{4-cyano-2-indanone-1} -amidinohydrazonu in 5 ml of absolute methanol was treated with 1.2 ml of a 1 N solution of sodium methoxide in methanol and heated at reflux for 16 hours. After cooling, solid ammonium chloride (0.16 g, 3 mmol) was added to the reaction mixture and stirred at 60 ° C for 1 hour. The reaction mixture was then evaporated and the residue was crystallized from dilute ethanol. This gives the starting compound A having a melting point higher than 330 C.

In the preparation steps, the compounds are prepared as follows:

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

In analogy to starting compound A under 1), 314 mg (2 mmol) of 4-cyan-1-indanone is dissolved in 20 ml of methanol, and the solution is treated with 272 mg (2 mmol) of aminoguanidine bicarbonate in 9 ml. water and 1 ml of 2 N hydrochloric acid and stirred for 4 days at reflux. After cooling, the reaction mixture was evaporated to dryness and the residue was crystallized from water. This gives the title compound having a melting point greater than 230 ° C.

¹ H-NMR (DMS0-d ₆ + D ₂ 0): δ = 8.16 (d, 1H), 7.9 (d, 1H), 7.55 (t, 1H), 3.28 (m 2 H, 2.9 (m, 2H) ppm.

IR (nujol / paraffin) 2190 cm ^-1 (CN).

19)

A solution of 6.12 g (45 mmol) of aminoguanidine bicarbonate in 100 ml of water and 46 ml of 1N hydrochloric acid was contacted with 9.45 g (44.9 mmol) of 4-amidino-1-indanone hydrochloride (see starting compound). A, under 1b) and stirred at 24 ° C for 24 hours. The crystallized substance is filtered off with suction, washed with a little water and recrystallized from 300 ml of water. This gives the starting compound A which contains 1 mole of crystal water and has a melting point higher than 330 ° C.

MS (FAB method): (M + H) &lt; ^{+ &gt}; = 231.

¹ H-NMR analysis (D ₂ O): δ = 8.08 (d, 1H), 7.75 (d, 1H), 7.58 (t, 1H), 3.35 (m, 2H), 2 96 (m, 2H) ppm.

)

A mixture of 0.32 g (1 mmol) of 4- (N-ethoxycarbonylethyl) -L-2-indanone ¹ -amidinohydrazonu (starting compound E), 0.36 ml (2 mmol) of triethylamine and 0.2 g (1 mmol) of pentacarbonyl iron in 10 ml of absolute tetrahydrofuran is refluxed for 16 hours. The reaction mixture was then evaporated and the residue crystallized from dilute hydrochloric acid to give the starting compound A, having a melting point above 330 ° C.

21) Starting compound Q:

4-amidino-2-propylindanone-1-amidinohydrazone dihydrochloride

The title compound was prepared in analogy to the starting compound 0, starting from 2-bromobenzyl bromide and diethyl malonate. The compound produced has a melting point greater than 250 ° C.

MS (FAB method): (M + H) ⁺ = 273.

¹ H-NMR analysis (D ₂ O): δ = 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) ppm.

Examples

The examples below serve to illustrate the invention but do not limit the scope thereof in any way.

Temperatures are also given here in degrees Celsius. If no temperature data is given, the reactions are always carried out at room temperature. When evaporation is carried out, this evaporation is carried out on a rotary evaporator unless otherwise stated.

Proton nuclear resonance spectroscopy values are reported in ppm (parts per million), based on tetramethylsilane (δ = 0), as an internal standard. Abbreviations of the following meanings are used: d = duplet, s = singlet, t = triplet, m = multiplet.

For elemental analyzes, the summary formula, molecular weight and calculated and found analysis values are given.

Abbreviations or abbreviations used, if any, have the following meanings:

elementary analysis

D ₂ 0 dideuterium oxide

DMSO-d ₆ completely deuterated dimethylsulfoxide ¹ H-HNR proton magnetic nuclear resonance spectroscopy

Example 1

4-Amidino-1-indanone-2'-amidinohydrazone dicyclamate

A solution of 460 mg (2 mmol) of 4-amidinoindahone-1-amidinohydrazone in 80 mL of methanol was treated with a solution of 717 mg (4 mmol) of N-cyclohexylsulfamic acid in 20 mL of methanol and evaporated to dryness. The residue is dissolved in ethanol and crystallized by addition of diethyl ether. The title compound is obtained, m.p. 210 DEG C. (dec.).

¹ H-NMR analysis (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) ppm.

Analysis for ^C 23 ^H 40 ^N 8 ^O 6 ^S 2 (MW 588.75): calculated: C 46.92, H 6.85, N 19.03, found: C 46.6, 9% H, 19.0% N.

The starting compound is prepared as follows:

(a) 4-Amidino-1-indanone-2'-amidinohydrazone

9.63 g (30 mmol) of 4-amidino-1-indanone-2'-amidinohydrazone dihydrochloride (starting compound A, prepared as described in the starting compounds section, e.g. below 16) are dissolved in 900 ml of water which is heated to 70 ° C to 80 ° C and then cooled to 10 ° C. 30 ml of 2 N sodium hydroxide solution are then added dropwise with stirring. The precipitated substance is filtered off with suction, washed with a little ice water and dried. This gives the title compound having a melting point of 250 ° C (dec.).

Example 2

Dioktonát 4-amidino-l-indanone-2 ¹ -amidinohydrazonu

A solution of 460 mg (2 mmol) of 4-amidinoindanone-1-amidinohydrazone (Example 1a) in 80 ml of methanol is treated with 631 μΐ (4 mmol) of octanoic acid and evaporated to dryness. The residue is dissolved in ethanol and crystallized by addition of diethyl ether. This gives the title compound having a melting point of 190 ° C (dec.).

¹ H-NMR analysis (DMSO-d 6): δ = 8.03 (d, 1H), 7.52 (d, 1H), 7.47 (t, 1H), 3.19 (m, 2H), 2 85 (m, 2H), 1.98 (t, 4H), 1.42 (m, 4H), 1.19 (s, 24H), 0.81 (t, 6H) ppm.

Analysis for C ₂₇ H ₄₆ N _g 0 ₄ (MW 518.70):

H, 8.94; N, 16.20. Found: C, 62.3; H, 8.9; N, 16.2.

67 Example 3

4-Amidino-1-indanone-2'-amidinohydrazone disalicylate

A solution of 690 mg (3 mmol) of 4-amidinoindanone-1-amidinohydrazone (Example 1a) in 100 ml of methanol is treated with 830 mg (6 mmol) of salicylic acid in 50 ml of ethanol and the reaction mixture is evaporated to half volume. The solution thus obtained is contacted with 70 ml of water to crystallize the title compound, m.p. 206 DEG-209 DEG C. (with decomposition).

Analysis for ^C 25 ^H 26 ^N 6 ° 6 ( ^m ° 1 ^e spherical mass 507.1):

calculated: 59.13% C, 5.19% H, 16.55% N, found: 59.3% C, 5.2% H, 16.8% N.

Example 4

4-Amidino-1-indanone-2'-amidinohydrazone dibenzenesulfonate

A solution of 690 mg (3 mmol) of 4-amidinoindanone-1-amidinohydrazone (Example 1a) in 100 ml of methanol is treated with a solution of 975 mg (3 mmol) of benzenesulfonic acid in 50 ml of methanol and evaporated to dryness. The residue is crystallized from ethanol. This gives the title compound having a melting point greater than 250 ° C (decomposition).

¹ H-NMR analysis (D ₂ O): δ = 7.38-7.95 (m, 16H), 3.21 (m, 2H), 2.78 (m, 2H) ppm.

Analysis for ^C 23 ^H 26 ^N 6 ^O 6 ^S 2 (MW 546.63): calculated: C 50.54, H 4.79, N 15.37, found: C 50.4, 8% H, 15.6% N.

Example 5: Other salts

Example 5a

4-Amidino-1-indanone-2'-amidinohydrazone succinate

A solution of 920 mg (4 mmol) of 4-amidino-l-indanone-2 -amidinohydrazonu ¹ in 120 ml of methanol was treated with 472 mg (4 mmol) of succinic acid in 120 ml of methanol. The crystallized substance is filtered off with suction, washed with a small amount of methanol and dried. The title compound is obtained, having a melting point of 200 ° C (dec.).

Analysis for ^C 20 ^H i5 ^N ° 6 4.1,04H ₂ O (molecular weight 367.10): calculated: 49.08% C, 6.06% H, 22.89% N Found: 49.13% C, H, 6.07; N, 23.04.

Example 5b

4-Amidino-1-indanone-2'-amidinohydrazone adipate

A solution of 230 mg (1 mmol) of 4-amidino-1-indanone-2'-amidinohydrazone in 30 ml of methanol is treated with a solution of 146 mg (1 mmol) of adipic acid in 25 ml of ethanol. The crystallized substance is filtered off with suction, washed with a small amount of ethanol and dried. The title compound is obtained, having a melting point of 200 ° C (dec.).

Analysis for C ^ H _{7 4 24} Ngo .0,25H ₂ O (molecular weight 380.92): calculated: 53.60% C, 6.48% H, 22.06% N: 53.79% H, 6.73; N, 21.93.

Example 5c

4-Amidino-1-indanone-2'-amidinohydra69 1,5-naphthalenedisulfonate zone

A solution of 920 mg (4 mmol) of 4-amidino-1-indanone-2'-amidinohydrazone in 120 ml of methanol is treated with a solution of 1.49 g (4 mmol) of 1,5-naphthalenedisulfonic acid in 100 ml of methanol. The crystallized solid is filtered off with suction, washed with a small amount of methanol and dried. This gives the title compound having a melting point of greater than 250 ° C (dec.).

Analysis for C ₂₁ H 6 ^N ₂ 2 ^N 2 ° 6 ^{'2' 36Η 2θ (m} ° l ° ^{of the ecu} l and weight 561.09) calculated: 44.95% C, 4.80% H, 14.98% N, Found: C, 45.06; H, 4.98; N, 15.21.

Example 5d

4-Amidino-1-indanone-2'-amidinohydrazone ethanedisulfonate

Similar to that described in a preceding or the examples is 4-amidino-l-indanone-2 -araidinohydrazonu ¹ was converted to the title compound with an acid of 1,2-ethanedisulfonic.

Example 5e

4-Amidino-1-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 treated with a solution of 600 mg (4 mmol) of L - (+) - tartaric acid in 100 ml of methanol. The crystallized solid is filtered off with suction, washed with a small amount of methanol and dried. The title compound is obtained, m.p. 190 DEG C. (dec.).

Analysis for C ₁₅ H ₂ O q N _{6 6} .0,26H ₂ O (MW 385.04):

calculated: 46.79% C, 5.37% H, 21.83% N, found: 46.83% C, 5.43% H, 21.87% N.

Example 5f

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 treated with a solution of 210 mg (1 mmol) of citric acid in 10 ml of methanol. The crystallized solid is filtered off with suction, washed with a small amount of methanol and dried. The title compound is obtained, having a melting point greater than 220 ° C (dec.).

Analysis for ^C 17 ^H 22 ^N 6 ° 7 (MW 422.40): Calculated: C, 48.34; H, 5.25; N, 19.90. Found: C, 48.23; H, 20.07% N.

Example 6

In analogy to the above examples, the starting compounds described below can be converted to acid addition salts which include octanoic acid, succinic acid, adipic acid, salicylic acid, cyclohexylsulfamic acid, ethanedisulfonic acid, benzenesulfonic acid, tartaric acid or citric acid as acid. 1,5-naphthalenedisulphonic acid.

(a) 4-amidino-1-indanone-2 '- (N-hydroxyamidino) hydrazone dihydrochloride (starting compound B),

b) 5-amidino-1-tetralone-2'-amidinohydra -71-dihydrochloride zone (starting compound C),

(c) 4-thiocarbamoyl-1-indanone-2'-amidinohydrazone hydrochloride (starting compound D),

d) of 4- (N-ethoxycarbonylethyl) -L-2-indanone ¹ -amidinohydrazonu (starting compound E).

(e) 4-amidino-2-methyl-1-indanone-2'-amidinohydrazone dihydrochloride (starting compound F);

(f) 5-amidino-6-methoxy-1-tetralon-2'-amidinohydrazone dihydrochloride (starting compound G);

(g) 4-amidino-6-methoxy-7-methyl-1-indanone-2'-amidinohydrazone dihydrochloride (starting compound H),

(h) 4-amidino-6,7-dimethyl-1-ifidanone-2'-amidinohydrazone dihydrochloride (starting compound I);

(i) 4-amidino-7-hydroxy-3-methyl-1-indanone-2'-amidinohydrazone dihydrochloride (starting compound J);

(j) 4- (methylamidino) -1-indanone-2'-amidinohydrazone dihydrochloride (starting compound K),

(k) 4-amidino-6,7-dimethoxy-1-indanone-2'-amidinohydrazone dihydrochloride (starting compound L);

(l) 4-amidino-6-methyl-1-indanone-2'-amidene-drazone dihydrochloride (starting compound M);

(m) 4-amidino-3-methyl-1-indanone-2'-amidazedrazone dihydrochloride (starting compound N);

(n) 4-amidino-2-ethyl-1-indanone-2'-amidinohydrazone dihydrochloride (starting compound 0);

(o) 4-amidino-2-n-butyl-1-indanone-2'-amidinohydrazone dihydrochloride (starting compound P); and

p) 4-amidino-2-n-propylindanone-1-amidinohydrazone (starting compound Q).

Example 7

Capsules containing 0.25 g of the active ingredient, for example the acid addition salts of Examples 1 to 6, can be prepared as follows:

Ingredients (for 5000 capsules) active ingredient 1250 g talc 180 g wheat starch 120 g magnesium stearate 80 g lactose 20 g

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

Example 8

10,000 tablets are prepared, each containing 5 mg of the active ingredient, for example, acid addition salts made according to any one of Examples 1 to 6, as follows:

Ingredients

active substance 50,00 g milk sugar 2535,00 g maize starch 125,00 g polyethylene glycol 6000 150,00 g magnesium stearate 40,00 g purified water quantum satis

Preparation method

Sieve all the powder components through a 0.6 mm sieve. Thereafter, the active ingredient, milk sugar, magnesium stearate and half of the starch are mixed in a suitable mixing device. The other half of the starch is suspended in 65 ml of water and the resulting suspension is added to a boiling solution of polyethylene glycol in 260 ml of water. The resulting paste is added to the powder mixture and granulated with optional addition of additional water. The granulate is dried overnight at 35 ° C, passed through a 1.2 mm sieve and compressed into tablets having a break line.

Claims (16)

PATENT CLAIMS CLAIMS 1. Pharmaceutically active base addition salts of the general formula I with acids in which A represents a direct bond or a group of formula - (CH ₂ ) _n -, wherein n is 1, 2 or 3, X is -C (= Y) -NR ₈ R ₇ , Y is NR 8, O or S, Z is NR 8, O or S, R and R ₂ are independently a hydrogen atom or one or more substituents other than hydrogen, R ₃ , R ₄ , R 8, R ₈ and R 8 are each independently hydrogen or lower alkyl; and R ₅ and R _? independently of one another are hydrogen, lower alkyl, hydroxy, etherified or esterified hydroxy, unsubstituted, monosubstituted or disubstituted amino, with (PA) an acid which is one or more protonated acids selected from carbonic acid, alkanoic acids which are not substituted; or are mono- or poly-substituted, except for formic acid, unsubstituted acetic acid, lysine and arginine, alkenoic acids which are not or are substituted, with the exception of unsubstituted fumaric acid, cycloalkylcarboxylic acids, arylcarboxylic acids, aryl (lower alkyl) carboxylic acids, where lower alkyl is not or is substituted, aryl (lower alkenyl) carboxylic acids, heterocyclocarboxylic acids, alkanesulfonic acids that are not or are substituted, with the exception of unsubstituted methanesulfonic acid, ar omatic sulfonic acids, alkylsulfuric acids, N-substituted sulfamic acids, organic acids not containing carboxy, sulfo, sulfate or phospho, and pyrophosphoric and hydroiodic acids, or tautomers thereof. Acid addition salts according to claim 1, derived from a base of the formula I, in which A represents a direct bond or a group of the formula - (CH ₂ ) _n -, wherein n represents 1 or 2, X represents a radical of formula -C (= Y) -NRgRy, Y represents NR, O or S, Z is a group of formula NR _g, O or S, R and _R2 are! independently of one another hydrogen or one or two substituents selected from the group consisting of lower alkyl, trifluoromethyl, cycloalkyl, aryl (lower alkyl), hydroxy, lower alkoxy, aryl (lower alkoxy), aryloxy, lower alkanoyloxy, a halogen atom, an amino group, N- (lower alkyl) amino, N, N-di (lower alkyl) amino, lower alkanoylamino, nitro, lower alkanoyl, arylcarbonyl, carboxy, (lower alkoxy) carbonyl, carbamoyl, N- (lower alkyl) carbamoyl N, N-di (lower alkyl) carbamoyl, N-arylcarbamoyl, cyano, mercapto, lower alkylthio, lower alkylsulfonyl, sulfamoyl, N- (lower alkyl) sulfamoyl or N, N-di (lower alkyl) ) sulfamoyl, wherein aryl denotes a phenyl group which is unsubstituted or substituted by a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen atom or a trifluoromethyl group, Ŕ ₃ , R ₄ , R _6, R ₈ and R _g are independently hydrogen or lower alkyl and R ₅ and R ₇ are each independently of the other hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, amino, lower alkylamino, di ( lower alkyl) amino, lower alkylene amino, or oxa (lower alkylene) amino, thia (lower alkylene) amino, or aza (lower alkylene) amino, with (PA) an acid that is carbonic acid, propionic acid, 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, glucaric acid, galactaric acid, glutamic acid, aspartic acid, N-methylglycine, acid acetylaminoacetic acid, N-acetylasparagine, N-acetylcystine, pyruvic acid, acetacetic acid, phosphoserine, 2-glycerophosphoric acid, 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1-phosphoric acid, fructose-1,6-diphosphoric acid , maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 1-hydroxynaphthyl-2-carboxylic acid, 3-hydroxynaphthyl-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid, acid 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, nicotinic acid, isonicotinic acid, glucuronic acid, galacturonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethan-1 , 2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid α, 1,5-naphthalenedisulfonic acid, 2-methylbenzenesulfonic acid, 3-methylbenzenesulfonic acid, 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methylsulfamic acid, N-ethylsulfautic acid, N N-propylsulfamic or ascorbic acid, or tautomers thereof. 3. The acid addition salts of claim 1, derived from a base of the formula I, wherein A is a direct bond or a group - (CH _{2) n} ^-, wherein n is 1 or 2, X is a radical of formula -C (= Y) -NR ₈ R ₇ , Y is NH, oxygen or sulfur, Z is NH, oxygen or sulfur, R f and R ₂ independently of one another are hydrogen or one or two substituents selected from the group consisting of lower alkyl, trifluoromethyl, phenyl (lower alkyl), hydroxy, lower alkoxy and halogen, R 2, R ₄ and R ₆ are hydrogen and R ₅ and R ₇ are hydrogen; independently of one another hydrogen, lower alkyl, hydroxy or amino, with a (PA) acid which is carbonic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid , glucose monocarboxylic acid, succinic acid, adipic acid, suberic acid, pimelic acid, azelaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, glutamic acid, aspartic acid, N-methylglycine, acetylaminoacetic acid, N-acetylasparagine , N-acetylcystine, pyruvic acid, acetacetic acid, phosphoserine, acid 2-glycerophosphoric acid, 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1-phosphoric acid, fructose-1,6-diphosphoric acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 1-hydroxynaphthyl-2-carboxylic acid, 3-hydroxynaphthyl-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid , mandelic acid, cinnamic acid, nicotinic acid, isonicotinic acid, glucuronic acid, galacturonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid , 2-methylbenzenesulfonic acid, acid 3-methylbenzenesulfonic acid, 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methylsulfamic acid, N-ethylsulfamic acid, Npropylsulfamic acid or ascorbic acid, or tautomers thereof. Acid addition salts according to claim 1, derived from a base of formula I, wherein A represents a direct bond or a group of formula -CH ₂ -, X represents a radical of formula -C (= Y) -NR ₈ R ₇ , Y represents a group of formula NH or a sulfur atom, Z represents a group of the formula NH, R 6 represents a hydrogen atom or one or two substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy and halogen, R ₂ represents hydrogen or lower alkyl, R ₃ , R ₄ and R ₆ mean! H and R ₅ and R ₇ Znamenaj! independently of one another a hydrogen atom, a lower alkyl group or a hydroxy group with a (PA) acid which is carbonic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, acid glucose monocarboxylic acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, glutamic acid, aspartic acid, N-methylglycine, acetylaminoacetic acid, N-acetylasparagine, N -acetylcystine, pyruvic acid, acetic acid, phosphoserine, 2-glycerophosphoric acid, 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1-phosphoric acid, fructose-1,6-diphosphoric acid, maleic acid, hydroxymaleinic acid, methylmaleic acid, cyclohexane acid arboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 1-hydroxynaphthyl-2-carboxylic acid, 3-hydroxynaphthyl-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4 -aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, nicotinic acid, isonicotinic acid, glucuronic acid, galacturonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2- naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2-methylbenzenesulfonic acid, 3-methylbenzenesulfonic acid, 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methylsulfamic acid, N-ethylsulfamic acid propylsulfamic or ascorbic acid, or a tautome thereof ery. 5. A compound according to claim 1, wherein A is a direct bond, X is -C (= NH) -NH ₂ ,. Z is NH and R ₁ , R ₂ R ₃ , R 4 and R ₅ are H; in each case a hydrogen atom, with a (PA) acid, wherein the one or more protonated acid is selected from carbonic acid, alkanoic acids which are unsubstituted or are singly or multiply substituted, except for formic acid, unsubstituted acetic acid, lysine and arginine, alkenoic acids which are not or are substituted, with the exception of unsubstituted fumaric acid, cycloalkylcarboxylic acids, arylcarboxylic acids, aryl (lower alkyl) carboxylic acids where lower alkyl is not or is substituted, aryl (lower alkenyl) carboxylic acids, heterocyclocarboxylic acids, alkanesulfonic acids which are not or are substituted, with the exception of unsubstituted methanesulfonic acid, aromatic sulfonic acids, alkylsulfuric acids, N-substituted sulfamic acids, non-carboxylic acids, sulfo, sulfate or and a pyrophosphoric acid and hydroiodic acid, or tautomers thereof. 6. The acid addition salt of claim 1, wherein A is a direct bond, X represents a radical of formula -C (= NH) -NH ₂ , Z represents a group of formula NH and R 1, R ₂ R ₃ , R ₄ and R ₅ each represent a hydrogen atom, with a (PA) acid which is carbonic acid, acid propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glucosomonocarboxylic acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid citric acid, glucaric acid, galactaric acid, glutamic acid, aspartic acid, N-methylglycine, acetylaminoacetic acid, N-acetylasparagine, N-acetylcystine, pyruvic acid, acetacetic acid, phosphoserine, acid 2-glycerophosphoric acid, 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1-phosphoric acid, fructose-1,6-diphosphoric acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 1-hydroxynaphthyl-2-carboxylic acid, 3-hydroxynaphthyl-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid , mandelic acid, cinnamic acid, nicotinic acid, isonicotinic acid, glucuronic acid, galacturonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid , 2-methylbenzenesulfonic acid, acid 3-methylbenzenesulfonic acid, 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methylsulfamic acid, N-ethylsulfamic acid, N82 propylsulfamic or ascorbic acid, or tautomers thereof. Acid addition salts according to claim 1, derived from a base of formula I in which A represents a direct bond, X represents a radical of formula -C (= NH) -NH ₂ , Z represents a group of the formula NH and R p R ₂ , R ₃ R ₄ and R ₅ each represent a hydrogen atom, with (PA) acids which are! N-cyclohexylsulfamic acid, octanoic acid, salicylic acid or benzenesulfonic acid. Acid addition salts according to claim 1, derived from a base of the formula I in which A represents a direct bond, X represents a radical of formula -C (= NH) -NH ₂ , Z represents a group of the formula NH and R p R ₂ , R ₃ R ₄ and R ₅ are each hydrogen, with (PA) acids selected from citric acid, lactic acid and tartaric acid. Acid addition salts according to claim 1, derived from a base of formula I, wherein A represents a direct bond, X represents a radical of formula -C (= NH) -NH ₂ , Z represents a group of the formula NH and R p R ₂ , R _g R ₄ and R ₅ are each hydrogen, with (PA) acids selected from succinic acid, adipic acid and 1,5-naphthalenedisulfonic acid. 10. The acid addition salts of claim 1, derived from a base of the formula I, wherein A is a direct bond, X is a radical of formula -C (= NH) -NH _2, Z is NH and R _p R _2, R ₃ , R ₄ and R ₅ are each hydrogen, with (PA) acids selected from succinic acid, adipic acid, ethanedisulfonic acid and 1,5-naphthalene-83 disulfonic acid. 11. The acid addition salt of claim 1, wherein A is a direct bond, X is -C (= NH) -NH ₂ , Z is NH and R _{1 (} R ₂ , R ₃ , R ₄ and R ₅ is each hydrogen, with (PA) acids selected from adipic acid; and acid% benzene. L * d 12. A pharmaceutical composition comprising an acid addition salt of any one of claims 1-11 or a tautomer thereof and at least one pharmaceutically acceptable carrier. The acid addition salt of any one of claims 1 to 11 for use in a method of therapeutic treatment of an animal or human body. Use of an acid addition salt according to any one of claims 1 to 11 or a tautomer thereof in the manufacture of a pharmaceutical composition for the treatment of a disease which is responsive to treatment with inhibition of the enzyme S-adenosyl methionine decarboxylase. Use of an acid addition salt according to any one of claims 1 to 11 or a tautomer thereof for the treatment of a disease caused by a tumor. 16. A method of treating a disease caused by the absence of S-adenosyl methionine decarboxylase suppression, comprising administering an acid addition salt of any one of claims 1 to 11 or a tautomer thereof to a warm-blooded individual in need of such treatment in a therapeutically effective amount of S-adelase inhibitor. Claim 1 A process for the production of acid addition salts is characterized in that: a) a base of the formula I in which the radicals have the meanings given for the acid addition formulas I, the salts of the base are reacted with (PA) acid, wherein the (PA) has the meanings given above, (b) a compound of formula (II) wherein CW ₁ W ₂ is a carbonyl group, a functional modified carbonyl group or a protected carbonyl group; and A, X, and _R2 are as defined for acid addition salts of bases of formula I with an acid, is condensed with an amine of the formula III Z r ₃ r ₄ (ΠΙ) in which Z, R ₃ , R ₄ and R _{5 have the} meanings indicated for the acid addition salts of the formula I in the presence of (PA) acid, wherein (PA) has the meanings given above, c) in a compound of formula IV i r ₃ (IV). N R ' Rs in which W ₃ means a residue which can be converted into a group X in the base of formula I and A, Z, R _T , R ₂ , R ₃ , R ₄ and R _{5 have the} meanings given under the general formula I, the residue W _{3 is} converted to the group X in the presence of (PA) acid, wherein (PA) has the meanings given above, the sky (d) any acid addition salt of formula (I) not falling under definition (PA) is converted to an acid addition salt of formula (I) with (PA) acid, wherein (PA) has the above meanings and, if desired, the resulting acid addition salt of formula (I) with (PA) acid is converted into another acid addition salt of formula (I) with (PA) acid and / or, if desired, the isomeric mixture is separated into individual isomers.