FI107916B - Process for the preparation of hydrazone derivatives - 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

107916

Process for the preparation of hydrazone derivatives -Förfarande för framställning av hydrazonderivat

The invention relates to a method of formula I

X

f ^ Sr-A-i

For the preparation of the therapeutically active hydrazone derivatives, their tautomers and their salts of R 1 -I 1 -R 2 (was R 3 R 4 *) wherein A represents a direct bond or -CH 2 -, X represents a -C (= Y) -NR 6 R 7 Y is NR8 / Z is NR9, R1 and R2 are independently hydrogen, lower alkyl or lower alkoxy, the residues R3, R4, R6, R8 and R9 are independently hydrogen or lower alkyl, and R5 and R7 are independently hydrogen, lower alkyl or hydroxy. The compounds of the invention may be used therapeutically for treating a human or animal, or for the preparation of a pharmaceutical.

». Tautomers may occur, for example, when Z is NR9 and R3 »»! and / or R4 and / or R5 are hydrogen:

The corresponding guanyl residue represented by the group of formula I. -N (R 3) -C (= Z) -NR 4 R 5 may also occur e.g. 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.

· · * Another example: When Y is NR8 and R5 and / or R7 represents *: hydrogen, the corresponding amidine structure defined in ··· 107916 in formula I as X = -C (= Y) -NR6R7 may also occur in tautomeric forms, -C (-YH) = NR7 or -C (-YH) = NR6. The presence of such and corresponding tautomers is known to those skilled in the art. All of these tautomers are of the general formula I.

In the case where A represents -CH 2 - and R 2 is other than hydrogen, the substituent (s) corresponding to R 2 may also be attached to the carbon atom of -CH 2 -.

In the context of this application, the general terms used above and below have the following meanings in particular:

The prefix "lower" refers to residues having from 1 to 7 and in particular up to 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, in particular ethyl and above all methyl.

Salts of the compounds prepared by the process of the invention are primarily pharmaceutically usable, non-toxic salts. For example, compounds of formula I containing basic groups may form an acid addition. salts, e.g., inorganic acids such as hydrochloric acid. sulfuric or phosphoric acid, or suitable organic carboxylic or sulfonic acids, e.g. acetic acid, fumaric acid or methanesulfonic acid, or e.g. amino acids such as: arginine or lysine. More basic groups. mono- or polysalt salts may be formed in the presence. One. acidic group, e.g. carboxyl, and one basic group, »·! e.g., amino-containing compounds of formula I may exist, e.g., in the form of internal salts, i. in a dual ionic (zwitterionic) form, or a portion of the molecule may exist as an internal salt and another portion as a normal salt.

3 107916

Pharmaceutically unsuitable salts, e.g. picrates or perchlorates, may also be used for isolation or purification. Only pharmaceutically useful, non-toxic salts are used therapeutically and are therefore preferred.

Depending on the structural conditions, the compounds of the present invention may exist in the form of isomeric mixtures or pure isomers.

The compounds prepared by the process of the invention have valuable, in particular pharmacologically useful properties. In particular, they have a strong specific inhibitory effect on the S-adenosylmethionine decarboxylase (SAMDC) enzyme. As a key enzyme, SAMDC plays an important role in polyamine synthesis, which is found in virtually all mammalian cells, including human cells. The SAMDC controls the cell polyamine concentration. Inhibition of the SAMDC enzyme results in a decrease in polyamine concentration. Because the reduction in polyamine concentration results in inhibition of cell growth, it is possible to inhibit the growth of both eukaryotic and pro-karyotic cells and even kill cells or prevent cell differentiation by initiating SAMDCs, inhibitors.

The inhibition of SAMDC can be demonstrated, e.g., by the method of H.G. Williams-Ashmann and A. Schenone ,; Biochem. Biophys. Res. Communs. 46, 288 (1972). The invention. the compounds have a minimum IC50 of about 0.005 μΜ.

I ·! Another advantage of the compounds prepared by the process of the invention is that they only slightly inhibit diamine oxidase compared to their potent inhibitory effect on SAMDC ♦ • 107916 4 and are well tolerated. Diamine oxidase inhibition is disadvantageous [J. Jaenne and D.R. Morris, Biochem. J. 218, 974 (1984)] because it can lead to the accumulation of putrescine and indirect activation of SAMDC.

Therefore, the compounds of the formula I can be used, for example, for the treatment of benign and malignant tumors. They can induce tumor regression and further inhibit the spread of tumor cells and the growth of micrometers. Further, they can be used to treat, e.g., protozoal infections such as trypanosomiasis, malaria, or pneumonia caused by Pneumocystis carin.

As selective SAMDC inhibitors, the compounds of formula I may be used alone or in combination with other pharmacologically active substances. Thus, for example, a combination of (a) inhibitors of other enzymes of polyamine biosynthesis, e.g., ornithine decarboxylase inhibitors, (b) protein kinase C inhibitors, (c) tyrosine protein kinase inhibitors, (d) cytokines, ) aromatase inhibitors, (g) anti-estrogens, or (h) classical cytostatic agents.

. Of the group of compounds of formula I, the following must be mentioned in particular as subgroups: (a) compounds of formula I wherein A represents a direct bond, (b) compounds of formula I wherein X represents a -C (= NH) -NH 2 / (c) ) compounds 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 2 are hydrogen.

• · * • · 5 107916

The invention relates to a process for the preparation of the particular compounds and their salts, in particular in the Examples.

The compounds of formula I may be prepared in a manner known per se, e.g.

(a) Formula II

X

r ^ Tr-A-i (il) \ v2

wherein the group CWiW2 represents a carbonyl, a functionally modified carbonyl or a protected carbonyl and the residues A, X, R1 and R2 have the meanings given in formula I,

Z

II

H * Nv.n / C ^ n / R5 (III)

II

R 3 with an amine of R 4 '' wherein Z, R 3, R 4 and R 5 are? the meaning given by formula I, or »» «

(b) Formula IV

JL3: R1 "T | Γ" Α ^ ~ β2 (IV) z ^ Ti 11 • N -C. .R5: 1-13 r3 r4 ♦ ♦ • · 6 107916 in which W3 represents thiocarbamoyl, cyano, bromine or N-hydroxyamidino and the residues A, Z, R1, R2, R3, R4 and R5 have the meanings given in formula I converting the residue W 3 into X, and optionally converting the resulting compound of formula I into another compound of formula I, and / or converting the resulting salt into the free compound or another salt, and / or converting the resulting free compound of formula I having salt-forming properties compound into salt.

In the following more detailed description of methods a) to b), the symbols A, X, Y, Z and R 1 -R 9 each have the meanings given in formula I, unless otherwise stated.

Method a);

Functionally modified or counter-protected carbonyl CWiW2 is exemplified by dialkylalkoxymethyl, C 1 -C 2 alkylenedioxymethyl, dihalomethyl, dialkylalkylthiomethyl or C 1 -C 2 alkylenedithiomethyl.

In particular, group CWiW2 is present in the compounds of formula II as free carbonyl.

The condensation reaction according to method a) takes place under conditions known per se to form hydrazones. It is: preferably catalyzed by acid. In particular, the compounds of formula II have protected carbonyl groups such as: CWiW2 which are converted to the free carbonyl under condensation conditions.

• »· • · 7 107916

The intermediates of formula II wherein Y at X is NH are obtained e.g.

CN

The compound of "-όο-" · ✓ \ w, w2 is first converted to the corresponding thiocarboxamide [-C (= S) -NH2] by treatment with hydrogen sulfide. This can also be obtained in another way by starting from the analogous carboxamide [-C (= O) -NH 2] e.g. by reacting Lawesson's reagent 2,4-bis- (4-methoxyphenyl) -2,4-dithioxo-1,3,2, 4-dithiadiphosphane]. The thiocarboxamides are S-alkylated with e.g. lower alkyl iodide or trialempalkyl oxonium tetrafluoroborate, and thus converted to the imino-Alem pialkylthiol ester hydroiodides [-C (= NH) -S-alkyl «H by reaction with ammonia or amines of formula NHR6R7 (cf. S. Patai (Ed.), The Chemistry of Amidines and Imidates, Wiley, London, etc. 1975, pp. 303-304).

Another possibility is the compounds of formula II. is prepared so that the compound of formula V, i! wherein the group CWiW2 has the meaning defined for Formula II, is treated with, e.g., ethanol and hydrochloric acid, e.g., chloroform or diethyl ether, to form. the corresponding iminoethyl ester hydrochloride which can be converted to the desired carboximidamide of formula II e.g. by reaction with ammonia and e.g. methanol.

- · However, in some cases, this method may fail with either Group A or the like. Due to the etheric barrier caused by Ri.

·· - 107916

O

The starting compounds of formula V are known per se or are prepared according to known compounds.

Compounds of formula V may be prepared, e.g., by intramolecular acylation according to the Friedel-Crafts method of formula VI.

The ω-phenyl-lower alkanoic acids according to T4 o "riT '/ S <: m R'", where W4 represents cyano or cyano precursor, or their acid derivatives, e.g. acid chlorides or acid anhydrides. and in the case of acid chlorides or anhydrides, e.g., AlCl 3.

Particularly used in this reaction are compounds of formula VI wherein W 4 is not a cyano but a cyano precursor, e.g., halogen, especially bromine, or a protected amino, e.g., acetylamino. After the cyclization step, the cyano precursors can then be converted in a manner known per se. reaction with cyano, e.g. bromine! copper (I) with cyanide or acetylamino by cleavage of the acetyl protecting group, diazotization and reaction with copper (I) cyanide.

. Compounds of formula V wherein CWiW2 represents

carbonyl, can be further prepared e.g. by oxidation, e.g. chromium trioxide (Cr

m t 1 · «» · 9 107916 VV4

Rl-- | "-I-R2 (VII)

H H

wherein W 4 represents cyano or cyano precursor as defined above. If a cyano precursor is used, this must in turn be converted to cyano after oxidation, e.g. as described above.

Another possibility for the preparation of compounds of formula V wherein CWxW2 represents carbonyl is by starting from compounds of formula II wherein X represents hydrogen and attaching a cyano group, for example, by nitration to the nitro group by the reaction sequence set forth in Example 10 in U.S. Pat. , diazotize and react with copper (I) cyanide (Sandmeyer reaction).

The preparation of aminoguanidines of formula III is known per se.

Aminoguanidines of formula III wherein Z is NR9 and R3, R4 / R5 and R9 are as defined in formula I. meaning are known per se and can be prepared ». e.g., the corresponding aminothiocyanates of Formula III by converting the latter to an S-alkylisothiuronium salt of the alkylating agent, e.g., alkyl thiosylate or halide, and reacting them with an amine of formula NHR 4 R 5.

Method b):> · "-»>

The cyano compounds of formula IV can be converted to formula I

• · * optionally mono or disubstituted amidine ··· 10797916 e.g. by reaction with an alkali metal amide, e.g. KNH2 or by reaction with a primary or secondary (di) lower alkyl ammonium halide, e.g. * NH3CH3Clie.

Compounds of formula IV wherein W 3 represents cyano may be prepared, for example, by reacting a compound of formula V with a compound of formula III according to method a). Other compounds of formula IV wherein W3 represents thiocarbamoyl, bromine or N-hydroxyamidino can be prepared from compounds of formula IV wherein W3 represents cyano in a manner known per se or as described above.

The compounds of formula I can be converted to other compounds of formula I.

Compounds of formula I wherein X represents the N-hydroxyamide amino residue -C (= NR8) -NHOH may be converted, for example, by reaction with iron pentacarbonyl [Fe (CO) 5] to other compounds of formula I wherein X represents the anologic amido residue -C (= NR8) -NH2 (see, e.g., J. Chem. Soc. Chem. Commun. 1975, 761).

»

The free compounds of formula I having »» salt-forming properties can be obtained according to the process. converts them into salts in a manner known per se, »! compounds having intrinsic properties, e.g., by treatment with t-acids or their appropriate derivatives, compounds having acidic properties, e.g., by treatment with a base. or their appropriate derivatives.

Due to the close relationship between the compounds of the formula I in free form and in the form of salts, 'above and below are meant the free compounds or i ·

M

and 107916 Vast, the salts thereof, and if appropriate, the corresponding salts or the corresponding free compounds.

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

Mixtures of isomers obtained according to the invention can be separated into individual isomers in a manner known per se, for example by forming salts with optically pure salt-forming reagents and separating the resulting diastereomeric mixture, e.g. by fractional crystallization.

The reactions described above may be carried out under reaction conditions known per se, without the use of solvents or diluents, or conventionally in the presence of solvents or diluents, in particular those which are inert to and used in the catalysts, condensing agents or neutralizing agents and or the type of agents involved in the reaction at reduced, normal or elevated temperatures, e.g., about -70 °. At 190 ° C, in particular at about -20 ° to about 150 ° C, e.g. at the boiling point of the solvent used, at atmospheric pressure or in a sealed vessel (optionally under pressure and / or inert atmosphere, e.g.

► i in a nitrogen atmosphere.

In particular, the methods of the present invention are used. starting materials which lead to compounds of high value initially.

The invention also relates to those embodiments of the process which, at some point in the process, start from the intermediate compound and carry out the missing steps of the process, or wherein the starting material is formed under reaction conditions or used in the form of a derivative, e.g.

The pharmacologically active compounds of formula I may also be used in pharmaceutical preparations. Particularly preferred are preparations for enteral, particularly oral, and parenteral use. The formulations contain the active ingredient alone or in particular in combination with a pharmaceutically acceptable carrier. The dosage of the active ingredient will depend on the disease being treated, as well as the species, age, weight and individual condition and route of administration.

The pharmaceutical preparations contain from about 0.1% to about 95% of the active ingredient, with particular dosage forms containing from about 1 to about n. 90% and non-unit dosage forms contain from about 0.1% to about 20% active ingredient. Dosage unit forms such as granules, tablets or capsules contain from about 1 mg to about 500 mg of active ingredient.

Pharmaceutical preparations containing the compounds of the formula I are prepared in a manner known per se, e.g. by conventional mixing, granulating, granulating, dissolving or lyophilizing methods. Thus, pharmaceutical compositions for oral use can be obtained by combining the active ingredient with one or more solid carriers, and possibly granulating the resulting mixture. and the mixture or the granulate is treated, optionally with the addition of additional auxiliaries, as tablets or granulators.

. Suitable carriers include in particular excipients such as sugars, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders such as * starches, e.g. rice or potato starch-> 13 107916 lys, methylcellulose, hydroxypropylretoethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and / or, if desired, disintegrating agents such as the above-mentioned starches, furthermore carboxymethyl starch, alginic acid, bridged,

additional adjuvants are primarily flow-adjusting and lubricating agents, e.g. silica, talc, stearic acid or its salts such as magnesium or calcium stearate and / or polyethylene glycol, or derivatives thereof.

The granulators may be provided with suitable coatings, which may be gastric fluid-resistant. concentrated sugar solutions, optionally containing acacia, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures, or acylated cellulose, Dyestuffs or pigments may be added to the tablets or granules, for example to identify or label various doses of the active ingredient.

Pharmaceutical compositions for oral use include gelatin capsules and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The capsules may contain the active ingredient in the form of a granulate, e.g. in admixture with excipients such as corn starch, binders and / or lubricants such as talc ··· or magnesium stearate and optionally stabilizers. ··· * with. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols, with or without the addition of stabilizers.

.. 107916 14

Other oral dosage forms include, for example, conventionally prepared syrups containing the active ingredient, e.g., in suspended form, and from about 0.1% to about 10%, particularly n.

At a concentration of 1% or a similar concentration which produces, for example, when measuring 5 or 10 ml a suitable single dose. Further, powder or liquid concentrates for the preparation of beverages, e.g., in milk, are also contemplated. Such concentrates may also be packaged in unit dose amounts.

Suitable pharmaceutical formulations for rectal administration are, for example, suppositories consisting of a combination of the active ingredient and a suppository base mass. Suitable suppository base masses are, for example, natural or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alkanols.

For parenteral administration, aqueous solutions of the active ingredient, preferably in a water-soluble form, e.g., a water-soluble salt, or aqueous suspensions containing viscosity-improving agents, e.g., sodium carboxymethylcellulose, sorbitol and / or dextrate, are suitable.

In this case, the active ingredient may be present, possibly in combination with excipients, also in the form of a lyophilisate, and may be reconstituted by the addition of suitable solvents prior to parenteral administration.

• ♦ • · · • ·

Solutions for parenteral administration, for example, may also be used as infusion solutions.

**: Compounds prepared by the process of this invention ** may be used prophylactically or therapeutically, in which case they are used in particular in the form of pharmaceutical preparations. A daily dose of about 1 mg to about 100 mg, particularly about 25 to 100 mg orally or equivalent, is then given to a daily weight of about 70 kg. 2-50 mg parenterally of a compound of formula I.

The following examples illustrate the present invention. Temperatures are presented in degrees Celsius. The following abbreviations are used: DMF = Ν, Ν-dimethylformamide, ether = diethyl ether, acetic ester = acetic acid ethyl ester, THF = tetrahydrofuran, MS (FAB) = mass spectrum ("Fast Atom Bombardment").

Example 1: 4-Amidino-1-indanone-2'-amidinohydrazone dihydrochloride

A solution of 3.8 g (27.9 mmol) of aminoguanidine hydrogencarbonate in 200 ml of water and 14.7 ml of 2N hydrochloric acid is heated to 60 ° and 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 evaporated to dryness after cooling. The residue is suspended in 50 ml of ethanol, filtered, washed with ethanol p. and ether and dried. This gives the title compound, '* * containing 1 mol of crystal water, m.p. > 330 °. MS (FAB): (M + H) @ + = 231.1 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).

The starting compounds may be prepared as follows: a) 4-Iiocarbamoyl-1-indanone * * * *

A solution of 12.1 g (77 mmol) of 4-cyano-1-indanone? *: · *: [Coll. Czechoslov. Chem. Commun. 43, 3227 (1978)] in 22 0 ml of pyridine and 10.6 ml (77 mmoles) of triethylamine, 1? 107916 Ιο is saturated at 40 ° C for 3 hours with hydrogen sulfide and further stirred for 16 hours at the same temperature. After cooling, the reaction mixture is evaporated to dryness and 300 ml of water are added to the residue. The crystallized yellow product is suction filtered, washed with water, dried and recrystallized from ethyl acetate. This gives the starting compound (a), m.p. 197 ° (dec.).

b) 4-amidino-1-indanone hydrochloride

To a solution of 9.8 g (51.3 mmol) of 4-thiocarbamoyl-1-indanone in 500 mL of abs. methylene chloride, 10.8 g (54 mmol) of triethyloxonium tetrafluoroborate are added 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. Stir briefly, filter and wash the filtrate with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The crude ethylthioimino ether thus obtained is dissolved in 160 ml of abs. ethanol, 3.3 g (60 mmol) of ammonium chloride are added and the mixture is refluxed for 20 hours. After cooling, the reaction mixture is evaporated to dryness. The starting compound (b) is purified; 215-218 ° (dec.).

• · • · · · · · · ·

Example 2: 4-Amidine-1,1-indanone-2 '- (N-hydroxyamidino) -? - * - * - hydrazone dihydrochloride * * To a solution of 316 mg (1.5 mmol) of 4-amidino-1 N-Hydrochloride (Example Ib) in 7 ml of methanol, "W is added a solution of 394 mg (1.5 mmol) of 1-amino-3- • · · hydroxyguanidine-4. toluene sulfonate in 6 mL of water and 0.75 mL (1.5 mmol) of 2N hydrochloric acid, heated at reflux for 2 hours; ··· for 1 hour at 107916 ° C. The reaction mixture is evaporated and the residue is purified by chromatography (Pharmacia column SR-28-100). ) in silica gel OPTI-UP C12 (water as eluent, 5 ml fractions, flow rate 27.5 ml / h) The contents of fractions 58-78 are combined, evaporated and the residue crystallized from ethanol to give the title compound in the form of waxy crystals. MS (FAB): (M + H) + = 247, 1 H-NMR (D 2 O): δ = 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

To a solution of 0.41 g (3 mmol) of aminoguanidine hydrogen carbonate in 31.5 mL of 0.1N hydrochloric acid is added 0.675 g (3 mmol) of 5-amidino-1-tetralone hydrochloride and refluxed for 72 hours. After cooling, the mixture is evaporated to dryness and the title compound is recrystallized from a mixture of methanol and ether, m.p. > 250 °, MS (FAB): (M + H) + = 245, 1 H-NMR (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 (rn, 4H), 1.9 { m, 4H).

The starting compounds are prepared as follows:; · · • · ··· ♦. a) 5-Cyano-1-tetralone * Λ Λ ·. **: To 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, add 0.41 g (4.5 mmol) of copper (I) cyanide and stir for 6 hours at 160 °. The reaction mixture is then cooled to * * 80 ° and then a solution of 1.6 g of iron (III) - · · · · ··· ** chloride-hexahydrate in 2.5 ml of water and 0.44 ml is added. in concentrated hydrochloric acid. Stir for 45 minutes, cool, then dilute the reaction mixture with water and extract with ♦: **: toluene. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. In this way, Ig 107916 gives the parent compound (a) as yellow-orange crystals, IR (CH 2 Cl 2): 2220, 1690 cm -1. 1 H-NMR (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).

b) 5-thiocarbamoyl-1-tetralone

According to Example 1a, 10.6 g (62 mmol) of 5-cyano-1-tetralone are treated with 200 ml of pyridine and 8.6 ml of triethylamine with hydrogen sulfide and the final steps are performed. This gives the starting compound (b) as yellow crystals, m.p. 200-205 °.

c) 5-amidino-1-tetralone hydrochloride

According to Example Ib, 8.6 g (42 mmol) of 5-thiocarbamoyl-1-tetralone are treated with 8.8 g (44 mmol) of triethyl oxonium tetrafluoroborate and 2.6 g (4 9 mmol) of ammonium chloride. This gives the starting compound (c) as slightly pink crystals, MS (FAB): (M + H) + = 189.

Example 4: 4-Thiocarbamoyl-1-Indanone-2'-Amidinohydric Razone Hydrochloride. To a solution of 1.9 g (10 mmol) of 4-thiocarbamoyl-1 · indanone (Example 1a) in 50 mL of ethanol is added 1.36 · · · · · ·

* g (10 mmol) of aminoguanidine hydrogencarbonate and 10 ml of 2N

. hydrochloric acid and reflux for 24 hours. After cooling, the reaction mixture is evaporated to dryness to give the title compound.

··· * ♦ ·· ··· • ♦ * ··· * Example 5: 4-amidino-1-indanone-2 ′-amidinohydrazone- «dihydrochloride • · 107916

According to Example Ib, 4-thiocarbamoyl-1-indanone-2'-amidinohydrazone hydrochloride (Example 4) is reacted with triethyloxonium tetrafluoroborate and ammonium chloride to give the title compound, m.p. > 330 °, MS (FAB): (M + H) + = 231, 1 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).

Example 6: 4-Amidino-1-indanone-2'-amidinohydrazone dihydrochloride

To a solution of 0.26 g (1 mmol) of 4-cyano-1-indanone-2'-amidinohydrazone hydrochloride in 5 mL of abs. methanol, add 1.2 ml of a 1N sodium methoxide solution in methanol and heat at reflux for 16 hours. After cooling, 0.16 g (3 mmol) of solid ammonium chloride is added to the reaction mixture and stirred for one hour at 60 °. The reaction mixture is then evaporated and the residue is crystallized from dilute ethanol. This gives the title compound, m.p. > 330 °.

The starting compound is prepared as follows: a) 4-Cyano-1-indanone-21-amidinohydrazone hydrochloride ·· * • · • ···

According to Example 1, 314 mg (2 mmol) of 4-cyano-1-indanone is dissolved in 20 ml of methanol, and a solution of 272 µg · 2 · 2 mg (2 mmol) of aminoguanidine bicarbonate is added. of water and 1 ml of 2N hydrochloric acid, and stir for 4 days ··· • · * · 'while cooling. After cooling, the reaction mixture is evaporated to dryness and the residue is crystallized from water. This gives the starting compound (a), m.p. &Gt; 230 °, 1 H NMR (DMSO-d 6 / D 2 O): δ = 8.16 (d, 1H), 7.9 (d, 1H), 7.55 (t, 1H), δ , 28 (m, 2H), 2.9 (m, 2H), IR (Nujol): 2190 cm -1 (CN).

*: **: Example 7: 4- (N-Hydroxyamidino) -1-indanone-2'-amidino- *: * ·: Hydrazone dihydrochloride 20 107916 0.2 g ( 3 mmol) hydroxylamine hydrochloride is suspended in 1 ml abs. ethanol and then 2 ml of 1N sodium ethoxide solution in ethanol are added. This mixture is stirred for one hour and then filtered. A solution of 0.26 g (1 mmol) of 4-cyano-1-indanone-21-amidinohydrazone hydrochloride (Example 6a) in 2 ml of water is added to the filtrate and refluxed for 6 hours. After cooling, the reaction mixture is evaporated and the title compound crystallized from water, m.p. > 250 °, 1 H-NMR (DMSO-d 6 + D 2 O): δ = 8.12 (m, 1H), 7.55 (m, 2H), 3.22 (m, 2H), 2.83 (m, 2H).

Example 8: 4-Amidino-2-methyl-1-indanone-21-amidino hydrazone dihydrochloride

The title compound is prepared according to Example 1 starting from 4-cyano-2-methyl-1-indanone (see U.S. Patent 3,956,363).

Example 9: 5-Amidino-6-methoxy-1-tetralone-2'-amidino-hydrazone dihydrochloride

The title compound is prepared according to Example 1 starting from: * · * 5-cyano-6-methoxy-1-tetralone [Chem. Pharm. Bull. 31, 2329 (1983)].

* Example 10: 4-Amidino-6-methyl-1-indanone-2 '*. -amidino-hydrazone dihydrochloride ··· • · · · · · · · · · · · · · ·

The title compound is prepared according to Example 3 starting from 4-bromo-6-methyl-1-indanone (Bull. Soc. Chim. France 1964, 3103).

Example 11: 4-Amidino-6-methoxy-7-methyl-1-indanone-2'-amidinohydrazone dihydrochloride

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

Example 12: 4-Amidino-6,7-dimethyl-1-indanone-21-amidinohydrazone dihydrochloride

The title compound is prepared according to Example 3 starting from 4-bromo-6,7-dimethyl-1-indanone [J. Het. Chem. 24, 677 (1987)].

Example .13: 4- (Methylamidino) -1-indanone-2'-amidino-hydrazone dihydrochloride

According to Example Ib, 4-thiocarbamoyl-1-indanone-21-amidinohydrazone hydrochloride (Example 4) is reacted with triethyloxonium tetrafluoroborate and methyl ammonium chloride to give the title compound.

Example 14: 4-amidino-1-indanone-2 1 -amidinohydrazone dihydrochloride.

To a solution of 6.12 g (45 mmol) of aminoguanidine * / bicarbonate in 100 ml of water and 46 ml of 1N hydrochloric acid is added 9.45 g (44.9 mmol) 4-amidino-1-indanone hydrochloride (see Example Ib) and stirred for 24 hours at 24 ° C. The crystallized product is suction filtered, washed with a small amount of water and recrystallized from 300 ml of water. This affords the title compound containing 1 22 107916

mole of crystalline water, m.p. > 330 °, MS (FAB): (M + H) + = 231, 1 H NMR

(D20): δ = 8.08 (d, 1H), 7.75 (d, 1H), 7.58 (t, 1H), 3.35 (m, 2H), 2.96 (m, 2H) .

Example 15: 4-Amidino-2-methyl-1-indanone-2'-amidino-hydrazone 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 N hydrochloric acid, stirred for 120 hours at 25 °. The crystallized product is suction filtered, washed with a little water and dried. This gives the title compound, m.p. > 250 °, MS (FAB): (M + H) + = 245, 1 H-NMR (D 2 O): δ = 7.95 (d, 1H), 7.66 (d, 1H), 7.48 (t , 1H), 3.45 (m, 2H), 2.85 (d, 1H), 1.12 (d, 3H).

The starting compounds are prepared as follows: a) 4-Iiocarbamoyl-2-methyl-1-indanone

According to Example 1a, 11.1 g (65 mmol) of 4-cyano-2-methyl-1-indanone (see U.S. Patent 3,956,363) are treated with 200 mL of pyridine and 9.7 mL of triethylamine with hydrogen sulfide. : ·· | and completing the final steps. This gives the title compound (a) as yellow crystals, m.p. 195-198 ° (dec), 1 H-NMR (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).

B) 4-amidino-2-methyl-1-indanone hydrochloride.

According to Example Ib, 10.2 g (50 mmol) of the starting compound *** (a) are treated with 11.0 g (55 mmol) of triethyloxonium • · · tetrafluoroborate and 3.2 g (60 mmol) of ammonium ··· · • t '• y * chloride. This gives the starting compound (b) as pink crystals. It will be further reacted directly.

• ·

Example 16: 4-Amidino-6,7-dimethyl-1-indanone-21-amidinohydrazone dihydrochloride 23 107916

The title compound is prepared according to Example 1 starting from 4-amidino-6,7-dimethyl-1-indanone hydrochloride, m.p.

> 240 °, MS (FAB): (M + H) + = 259, 1 H-NMR (D 2 O): δ = 7.43 (s, 1H), 3.12 (m, 2H), 2.75 (m , 2H), 2.43 (s, 3H), 2.24 (s, 3H).

The starting 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. 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 200 ml of toluene are added successively and a solution of 31.2 g of ferric chloride hexahydrate in 47 ml of water and 8.2 ml of concentrated hydrochloric acid is added. After stirring for 20 minutes at 70 ° C, cool and then dilute the reaction mixture with toluene and water. The organic phase is separated off, washed with water, half-saturated sodium bicarbonate solution and again with water, dried and evaporated. The residue is crystallized from acetic ester and ether and i.e. corresponds to the starting compound (a). Beige crystals are obtained, m.p.

160-163 °, IR (CH 2 Cl 2): 2220, 1710 cm -1.

B) 4-Thiocarbamoyl-6,7-dimethyl-1-indanone ···

According to Example 1a, 10 g (54.1 mmol) of the starting compound (a) are treated with 200 ml of pyridine and 7.5 ml of triethylamine with hydrogen sulfide and the final reaction is carried out. errors. This gives the starting compound (b) in the form of yellow crystals O, m.p. 207-208 °, 1 H-NMR (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).

c) 4-amidino-6,7-dimethyl-1-indanone hydrochloride 24 107916

According to Example 1b, 4.4 g (20 mmol) of the starting compound (b) are treated with 4.26 g (21 mmol) of triethyloxonium tetrafluoroborate and 1.2 g (24 mmol) of ammonium chloride. This gives the starting compound (c) as beige crystals.

Example 17: 4-Amidino-6,7-dimethoxy-1-indanone-2'-amidinohydrazone dihydrochloride

To a solution of 0.4 g (3 mmol) of aminoguanidine-bicarbonate in 6 mL of 0.5 N hydrochloric acid is added 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 to give the title compound, m.p. > 220 °, MS (FAB): (M + H) + = 291, 1 H NMR (D 2 O): δ = 7.45 (S, 1H), 3.97 (s, 6H), 3.27 (m , 2H), 2.98 (m, 2H).

The starting 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-dimethyl] -oxyn-1-indanone (Can. J. Chem. 57, 1603 (1979)) and 2.5 g. * · T '·' * (28 mmol) copper (I) cyanide in 7 mL of DMF, stir for • · ... 5.75 hours at 170 ° C. The reaction mixture is then cooled to 100 ° C. And 70 ml of toluene are added successively and a solution of 9.7 g (36 mmol) of iron (III) chloro-«... di-hexahydrate in 15.6 ml of water and 5 ml of concentrated hydrochloric acid, stirred for 30 minutes at 80 °, cooled and then diluted with toluene and water, the organic phase is separated off, washed with The residue 25 107916 is distilled at 150-160 ° / 0.1 mbar in a balloon distillation apparatus and corresponds to the starting compound (a), m.p. 150 °, IR (CH 2 Cl 2). : 2220, 17 10 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).

t>) 4 -1-iocarbamoyl-6,7-dimethoxy-1-indanone

According to Example 1a, 3.7 g (17 mmol) of the starting compound (a) are treated with 100 ml of pyridine and 2.4 ml of triethylamine with hydrogen sulfide and the final steps are performed. This gives the title compound (b) in the form of light yellow crystals, m.p. 196-199 °, 1 H-NMR (DMSO-d 6): δ = 10.06 (s, 1H), 9.50 (S, 1H), 7.41 (S, 1H), 3.84 (s, 6H) ), 3.13 (m, 2H), 2.63 (m, 2H).

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

According to Example Ib, 3.3 g (13 mmol) of the starting compound (b) are treated with 2.8 g (14 mmol) of triethyloxonium tetrafluoroborate and 0.8 g (15 mmol) of ammonium chloride. This gives the starting compound (c) in the form of beige crystals, m.p. 188 ° (dec), 1 H-NMR (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

** · *: (m, 2H).

• · · • · · · ·. . Example 18: 4-Amidino-3-methyl-1-indanone-2'-amidino- · 1 · · · · · · · · · · · · · hydrazone dihydrochloride.

To a solution of 300 mg (1.3 mmol) of 4-amidino-3-methyl-1-indanone hydrochloride in 6 ml of water is added 300 ·, * ·· mg (2.3 mmol) of aminoguanidine bicarbonate In 4 ml • # 0.5N hydrochloric acid and heated at 80 ° for 24 hours. The reaction mixture is cooled, evaporated and the residue purified by chromatography on 180 ml of Amberlite® ER-180 resin * * using water as the eluent. The title compound is recrystallized * * from a mixture of methanol and ether, m.p.> 250 °, Rf = 107916 ΖΌ 0.18 (silica gel, methylene chloride / methanol / concentrated ammonia 5: 3: 1), MS (FAB): (M + H) + = 245, 1 H NMR (D 2 O): δ = 7.97 (d, 1H), 7.64 (d, 1H), 7.49 (t, 1H), 3.86 (m, 2H), 3.17 (q, 1H), 2.49 (d, 1H), 1, 24 (d, 3H).

The starting 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 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 50 ml of toluene are added successively, 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 concentrated hydrochloric acid. After stirring for 20 minutes at 70 ° C, cool and then dilute the reaction mixture with toluene and water. The organic phase is separated off, washed with water, half-saturated sodium bicarbonate solution and again with water, dried and evaporated. The residue is distilled at 100-120 ° / 0.05 mbar in a balloon distillation apparatus and corresponds to the starting compound (a), m.p. 109-111 °, δ IR (CH 2 Cl 2): 2220, 1710 cm -1, ¹H-NMR (CDClδ): δ = 7.92 (m, 2H), 7,5 7.52 (t, 1H), 3.73 (m, 1H), 3.03 (q, 1H), 2.40 (q, 1H), 1.55 *. 1 (d, 3H).

(B) 4-Thiocarbamoyl-3-methyl-1-indanone • 1.45 g (8.47 mmol) of the starting compound according to Example 1a. (a) Treat 25 ml of pyridine and 1.2 ml of triethylamine with hydrogen sulfide and complete the final steps to give the title compound (b) in the form of light yellow crystals. mp 198-200 °, 1H NMR (DMSO-d6): 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), δ: 1.25 (d, 3H).

c) 4-amidino-3-methyl-1-indanone hydrochloride 27 107916

According to Example 1b, 0.96 g (4.68 mmol) of the starting compound (b) is treated with 1.0 g (4.93 mmol) of triethyloxonium tetrafluoroborate and 0.3 g (6 mmol) of ammonium chloride. This gives the starting compound (c) in the form of beige crystals, 1 H-NMR (DMSO-d 6): δ = 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 19: 4-Amidino-1-indanone-2'-amidinohydrazonide hydrochloride

A mixture of 0.32 g (1 mmol) of 4- (N-hydroxyamidino) -1-indanone-2'-amidinohydrazone dihydrochloride (Example 7), 0.36 mL (2 mmol) of triethylamine and 0.2 g ( 1 mmol) of iron pentachloride in 10 ml of absolute THF are refluxed for 16 hours. The reaction mixture is then evaporated and the residue crystallized from dilute hydrochloric acid to give the title compound, m.p. > 330 °.

Example 20: 4-Amidino-2-ethyl-1-indanone-2'-amidino-

• M

Ats ··· Hydrazone dihydrochloride • · · · · · · · · · · · 3- (2-Bromophenyl) -2-ethyl-propionic acid (German • 9 · ** * · Patent 2,733,868) is cyclized by heat with polyphosphoric acid • · ... to the corresponding 1-indanone and converted to the title compound of Example 3.

• ·

Example 21: 4-Amidino-2-n-butyl-1-indanone-2 1-amidino-hydrazone dihydrochloride · 3 · 2 '··· * 3- (2-bromophenyl) -2- n-Butyl-propionic acid (German Patent 3,733,868) is cyclized with polyphosphoric acid • · to the corresponding 1-indanone and converted to the title compound of Example 3.

28 107916

Example 22: Capsules containing 0.25 g of active ingredient, e.g., one of the compounds of Examples 1-21, can be prepared as follows:

Composition (5000 capsules) Active substance 1250 g Talc 180 g Wheat starch 120 g Magnesium stearate 80 g Lactose 20 g

The powdered substances are forced through a 0.6 mm sieve and mixed. In each case, 0.33 g portions of the mixture are filled into a gelatin capsule by a capsule filling machine.

Example 23: Preparation of 10,000 tablets each containing 5 mg of active ingredient, e.g., one of the compounds of Examples 1-21: ··· • 1 * ··· «

Composition: 9 * 1 active ingredient 50.00 g • 1 • 1 1 * · 1 · milk sugar 2535.00 g maize starch 125.00 g • ♦ · * · 1 liter polyethylene glycol 6000 150.00 g magnesium stearate 40.00 g purified water quantum satis • · * «· 9 ..I: Method: All powdered ingredients are sieved through a · · · · · · · · 1 · 0.6 mm mesh. The active ingredient, milk sugar, magnesium stearate and half of the starch are then blended in a suitable blender. The remaining starch is suspended in 29 107916 ml of water and the resulting suspension is added to a boiling solution of polyethylene glycol in 260 ml of water. The paste formed is added to the powder mixture and granulated, optionally with additional water, the granulate is dried overnight at 35 °, forced through a sieve with a mesh size of 1.2 mm and compressed into tablets with a fracture groove.

»·· • · ·························································· · · · · · · · · · · ·· ♦ »t» • M · • ·· • · • ♦ · »« 1 · ♦

Claims (4)

107916 A process for the preparation of the therapeutically active hydrazone derivatives, their tautomers and their salts, of formula IX R 1 '- 1 - 1 - 2 - (2) - N - (2) - (2) n -. a bond or a group -CH 2 -, X represents a radical -C (= Y) -NR 8 R 7, Y represents NR 8, Z represents NR 8, R 2 and R 2 independently represent hydrogen, lower alkyl or lower alkoxy, R 3, R 4, R 8, R 8 and R 8 independently of one another hydrogen or lower alkyl, and R 5 and R 6 '; independently of one another hydrogen, lower alkyl or hydroxy, characterized in that. (a) A compound of formula II ## STR3 ## A * * * i: \ j Rf-i- {, l) w ',' w2 • · · • the group CWj ^ denotes carbonyl, ···. l, functionally modified carbonyl, or protected carbonyl, and the residues A, X, R 1, and R 2 have the meaning given by formula I *, ·, · · · · · · · · · · · · · · with an amine of formula III (Z) (III) I Ί R3 R4 wherein Z, R3, R4 and R5 have the meanings given for formula I, or b) a compound of formula IV ^ X · \ · v,, V. N.C. R 5 in the compound of R 11 'R 4 where W 3 represents thiocarbamoyl, cyano, bromine or N-hydroxyamidino, and A, Z, R 1, R 2, R 3, R 4 and r 5 are as defined for Formula I. is converted into a group X, and the desired compound of formula I is converted to one of J · · ·: · 1 into another compound of formula I, and / or if desired. converting the resulting salt into a free compound or other salt, and / or, if desired, converting the resulting *: **: free compound of formula I, having salt-forming properties, into the salt. The method of claim 1, 4-amidino-1% · · · ···. for the preparation of indanone-2'-amidinohydrazone or a pharmaceutically acceptable salt thereof, characterized in that the corresponding substituted starting materials are used. Process for the preparation of 4-amidino-1-indanone-2 '- (N-hydroxyamidino) hydrazone or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the corresponding substituted starting material is used. Process for the preparation of 5-amidino-1-tetralone-2'-amidinohydrazone or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the corresponding substituted starting material is used. · T t t1 ·· 1 • 1 »» »» »» 1 1 1 1 1 1 1 1 1 • · · · · · m • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 10 1010