NO175097B - Analogous Process for Preparation of Therapeutically Active Hydrazones - Google Patents

Abstract

Compounds of the formula I <IMAGE> in which A denotes a direct bond or -(CH2)n-, in which n represents 1, 2 or 3; X represents a -C(=Y)-NR6R7 radical; Y represents NR8, O or S; Z represents NR9, O or S; R1 and R2, independently of one another, denote hydrogen or one or more substituents other than hydrogen; the radicals R3, R4, R6, R8 and R9 independently of one another denote hydrogen or lower alkyl; and R5 and R7 independently of one another represent hydrogen, lower alkyl, hydroxyl, etherified or esterified hydroxyl or unsubstituted or mono- or disubstituted amino; tautomers thereof, and salts thereof. They have useful pharmaceutical properties and are particularly active against tumours. They are prepared in a manner known per se.

Description

The invention relates to an analog manufacturing method

of therapeutically active compounds of formula (I)

where A means a direct bond or -(CH2)-; X represents a residue -C(=Y)-NR 6 R 7 ; Y stands for NRg; Z stands for NR9; R 1 , R 2 and R 10 independently mean hydrogen, lower alkyl or lower alkoxy; the radicals R 3 , R 4 , R 4 , R 8 and R 9 independently mean hydrogen or lower alkyl; and R5 and R7 stand independently of each other for hydrogen, lower alkyl or hydroxy, and salts thereof, characterized

in that one

(a) condenses a compound of formula (II)

where the group CW-jV^ stands for carbonyl and A, X,-R^, R 2 and R 10 have the indicated meaning as under formula I, with an amine of formula (III) where Z, R 3 , R 4 and R 5 are defined as under formula (I), or (b) in a compound of formula (IV)

where W 3 means thiocarbamoyl, cyano or imino-lower oxycarbonyl, and A, Z, R 1 , R 2 , R 3 , R 4 , R 5 and R 10 are defined as under formula (I), the residue transfers W 3 to the group X; and, when desired, converts an obtained compound of formula (I) into another compound of formula (I), and/or when desired, converts an obtained salt into the free compound or into another salt, and/ or when desired, converts an obtained free compound of formula (I) with salt-forming properties into a; salt.

Tautomers of these compounds can e.g. occur when Z stands for NRg and R3 and/or R4 and/or R5 means hydrogen: The corresponding guanyl residue as :l formula I is prepared as -N(R3)-C(=Z)-NR4R5, can thus e.g. also exist in the tautomeric forms -N=C(-ZH)-NR4R5, -N(R3)-C(-ZH)=NR5 or

-N(R3)-C(-ZH)=NR4.

A further example: If Y stands for NRg and R^, and/or R7 is hydrogen, then the corresponding amidine structure, which in formula I is defined as X=—C(=Y)-NR(,R7, can also occur in tautomers forms -C(-YH)=NR7 or -C(-YE)=NR^, To a person skilled in the art, the present are common and well-known tautomers.

In the case that A means a group -(CHg)- and Rg is different from hydrogen, the residue or residues Rg corresponding to substituents can also be linked to the hydrogen atom in the group -(CHg)-.

The preceding and following general terms used within the scope of the present invention preferably have the following meaning: The prefix "lower" denotes a residue with up to and including 7 and especially up to and including 4 carbon atoms.

Lower alkyl is e.g. n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably ethyl or above all methyl.

Salts of the compound according to the invention are primarily pharmaceutically usable, non-toxic salts. Examples can be compounds of formula I with basic groups that form acid addition salts, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, e.g. acetic acid, fumaric acid or methanesulfonic acid, or e.g. with amino acids, such as arginine or lysine. In the absence of several basic groups, mono- or polysalts can be formed.

For isolation or purification, there can also be a use for pharmaceutically unsuitable salts, e.g. picrate or perchlorate, for therapeutic use the pharmaceutically usable, non-toxic salts are used, which are also preferred.

According to the structural facts, the compounds of the present invention can exist in the form of isomer mixtures or of pure isomers. Stands e.g. Rg for a different hydrogen substituent, then the corresponding compound of formula I can exist as a racemate or pure enantiomers.

The compounds according to the invention exhibit valuable, particularly pharmacologically usable, properties. In particular, they have a strong, specific inhibitory effect on the enzyme S-adenosylmethionine decarboxylase (SAMDC). SAMDC is a key enzyme and plays an important role in polyamine synthesis, which takes place in virtually all mammalian cells, including humans. With SAMDC, the polyamine concentration in the cell is regulated. Inhibition of the enzyme SAMDC results in a reduction in the polyamine concentration. As a decrease in the polyamine concentration causes an inhibition of cell growth, it is possible by administration of SAMDC-inhibiting substances to inhibit growth in both eukaryotic as well as prokaryotic cells and even kill cells or inhibit initiation of cell differentiation.

The inhibition of the enzyme SAMDC can e.g. be carried out with the method of E.G. Williams-Ashmann and A. Schenone, Biochem. Biophys. Res. Communs. 46, 288 (1972). Application of the invention shows ICsg values of a minimum of approx. 0.005 jM.

A further advantage of the compounds according to the invention consists in the fact that they only inhibit diaroin oxidase in a smaller mass compared to their strong inhibitory action of SAMDC and are well tolerated. The inhibition of diamine oxidase is unfavorable according to J.J. Jaenne and D.R. Morris, Biochem. J. 218, 974

(1984), as they can lead to the accumulation of putresine and an indirect SAMDC activation.

Therefore, the compound of formula I e.g. useful for the treatment of low and malignant tumors. They can cause tumor regression and further spread of tumor cells, as well as prevent the growth of micrometastases. Furthermore, they can serve e.g. for the treatment of protozoan infections, such as trypanosomiasis, malaria or pneumonia caused by Pneumocystis carinii.

As selective SAMDC inhibitors, the compounds of formula I can be used alone or in combination with other pharmacologically active substances. One can e.g. imagine a combination with (a) 'facilitators of other enzymes of polyamine biosynthesis, e.g. ornithine decarboxylase inhibitors, (b) protein kinase C inhibitors, (c) tyrosine protein kinase inhibitors, (d) cytokines, (e) negative growth regulators, (f) aromatase inhibitors, (g) antiestrogens or (h) classical cytostatic agents.

Preferably, the invention relates to a method of 4-amidino-1-indanone-2'-amidinohydrazone or a pharmaceutically usable salt thereof which is characterized by the use of corresponding starting materials.

The invention also relates to a process for the production of 4-amidino-1-indanone-2'-(N-hydroxyamidino)-hydrazone or a pharmaceutically usable salt thereof, which is characterized by the use of corresponding starting materials.

The invention also relates to a method for the production of 5-amidino-1-tetralone-2'-amidinohydrazone or a pharmaceutically usable salt thereof which is characterized by the use of corresponding starting materials.

As subgroups of the group of compounds of formula I, the following can be highlighted: (a) Compound of formula I where A means a direct bond; (b) compound of formula I wherein X represents a residue —C(=NH)-NHg; (c) compound of formula I wherein Z is NH, R 4 is hydrogen, and R 5 is hydrogen or hydroxy; and (d) compounds of formula I, wherein R 1 and R 8 are hydrogen.

The invention relates above all to the described specific compounds and their salts in the examples.

The compounds of formula I can be prepared in a manner known per se.

In the following description of the methods (a)-(b), the symbols A, X, Y, Z and R^-Rg each have the indicated meaning under formula I, unless otherwise indicated.

Procedure (a):

The group CW^Wg in the compounds of formula II is preferably present as free carbonyl.

The condensation reaction according to method (a) takes place under conditions known per se by forming hydrazones. It is preferably catalyzed with acid. In the compound with formula II it is; otherwise suitable with such protected carbonyl groups CW-jWg, which change to free carbonyl under the condensation conditions.

For the preparation of the compound of formula I, where R5 means amino, it is recommended to use the compounds of formula III in excess.

The intermediates of formula II, where Y in the residue X means NH, are e.g. obtained by transferring a compound of formula V

first by treatment with hydrogen sulphide in the corresponding thiocarboxamide [—C(=S)-NH2]. The latter can also be obtained in another way by starting from analogous carboxamide [—C(=0j-NHg], e.g. by reaction with Lawesson's reagent [2,4-bis-(4-methoxyphenyl )-2,4 -dithioxo-1,3,2,4-dithiadiphosphetane].

Thiocarboxamide becomes e.g. S-alkylated with lower alkyl iodide or tri-lower alkyl oxonium tetrafluoroborate and thus transferred to imino-lower alkyl thioester hydroiodide [—C(=NE)-S-alkyl'HI] or —tetrafluoroborate, which can easily be transferred by reaction with ammonia or amines of formula NHR^Ry to the desired carboxamides of formula II (cf. S. Patai (Ed.), The Chemistry of amidines and imidates, Wiley, London etc. 1975, pp. 303-304].

Preparation of carboxamide with formula II from the cyano compound with formula V proceeds analogously to the described preparation by method (b) of carboxamides with formula I from cyano compounds with formula IV and is described in detail there.

A further possibility for preparing compounds of formula II consists in treating a compound of formula V, where the group CW^Wg is defined as under formula II, e.g. with ethanol and hydrochloric acid in e.g. chloroform or diethyl ether, whereby a corresponding iminoethyl ester hydrochloride is formed, which e.g. by reaction with ammonia or in a primary or secondary amine with formula NER5R7 and e.g. methanol can be converted to the desired carboximidamide of formula II. However, this method can distinguish some cases by steric hindrance with the groups A or R^.

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

The compounds with formula V can e.g. prepared by intramolecular Friedel-Craf ts acylation of co-phenyl lower alkanoic acids of formula VI, where W4 means cyano or a cyano preference, or acid derivatives thereof, e.g. acid chlorides or acid anhydrides. Free acids can be used as catalysts, e.g. polyphosphoric acid and in the case of acid chlorides or anhydrides, e.g. AICI3.

A compound of formula VI is preferably used in these reactions where W4 does not mean cyano, but a cyano preference, e.g. halogen, especially bromine or protected amino, e.g. acetylamino. After the cyclization step, the cyano step can then be transferred in a manner known per se to cyano, e.g. bromine by reaction with copper (I) cyanide or acetylamino by removal of the acetyl protecting group, diazotization and reaction with copper (I) cyanide.

Compound with formula V where the group CW-jWg means carbonyl, can be further prepared, e.g. by oxidation, e.g. with chromium trioxide (CrC^), from the corresponding non-carbonyl compound of formula VII

where W4 means cyano or a cyano preference as defined above. If a cyanophore is used, this is again transferred after oxidation to cyano, e.g. as stated above.

A further possibility for the preparation of a compound of formula V in which the group CW^Wg means carbonyl consists in starting from the compound of formula II, where X means hydrogen, by introducing e.g. by a reaction sequence analogous to US patent 3,956,363, example 10, which consists of nitration, reduction of the nitro group to amino, diazotization and reaction with copper (I) cyanide (Sandmeyer reaction).

Preparation of aminoguanidines of formula III is known per se. Aminourea [= semicarbazide] becomes e.g. prepared in an analogous manner to the corresponding simple urea. Thus, e.g. instead of amines, corresponding hydrazines with the formula H2N-NHR3 and e.g. reacted with an isocyanate with the formula R4N=C=0 or R5N=C=0.

Aminoguanidines of formula III where Z stands for NRg and R3, R4, R5 and R9 are defined as under formula I, are known per se and can be prepared e.g. from the corresponding aminothiourea of formula III, by reacting the latter by alkylation, with an alkyl tosylate or -halide, transferring into corresponding S-alkylisothiouronium salts and reacting these with an amine of formula NHR4R5. Aminothiourea can e.g. be prepared by using corresponding hydrazines with the formula H2N-NHR3, and reacting with an isothicyanate with the formula R4N=C=S or R5N=C=S. Furthermore, there is e.g. also possible with the reaction of a hydrazine with the formula H2N-NHR3 with an acyl isothiocyanate, e.g. acetyl isothiocyanate, and subsequent acid hydrolysis.

Procedure (b):

In the intermediates of formula IV, ¥ 3 means a functional converted carboxy selected from cyano, imino-lower oxycarbonyl or thiocarbamoyl.

The group W3 in connection with formula IV can, in the preparation of amidines with formula I (Y=NRg), e.g. means: an acid addition salt of an imino lower alkyl ester (= imino lower alkyl ether) or cyano.

When reacting an imino-lower alkyl ester of formula IV (as salt) with ammonia or primary or secondary amines give the unsubstituted or The mono- or di-substituted amidines of formula I. The cyano compound of formula IV can e.g. be transferred by reaction with an alkali metal amide, e.g. KNHg, or by reaction with a primary or secondary (di-)lower alkylammonium halide, e.g. +<N>H3CH3-Cl~, in a suitable mono- or disubstituted amidine of formula

IN.

The carboxylic acid ester imide is obtained, e.g. by acid-catalyzed addition of alcohols to nitriles of formula IV. From the ester imides, a Pinner cleavage is obtained with the amide by thermal cleavage of the ester imide salt at temperatures above approx. 80°C.

Compounds of formula IV, where W3 means cyano, can e.g. be prepared by reacting a compound of formula V with a compound of formula III according to method a). From the compound of formula IV, where W3 means cyano, it is possible to prepare other compounds of formula IV, where W3 means, as described above, functional converted carboxy, in a manner known per se or as described above.

Compound of formula I can be transferred to other compounds of formula I.

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

The obtainable free compounds of formula I according to the method with salt-forming properties can be transferred in a manner known per se to their salts, compounds with basic properties, e.g. by treatment with acids or suitable derivatives thereof, compounds with acidic properties, e.g. by "treatment with bases or suitable derivatives thereof.

As a result of the close connection between compounds of formula I in free form and in the form of salts, in the foregoing and following, free compounds or their salts the corresponding salts respectively free connections.

The compounds, including their salts can also be obtained in the form of hydrates, or their crystals can e.g. include the solvent used for the crystallization.

The obtainable mixtures of isomers according to the invention can also be separated in a manner known per se into the individual isomers, the racemates, e.g. by forming salts with optically pure salt-forming reagents and separating the diastereomer mixture thus obtained, e.g. by means of fractional crystallization.

The above-mentioned reactions can be carried out under reaction conditions known per se, in the absence or usually the presence of solvents or diluents, preferably those which are inert and dissolve the reagents used, in the absence or presence of catalysts, condensing agents or neutralizing reagents, after which reaction type and/or reaction participants at a lower, normal or elevated temperature, e.g. in the temperature range from approx. -70°C to approx. 190°C, preferably from approx. -20°C to approx. 150°C, e.g. at the boiling point. to the solvents used, under atmospheric pressure or in a closed equipment, possibly under pressure, and/or in an inert atmosphere, e.g. under nitrogen atmosphere.

In the method of the present invention, such starting materials are preferably used which lead to the previously particularly described valuable compounds. The compounds of formula I are suitable for the production of pharmaceutical preparations, which as active ingredient contain one of the pharmacologically active compounds of formula I, especially preparations for enteral, especially oral, as well as parenteral administration. The preparations contain the active ingredient alone or preferably together with a pharmaceutically usable carrier material. The dosage of the active substance depends on the disease treated, as well as the species, age, weight and individual condition, as well as the method of application.

The pharmaceutical preparations contain from approx. 0.1% to approx. 95% active ingredient, whereby single-dose application forms preferably exhibit from approx. 0.1% to approx. 90% and non-single-dose application forms preferably show approx. 0.1% to approx. 20% active ingredient. The dosage unit form, such as dragées, tablets or capsules, contains from approx. 1 mg to approx. 500 mg active ingredient.

The pharmaceutical preparations are prepared in a manner known per se, e.g. using conventional leafing, granulating, coating, dissolving or lyophilizing methods. Thus, pharmaceutical compositions for oral use can be obtained by combining the active substance with one or more solid carriers, possibly granulating a resulting mixture, and processing the mixture or the granulate when desired, possibly by adding additional excipients, to tablets or dragée cores.

Suitable carriers are especially fillers such as sugar, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphate, e.g. tricalcium phosphate or calcium hydrogen phosphate, further bulking agents such as starch, e.g. corn, wheat, rice or potato starch, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and/or when an explosive is desired, such as the above-mentioned starch, further carboxymethyl starch, cross-branched polyvinylpyrrolidone, alginic acid or a salt thereof such as sodium alginate .

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

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

Orally usable pharmaceutical compositions are likewise gelatin suppositories, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerin or sorbitol. The stick capsules may contain active substance in the form of a granule, e.g. in a mixture with fillers, such as corn starch, binders and/or lubricants, such as talc or magnesium stearate, and possibly stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, whereby any stabilizers can be added.

Further oral forms of application are e.g. the prepared syrups in the usual way, which contain the active ingredient, e.g. in suspended form and in a concentration of approx. 0.1$ to 10$, preferably approx. 1% or in a similar concentration, such as e.g. when measuring 5 or 10 ml of a suitable single dosage gives. Furthermore, it can e.g. take into account powdery or liquid concentrates that are prepared in e.g. milkshake. Such concentrates can also be packaged in single dosage amounts.

As rectally usable pharmaceutical preparations, it can e.g. take into account suppositories, which consist of a combination of the active ingredient with a suppository base. As a suppository base material, it is suitable, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

For parenteral administration, aqueous solutions of an active substance in water-soluble form are suitable in the first place, e.g. a water-soluble salt, or aqueous injection suspensions, which contain viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and any stabilizers. Furthermore, the active ingredient can optionally, in accordance with the excipient, also be present in the form of a lyophilisate and before the parenteral administration be brought into solution by the addition of suitable solvents.

The solutions, such as those that were used for parenteral administration can also be used as infusion solutions.

The following examples illustrate the present invention; the temperatures are indicated in degrees Celsius. The following abbreviations are used: DMF = N,N-Dimethylformamide; ether = diethyl ether; acetic ester = acetic acid ester; THF = tetrahydrofuran; MS (FAB) = mass spectrum ("Fast Atom Bombardment"). Example 1: 4-amidinol-indanone-2'-amidinohydrazone dihydrochloride A solution of 3.8 g (27.9 mmol) of aminoguanidine hydrogen carbonate in 200 ml of water and 14.7 ml of 2N hydrochloric acid is heated to 60° and mixed with stirring during 30 minutes with a solution of 5.85 g (27.8 mmol) of 4-amidino-1-indanone hydrochloride in 200 ml of methanol. The reaction mixture is refluxed for 24 hours and after cooling is evaporated to dryness. The residue is suspended in 50 ml of ethanol, filtered, washed with ethanol and ether and dried. One thus obtains the title compound, which contains one mole of crystal water, mp>330°; MS(FAB): (M+H)<+=>231; 1 H-NMR (D 2 O): S=8.08 (d, 1H); 7.75 (d,1H); 7.58 (t,1H); 3.35 (m, 2H); 2.96 (m, 2H).

The output connection is produced as follows:

(a) 4- 1 i ocarb amoyl- 1- indanone

A solution with 12.1 g (77 mmol) of 4-cyano-1-indanone [Coll. Czechoslovak. Chem. Commun. 43, 3227 (1978)] in 220 ml of pyridine and 10.6 ml (77 mmol) of triethylamine is saturated at 40° for 3 hours with hydrogen sulphide and stirred for a further 16 hours at the same temperature. After cooling, the reaction mixture is evaporated to dryness and the residue is mixed with 300 ml of water. The crystallized yellow product is suctioned off, washed with water, dried and recrystallized from acetic acid. One thus obtains the starting compound (a), Smp. 197° (cleavage).

(b) 4-amidino-l-indanone hydrochloride

A solution of 9.8 g (51.3 mmol) of 4-thiocarbamoyl-1-indanone in 500 ml of abs. Methylene chloride is mixed with 10.8 g (54 mmol) of triethyloxonium tetrafluoroborate at room temperature under argon. After 16 hours, a mixture of 4.2 g of potassium carbonate and 4.2 ml of water is added to the reaction solution. You then stir briefly, filter and wash the filtrate with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The crude ethyl thioimino ether thus obtained is dissolved in 160 ml abs. ethanol, mixed with 3.3 g (60 mmol) of ammonium chloride and heated for 20 hours at reflux. After cooling, the reaction mixture is evaporated to dryness. The starting compound (b) is purified by chromatography on 1000 ml of Amberlit ER-1800 resin (water as eluent) and recrystallized from ethanol/ether, mp. 215-218" (cleavage).

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

A solution of 316 mg (1.5 mmol) of 4-amidino-1-indanone hydrochloride (Example 1b) in 7 ml of methanol is mixed 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 2N hydrochloric acid, heated for 2 hours at reflux and stirred for 16 hours at room temperature. The reaction mixture is evaporated and the residue purified by chromatography (Pharmacia column SR-28-100) on silica gel 0PTI-UP C^g (water as eluent, 5 ml fractions, gennorn flow rate 27.5 ml/h). Contents of fractions 58-78 are combined, evaporated and the residue crystallized from ethanol. The title compound is thus obtained in the form of waxy crystals, MS(FAB): (M+H)<+> = 247; <1>H-NMR (D 2 O): S=8.06 (d,1H); 7.73 (d,1H); 7.58 (t,1H); 3.36 (m, 2H); 2.98 (m, 2H).

Example 3:

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

A solution of 0.41 g (3 mmol) of aminoguanidine bicarbonate in 31.5 ml of 0.1N hydrochloric acid is mixed with 0.675 (3 mmol) of 5-amidino-1-tetralone hydrochloride and heated for 72 hours at reflux. After cooling, it is evaporated to dryness and the title compound is crystallized from methanol/ether, mp>250°; MS(FAB): (M+H)<+> = 24J:i; -'•H-NMR (DMS0-d6) : S = 11 , 3 (s,1H); 9.5 (m, 4H); 8.65 (d,lE); 7.92 (m, 3H); 7.52 (d,1H); 7.46 (t,1H); 2.7-2.85 (m, 4H); 1.9 (m, 4H).

The output connection is produced as follows:

(a) 5-cyano-l-tetralone

A solution of 1.0 g (4.4 mmol) of 5-bromo-1-tetralone [J. Org. Chem. 49» 4226 (1984)] in 1.3 ml of DMF is mixed with 0.41 g (4.5 mmol) of copper(I) cyanide and stirred for 6 hours at 160°. The reaction mixture is then cooled to 80°, and a solution of 1.6 g of iron(III) chloride hexahydrate in 2.5 ml of water and 0.44 ml of conc. hydrochloric acid. It is then stirred for 45 minutes, cooled, the reaction mixture diluted with water and extracted with toluene. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The starting compound (a) is thus obtained as yellow-orange crystals, IR (CH2C12): 2220, 2690 cm-<1>; 1 H-NMR (CDCl 3 ): S=8.26 (q,1H); 7.81 (q,1H); 7.43 (t,1H); 3.21 (t, 2H); 2.72 (t, 2H); 2.23 (m,2E).

(b) 5-thiocarbamoyl-1-tetralone

Analogously to example 1a, 10.6 g (62 mmol) of 5-cyano-1-tetralone in 200 ml of pyridine and 8.6 ml of triethylamine are treated with hydrogen sulphide and worked up. The starting compound (b) is thus obtained as yellow crystals, m.p. 200-205°.

(c) 5-amidino-1-tetralone hydrochloride

Analogous to example 1b, 8.6 g (42 mmol) of 5-thiocarbamoyl-1-tetralone are obtained with 8.8 g (44 mmol) of triethyloxonium tetrafluoroborate and 2.6 g (49 mmol) of ammonium chloride. The starting compound (c) is thus obtained as light pink colored crystals, MS (FAB): (M+H)<+> = 189.

Example 4: 4-amidino-l-indanone-2'-amidinohdrazone dihydrochloride Analogously to example 1b, 4-thiocarbamoyl-l-indanone-2'-amidinohydrazone hydrochloride (example 4) is reacted with triethyloxonium tetrafluoroborate and ammonium chloride, after which one obtains the title compound, mp>330°; MS(FAB): (M+H)<+> = 231; <i>H-NME (D2O): S=8.08 (d,1H); 7.75 (d,1H); 7.58 (t.1H); 3.35 (m, 2H); 2.96 (m, 2H).

Example 5: 4-amlidino-1-indanone-2'-amidinohydrazone dihydrochloride A solution of 0.26 g (1 mmol) 4-cyano-1-indanone-2'-amidinohydrazone hydrochloride in 5 ml abs. Methanol is mixed with 1.2 ml of a 1N sodium methoxide solution in methanol and heated for 16 hours at reflux. After cooling, 0.16 g (3 mmol) of solid ammonium chloride is added to the reaction mixture and stirred for 1 hour at 60". The reaction mixture is then evaporated and the residue crystallized from dilute ethanol. The title compound is thus obtained, mp>330°.

The output connection is produced as follows:

(a) 4-cyano-l-indanone-2'-amidinohydrazone hydrochloride Analogous to example 1, 314 mg (2 mmol) of 4-cyano-l-indanone in 20 ml of methanol, mixed with a solution of 272 mg (2 mmol ) aminoguanidine bicarbonate in 9 ml of water and 1 ml of 2N hydrochloric acid and stirred for 4 days under reflux. After cooling, reaction mixtures become;. evaporated to dryness and the residue crystallized from water. The starting compound (a) is obtained, mp>230°; 1 H NMR (DMSO-d 6 /D 2 O): δ=8.16 (d,1E); 7.9 (d,1B); 7.55 (t,1H); 3.28 (m, 2H); 2.9 (m, 2H); IR (Nujol): 2190 cm-<1> (CN).

Example 6: 4-(N-hydroxyamidino)-1-indanone-; 2'-amidinohydrazone dihydrochloride

0.2 g (3 mmol) of hydroxylamine hydrochloride is suspended in 1 ml of abs. ethanol and mixed with 2 ml of a 1N sodium ethoxide solution in ethanol. This mixture is stirred for 1 hour and filtered. A solution of 0.26 g (1 mmol) of 4-cyano-1-indanone-2'-amidinohydrazone hydrochloride (Example 5) in 2 ml of water is added to the filtrate, and it is heated for 6

hours at reverse flow. After cooling, the reaction mixture is evaporated and the title compound crystallized from water, mp>250°; <1>H-NMR (DMSO-d6+D20=: §=8.12 (m,1H); 7.55 (m,2H); 3.22 (m,2H); 2.83 (m,2H ).

Example 7: 4-amidino-2-methyl-1-indanone-2'-amidinohydrazone-dihydrochloride Analogous to example 1, starting from 4-cyano-2-methyl-1-indanone (p. US patent 3,956. 363) produced the title compound.

Example 8: 5-amidino-2-methoxy-1-tetralone-2'-amidinohydrazone-dihydrochloride

Analogous to example 1, starting from 5-cyano-6-methoxyl-r-tetralone [Chem. Pharm. Bull. 31, 2329 (1983)] produced the title compound.

Example 9: 4-amidino-6-methyl-1-indanone-2'-amidinohydrazone-dihydrochloride Analogous to example 3, starting from 4-bromo-6-methyl-1-indanone (Bull. Soc. Chim. France 1964, 3103) prepared the title compound.

Example 10: 4-amidino-6-methoxy-7-methyl-1-indanone-2'-amidinohydrazone-dihydrochloride

Analogously to example 3, starting from 4-bromo-6-methoxy-7-methyl-1-indanone (J. Chem. Soc. Perkin Trans. 1 1974, 1911) the title compound is prepared.

Example 11: 4-amidino-6. 7-dimethyl-1-indanone-2'-amidinohydrazone dihydrochloride

Analogous to example 3, starting from 4-bromo-6,7-dimethyl-1-indanone [J. Hot. Chem. 24» 677 (1987)] produced the title compound.

Example 12: 4-(methylamidino)-1-indanone-2'-amidinohydrazone-dihydrochloride

Analogously to example 1b, 4-thiocarbamoyl-1-indanone-2'-amidinohydrazone hydrochloride (A solution of 1.9 g (10 mmol) 4-thiocarbamoyl-1-indanone (example la) in 50 ml of ethanol is mixed with 1 .36 g (10 mmol) of aminoguanidine hydrogen carbonate and 10 ml of 2N hydrochloric acid and heated for 24 hours at reflux. After cooling, the reaction mixture is evaporated to dryness, whereby the title compound is obtained) reacted with triethyloxonium tetrafluoroborate and methylammonium chloride, whereby the title compound is obtained .

Example 13: 4-amidinol-indanone-2'-amidinohydrazone dihydrochloride A solution of 6.12 g (45 mmol) of aminoguanidine hydrogen carbonate in 100 ml of water and 46 ml of IN hydrochloric acid is mixed with 9.45 g (44, 9 mmol) 4-amidino-1-indanone hydrochloride (see example 1b) and stirred for 24 hours at 24°. The crystallized product is sucked off, washed with a little water and recrystallized from 300 ml of water. The title compound is thus obtained, which contains 1 mol of crystal water, mp>330°; MS (FAB): (M+E)<+> = 231; 1 H NMR (D 2 O): S=8.08 (d, 1H); 7.75 (d.1H); 7.58 (t,1E); 3.35 (m, 2H); 2.96 (m, 2H).

Example 14: 4-amidino-2-methyl-1-indanone-2'-amlidinohydrazone-dihydrochloride A solution with 1.0 g (5.0 mmol) of 4-amidino-2-methyl-1-indanone hydrochloride and 0. 68 g (5.0 mmol) of aminoguanidine hydrogen carbonate in 10 ml of 0.5 hydrochloric acid is stirred for 120 hours at 25°. The crystallized product is sucked off, washed with a little water and dried. One thus obtains the title compound, mp>250°; MS(FAB): (M+H)<+> = 245; <1>H-NMR (D 2 O): S=7.95 (d,1H); 7.66 (d,1H); 7.48 (t,1H); 3.45 (m,2E); 2.85 (d.1H); 1.12 (d, 3H).

The output connection is produced as follows:

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

Analogously to example 1a, 11.1 g (65 mmol) of 4-cyano-2-methyl-1-indanone [see US patent 3,956,363] in 200 ml of pyridine and 9.7 ml of triethylamine are treated with hydrogen sulphide and worked up. The starting compound (a) is thus obtained as yellow crystals, m.p. 195-198° (Decomposition); - 1 H-NMR (DMSO-d 6 ): δ = 9.61 (s, 1H); 7.71 (m,1H); 2.81 (m, 2H); 1.23 (s, 3H); 1.19 (p, 3H).

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

Analogously to example 1b, 10.2 g (50 mmol) of the starting compound (a) is treated with 11.0 g (55 mmol) of triethyloxonium tetrafluoroborate and 3.2 g (60 mmol) of ammonium chloride. The starting compound (b) is thus obtained as pink crystals. They are directly sold on.

Example 15

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

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

The output connections are made as follows:

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

A mixture with 17.8 g (74.5 mmol) of 4-bromo-6,7-dimethyl-1-indanone [J. Hot. Cehm. 24» 677 (1987)] and 7.3 g (82 mmol) of copper(I) cyanide in 18 ml of DMF are stirred for 6 hours at 170°. The reaction mixture is then cooled to 100° and mixed successively with 200 ml of toluene and a solution of 31.2 g of iron(III) chloride hexahydrate in 47 ml of water and 8.2 ml of conc. hydrochloric acid. The reaction mixture is then stirred for 20 minutes at 70°, cooled and diluted with toluene and water. The organic phase is rinsed off, washed with water, a half-saturated sodium hydrocarbon solution and again washed with water, dried and evaporated. The residue is crystallized from ethyl acetate and ether and corresponds to the starting compound (a). Beige crystals are obtained with m.p. 160-163°; IR(CH 2 Cl 2 ):2220, 1710 cm<-->'-.

(b) 4- Thiocarbamoyl-6.7-Dimethyl-1-indanone

Analogous to example la, 10 g (54.1 mmol) of the starting compound (a) in 200 ml of pyridine and 7.5 ml of triethylamine are treated with hydrogen sulphide and worked up. The starting compound (b) is thus obtained in the form of yellow crystals, m.p. 207-208°; <1->H-NMR (DMS0-d6): S = 10.03 (s,1H); 9.49 (s, 1H); 7.49 (s, 1H); 3.12 (m, 2E); 2.61 (m, 2H); 2.54 (s, 3H); 2.29 (p, 3H).

(c) 4-amino-6,7-dimethyl-1-indanone hydrochloride

Analogously to example 1b, 4.4 g (20 mmol) of the starting compound (b) is treated with 4.26 g (21 mmol) of triethyloxonium tetrafluoroborate and 1.2 g (24 mmol) of ammonium chloride. The starting compound (c) is thus obtained in the form of beige crystals.

Example 16: 4-amiidino-6,7-dimethoxy-1-in. danone-2>-amidinohydrazone dihydrochloride

A solution of 0.4 g (3 mmol) of aminoguanidine bicarbonate in 6 ml of 0.5 N hydrochloric acid is mixed with 0.73 g (2.7 mmol) of 4-amidino-6,7-dimethoxy-1-indanone hydrochloride and stirred for 24 hours at 50°. After cooling, the crystallized product is suctioned off, washed with a little water and dried, whereby the title compound is obtained, m.p. >229°; MS (FAB): (M+H)<+> = 291; <i>H-NMR (D 2 O): S=7.45 (s,1H); 3.97 (s, 6H); 3.27 (m, 2H); 2.98 (m, 2H).

The output connections are made as follows:

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

A mixture with 6.57 g (24.2 mmol) of 4-bromo-6,7-dimethoxy-1-indanone [Can. J. Chem. 57, 1603 (1979)] and 2.5 g (28 mmol) of copper (I) cyanide in 7 ml of DMF are stirred for 5.75 hours at 170'. The reaction mixture is then cooled to 100° and successively mixed with 70 ml of toluene and a solution of 9.7 g (36 mmol) of iron(III) chlorid hexahydrate in 15.6 ml of water and 3.5 ml of conc. hydrochloric acid. The reaction mixture is then stirred for 30 minutes at 80°, cooled and diluted with toluene and water. The organic phase is rinsed off, washed with water, a half-saturated sodium bicarbonate solution and again with water, dried and evaporated. The residue is distilled at 150-160°/0.1 mbar in • a ball tube still and it corresponds to the starting compound (a), m.p. 150°; IR (CH 2 Cl 2 ); 2220, 1710 cm-<1>; 1 H-NMR (CDCl 3 ): δ=7.33 (s,1H); 4.12 (s, 3H); 3.90 (s, 3H); 3.19 (m, 2H); 2.76 (m, 2H).

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

Analogously to example 1a, 3.7 g (17 mmol) of the starting compound (a) in 100 ml of pyridine and 2.4 ml of triethylamine are treated with hydrogen sulphide and worked up. The starting compound (b) is thus obtained in the form of pale yellow crystals, m.p. 196-199°; <i>H-NMR (DMS0-d6): δ=10.06 (s,1H); 9.50 (s.1H); 7.41 (s, 1H); 3.84 (s, 6H); 3.13 (m, 2E); 2.63 (m, 2H).

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

Analogously to example 1b, 3.3 g (13 mmol) of the starting compound (b) is treated with 2.8 g (14 mmol) of triethyloxonium tetrafluoroborate and 0.8 g (15 mmol) of ammonium chloride. The starting compound (c) is thus obtained in the form of beige crystals, m.p. 188° (with cleavage); -1 H-NMR (DMS0-d6): δ = 9.4 (s,3H); 7.63 (s, 1H); 3.92 (p.3E); 3.89 (s, 3H); 3.18 (m, 2H)); 2.68 (m, 2H).

Example 17: 4-amidino-3-methyl-1-indanone-2'-amidinohydrazone-dihydrochloride A solution of 300 mg (1.3 mmol) 4-amidino-3-methyl-1-indanone hydrochloride in 6 ml of water is mixed with 300 mg (2.3 mmol) of aminoguanidine bicarbonate in 4 ml of 0.5 N hydrochloric acid and stirred for 24 hours at 80°. The reaction mixture is cooled, evaporated and the residue purified by chromatography on a 180 ml amberlite ER-180 resin eluting with water. The title compound is crystallized from methanol/ether, m.p.

>259°; Rf=0.18 (silica gel, methylene chloride/methanol/con. ammonia 5:3:1); MS (FAB); (M-1-H)<+> = 245; 1 H NMR (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, 3E).

The output connections are made as follows:

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

A mixture with 2.6 g (11.5 mmol) of 4-bromo-3-methyl-1-indanone [J. Org. Chem. 22, 1019 (1957)] and 1.14 g (12.7 mmol) of copper (I) cyanide in 2.5 ml of DMF are stirred for 6 hours at 170°. The reaction mixture is then cooled to 100° and successively mixed with 50 ml of toluene and a solution of 4.5 g (16.5 mmol) of iron(III) chloride hexahydrate in 7 ml of water and 1.7 ml of conc. hydrochloric acid. The reaction mixture is then stirred for 20 minutes at 70°, cooled and diluted with toluene and water. The organic phase is separated, washed with water, a half-saturated sodium bicarbonate solution and washed again with water, dried and evaporated. The residue is distilled at 100-120°/0.05 mbar in a ball tube still and it corresponds to the starting compound (a), m.p. 109-111°; IR (CH 2 Cl 2 ): 2220, 1710 cm-<1>; % NMR (CDCl 3 ): δ=7.92 (m, 2H); 7.52 (t.1E); 3.73 (m, 1H); 3.03 (q,1H); 2.40 (q.1H); 1.55 (d, 3H).

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

Analogously to example la, 1.45 g (8.47 mmol) of the starting compound (a) is treated and worked up in 25 ml of pyridine and 1.2 ml of triethylamine with hydrogen sulphide. The starting compound (b) is thus obtained in the form of pale yellow crystals, m.p. 198-200°; <i>H-NMR (DMS0-d6): δ=9.78 (s,1H); 7.65 (m, 2H); 7.46 (m, 1H); 3.98 (m,1H); 2.95 (q,1E); 2.26 (q,1H); 1.25 (d, 3H).

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

Analogously to example 1b, 0.96 g (4.68 mmol) of the starting compound (b) is treated with 1.0 g (4.93 mmol) triethyloxonium tetrafluoroborate and 0.3 g (6 mmol) ammonium chloride. The starting compound (c) is thus obtained in the form of beige crystals, 3-H-NMR (DMS0-d6) S=9.59 (s,4H); 7.65 (m, 2H); 7.46 (m,1H); 3.98 (m,1H); 2.95 (q,1H); 2.26 (q, 1H); 1.25 (d, 3H).

Example 18: 4-amidino-1-indanone-2'-amidinohydrazone-dihydrochloride A mixture with 0.32 g (1 mmol) 4-(N-hydroxyamidino)-1-indanone-2'-amidinohydrazone-dihydrochloride (Example 6) , 0.36 ml (2 mmol) of triethylamine and 0.2 g (1 mmol) of iron pentacarbonyl in 10 ml of absolute THF are refluxed for 16 h. The reaction mixture is then evaporated and the residue crystallized from dilute hydrochloric acid, whereby the title compound is obtained, m.p. >330°.

Example 19: 4-amidono-2-ethyl-1-indanone-2'-amidinohydrazone-dihydrochloride 3-(2-bromophenyl)-2-ethylpropionic acid (German patent 2,733,868) is cyclized in heat with polyphosphoric acid to the corresponding 1-indanone and converted analogously to example 3 to the title compound.

Example 20: 4-amidino-2-n-butyl-1-indanone-2'-amidinohydrazone-dihydrochloride

3-(2-bromophenyl)-2-n-butylpropionic acid (German patent 2,733,868) is cyclized in the heat with polyphosphoric acid to the corresponding 1-indanone and converted analogously to example 3 to the title compound.

Example 21:

Capsules containing 0.25 g of active ingredient, e.g. of a compound of examples 1-20, can be prepared as follows: Composition<g> (for 5000 capsules)

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

Example 22:

10,000 tablets are produced, each of which contains 5 mg of active ingredient, e.g. of one of the prepared compounds in examples 1-20, and contains:

Composition:

Approach:

All powdery components are passed through a sieve with a mesh size of 0.6 mm. Then the active ingredient, milk sugar, magnesium stearate and; half of the starch mixed in a suitable mixer. 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 optionally granulated with the addition of more water. The granulate is dried overnight at 35°C, passed through a sieve with a 1.2 mm mesh size and pressed into tablets, which exhibit a fracture drill.

Claims (4)

1. Analogous process for the preparation of therapeutically active compounds of formula (I) where A means a direct bond or —(CH2)—; X represents a residue -C(=Y)-NR 6 R 7 ; Y stands for NRg; Z stands for NRg; R 1 R 2 and R-L 0 independently of each other mean hydrogen, lower alkyl or lower alkoxy; the radicals R 3 , R 4 , R 4 , R 8 and R 9 independently mean hydrogen or lower alkyl; and R5 and R7 independently stand for hydrogen, lower alkyl or hydroxy, and salts thereof, characterized by (a) condensing a compound of formula (II) where the group CW^Wg stands for carbonyl and A, X, R^, R2 and R10 have the indicated meaning as under formula I, with an amine of formula (III) where Z, R3, R4 and R5 are defined as under formula (I), or (b) in a compound of formula (IV) where W3 is thiocarbamoyl, cyano or imino-lower oxycarbonyl, and A, Z, R^, Rg, R3, R4, R5 and R^q are defined as under formula (I), the residue transfers W3 to the group X; and, when desired, converts an obtained compound of formula (I) into another compound of formula (I), and/or when desired, converts an obtained salt into the free compound or into another salt, and/ or, when desired, converts an obtained free compound of formula (I) with salt-forming properties into a salt. 2. Method according to claim 1 for the production of 4-amidino-1-indanone-2'-amidinohydrazone or a pharmaceutically usable salt thereof, characterized in that corresponding starting materials are used. 3. Process according to claim 1 for the production of 4-amidino-1-indanone-2'-(N-hydroxyamidino)-hydrazone or a pharmaceutically usable salt thereof, characterized in that corresponding starting materials are used. 4. Process according to claim 1 for the production of 5-amidino-1-tetralone-2'-amidinohydrazone or a pharmaceutically usable salt thereof, characterized in that corresponding starting materials are used.