IL103448A

IL103448A - Salts of the base 4-amidino- 1-indanone-2(- amidinohydrazone, pharmaceutical compositions containing them and their preparation

Info

Publication number: IL103448A
Application number: IL103448A
Authority: IL
Original assignee: Ciba Geigy Ag
Priority date: 1991-10-16
Filing date: 1992-10-15
Publication date: 1998-01-04
Also published as: SG43185A1; CA2080545C; FI112212B; NZ244725A; AU658931B2; NO924001L; HK1005023A1; SK279938B6; NO924001D0; HU9203234D0; JPH05239011A; FI924650A0; CZ279601B6; SA93130417B1; KR100265307B1; ES2095444T3; EP0538193B1; GR3021903T3; JP2788579B2; ZA927957B

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

103448/3 SALTS OF THE BASE 4-AMIDINO-1-INDANONE-2'-AMIDINOHYDRAZONE, PHARMACEUTICAL COMPOSITION CONTAINING THEM AND THEIR PREPARATION TjnDm ΏΤΠΝ ΓΠΤΤΪ?ΙΊ 4-18815/A The invention relates to acid addition salts of the base 4-amidino-l-indanone-2'-amidinohydrazone (I) with an acid selected from N-cyclohexylsulfamic acid and lactic acid.

The invention relates also to pharmaceutical compositions comprising those acid addition salts, and to the use of those acid addition salts in the preparation of pharmaceutical compositions.

Within the framework of the present Application, the general terms used hereinbefore and hereinafter have preferably the following meanings: The aim of the present invention is to provide novel acid addition salts of pharmacologically acceptable compounds, which salts have a good solubility in physiological liquids and/or liquids that are similar to physiological liquids, such as physiological saline solution, mannitol solution or phosphate buffers, and/or good absorbability in the case of enteral, such as oral, administration, for example by the formation of ion pairs, such as lipophilic ion pairs. selection invention The acid addition salts according to the invention have valuable pharmacologically exploitable properties. They exhibit, especially, a strong, specific inhibitory action on the enzyme S-adenosylmethionine decarboxylase (SAMDC). As a key enzyme, SAMDC plays an important role in polyamine synthesis, which takes place in practically all cells of mammals, including humans. SAMDC regulates the concentration of polyamine in the cell. Inhibition of the enzyme SAMDC results in a reduction in polyamine concentration. Because a reduction in polyamine concentration brings about inhibition of cell growth, it is possible, by administering SAMDC-inhibiting substances, to inhibit the growth of both eukaryotic and prokaryotic cells and even to kill cells or to inhibit the onset of cell differentiation.

Inhibition of the enzyme SAMDC can be demonstrated, for example, using the method of H.G. Williams-Ashmann and A. Schenone, Biochem. Biophys. Res. Communs. 46, 288 (1972). The acid addition salts of the invention in this case exhibit IC50 values as low as 0.005 μΜ or lower.

A further advantage of the acid addition salts according to the invention is that, compared with their strong inhibitory action on SAMDC, they inhibit diaminoxidase to only a slight extent and are well tolerated. According to J. Jaenne and D.R. Morris, Biochem.

J. 218, 974 (1984), inhibition of diaminoxidase is unfavourable because it can lead to the accumulation of putrescine and indirect SAMDC-activation.

The acid addition salts of formula I can accordingly be used, for example, in the treatment of benign and malignant tumours. They can induce tumour regression and can also prevent the spread of tumour cells resulting in metastase formation, and also the growth of micro-metastases. They can also be used, for example, in the treatment of protozoa infections, such as, for example, trypanosomiasis, malaria or pulmonary inflammation caused by Pneumocystis carinii.

As selective SAMDC-inhibitors, the acid addition salts of bases of formula I with an acid [PA] can be used alone or also in combination with other pharmacologically active substances. A possible combination is, for example, one with (a) inhibitors of other enzymes of polyamine biosynthesis, for example ornithine decarboxylase inhibitors, (b) inhibitors of protein kinase C, (c) inhibitors of tyrosine protein kinase, (d) cytokines, (e) negative growth regulators, (f) aromatase inhibitors, (g) antioestrogens or (h) conventional cytostatic active substances.

The acid addition salts of the base 4-amidino-l-indanone-2'-amidinohydrazone with an acid selected from N-cyclohexylsulfamic acid and lactic acid are prepared in accordance with processes known per se, for example as follows: a) the base 4-amidino-l-indanone-2'-amidinohydrazone is reacted with an acid as defined above, or b) a compound of the formula wherein the group CWjW2 is carbonyl, functionally modified carbonyl or protected carbonyl, A is a bond and X is amidino, is condensed with an amine of the formula in the presence of an acid as defined above under a), or c) in a compound of the formula wherein W3 is a radical that can be converted into a group X in a base of formula I, A is a bond and Z is amidino, the radical W3 is converted into the group X in the presence of an acid [PA] that is as defined above under a) ; or d) any desired acid addition salt of a base of formula I with an acid that does not fall within the definition of the acids mentioned under a) is converted into an acid addition salt of a base of formula I with an acid [PA] that is as defined above under a); and, if desired, a resulting acid addition salt of a base of formula I with an acid as defined under a) is converted into a different acid addition salt of a base of formula I with an acid as defined under a), and/or, if desired, isomeric mixtures are separated into the individual isomers.

In the following more detailed description of processes a)-d), each of the symbols A and X Z, RrR9 and [PA] is as defined in the definition of the acid addition salts of the base 4-amidino-l-indanone-2'-amidinohydrazone with acids as defined above under a), unless otherwise indicated.

Process a) The reaction of a base of formula I with an acid to form the corresponding acid addition salt is carried out in accordance with methods known per se for the formation of acid addition salts of basic compounds.

The reaction to form the acid addition salt takes place, for example, in solvents, especially in organic solvents, more especially in polar organic solvents, most especially in esters, for example lower alkanoyl-lower alkyl esters, such as acetic acid ethyl ester, in amides, for example N,N-di-lower alkyl-lower alkanoylamides, such as dimethylformamide, in alcohols, for example hydroxy-lower alkanes, such as methanol, ethanol, ethylene glycol or glycerol, or aryl alcohols, such as phenols, for example phenol, or in dimethyl sulfoxide, in the absence or presence of water, preferably in the absence of water. The reaction in alcohols, such as the last-mentioned hydroxy-lower alkanes, is especially preferred.

The reaction takes place, for example, in free solution but may also be carried out using chromatographic columns, for example by gel filtration, or using ion exchangers, or via semi-permeable membranes by osmotic processes.

The reaction is carried out at temperatures from the freezing point to the boiling point of the solutions concerned, preferably at from 0 to 50°C, especially 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 base 4-amidino-l-indanone-2'-amidinohydrazone and the acids are used in suitable molar ratios, or the acid is used in excess. The individual components are used preferably in the molar ratio corresponding to the ratio of the molarity of the base 4-amidino-l-indanone-2'-amidinohydrazone and the acid in the acid addition salts according to the invention.

The resulting salts precipitate, for example, spontaneously, in some cases only after cooling, or they are precipitated by the addition of solvents, especially non-polar solvents, for example ethers, such as diethyl ether, or water and/or are obtained by partial or complete concentration by evaporation.

Process b) There may be mentioned as functionally modified or protected carbonyl CW1W2, for example: di-lower alkoxymethyl, Cj-C^alkylenedioxymethyl, dihalomethyl, di-lower alkylthiomethyl or Cj-C^alkylenedithiomethyl.

The group O^W^ in the compounds of formula II is preferably in the form of free carbonyl.

The condensation reaction according to Process b) is effected under the conditions known per se for the formation of hydrazones and is carried out in the presence of an acid selected from N-cyclohexylsulfamic acid and lactic acid that at the same time acts as a catalyst. The amount of acid is preferably such that the reacting amino group in the compound of formula III is protonated to such a slight extent that it is still reactive. For that purpose, the starting compounds, provided they contain salt-forming groups, are used especially preferably in the form of salts of the acid which are, if desired, formed in situ either from the free compounds or salts of readily volatile acids, such as hydrohalic acids, for example HBr or HC1, formic acid, acetic acid or carbonic acid (in the form of the carbonate salt or hydrogen carbonate salt), it also being possible for the reaction to take place, for example, in the presence of a catalytically active small excess of the acid selected from N-cyclohexylsulfamic acid and lactic acid . The solvent used is preferably one of the solvents mentioned under Process a), especially an aqueous solvent, such as water, at preferred temperatures of from 20°C up to the boiling point of the reaction mixture concerned, especially at the boiling point of the mixture concerned, in the presence or absence of a protective gas, such as nitrogen or argon. Suitable for compounds of formula Π are those protected carbonyl groups 0\ν^2 that pass over into free carbonyl 1 0 3 4 - 6 - under the conditions of the condensation reaction.

Process c) In the intermediates of formula IV, W3 is, for example, free or functionally modified carboxy, especially halocarbonyl, cyano, imino-lower alkoxycarbonyl, imino-lower alkyl-thiolcarbonyl or thiocarbamoyl.

In the preparation of the amidine 4-amidino-l-indanone-2'-amidinohydrazone, the group W3 in a compound of formula IV may be, for example: an acid addition salt of an imino-lower alkyl ester ( = imino-lower alkyl ether) or imino-lower alkyl thiol ester with one of the mentioned acids, for example -C(=NH)-OC2H5 . [PA] or -C(=NH)-SC2H5 . [PA], respectively, also thiocarbamoyl or cyano.

By reacting an imino-lower alkyl ester of formula IV (in the form of a salt of one of the acids selected from N-cyclohexylsulfamic acid and lactic acid, as defined above) with ammonia, the unsubstituted acid addition salts, respectively, of the corresponding amidine are obtained. Cyano compounds of formula IV can be converted, into an unsubstituted acid addition salt of the base 4-amidino-l-indanone-2'-amidinohydrazone.

Acid addition salts of bases of formula I, wherein X is a radical -C(= H)-NR6R7, with acids [PA] can also be obtained by reacting compounds of formula IV or the acid addition salts thereof with one of the above-mentioned acids selected from N-cyclohexylsulfamic acid and lactic acid wherein W3 is the radical -C(=S)-NH2> wim S-alkylation, for example with tri-lower alkyloxonium tetrafluoroborate, and subsequent reaction with an ammonia salt of one of the mentioned acids.

The reactions indicated under c) can, unless otherwise indicated, be carried out under reaction conditions known per se, in the absence or, generally, in the presence of solvents or diluents, preferably those that are inert towards the reagents used and dissolve those reagents, in the absence or presence of catalysts, condensation agents or neutralising agents, depending on the type of reaction and/or reactants, at reduced, normal or elevated temperature, for example in a temperature range of from approximately -70°C to approximately 190°C, preferably from approximately -20°C to approximately 150°C, for example at room temperature or at the boiling point of the solvent used in the reaction mixture concerned, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under a nitrogen atmosphere.

Process d) The reaction of any desired acid addition salt of a base of formula I with an acid that does not fall within the definition of an acid selected from N-cyclohexylsulfamic acid and lactic acid is carried out in accordance with the customary methods for converting salts.

Acids that do not fall within the definition of an acid selected from N-cyclohexylsulfamic acid and lactic acid include all other protic acids, for example organic acids that do not fall within the definition of said acid, such as formic acid, acetic acid and methanesulfonic acid, or inorganic acids, such as sulfuric acid, hydrohalic acids, such as HF, HC1, HBr or HI, also hydrazoic acid or phosphoric acid. The salts of hydrohalic acids are especially preferred.

The reaction of such salts of acids that do not fall within the definition of an acid selected from N-cyclohexylsulfamic acid and lactic acid to form the acid addition salt of such an acid is carried out, for example, in solvents, especially in organic solvents, more especially in polar organic solvents, most especially in esters, for example lower alkanoyl-lower alkyl esters, such as acetic acid ethyl ester, in amides, for example N,N-di-lower alkyl-lower alkanoylamides, such as dimethylformamide, in alcohols, for example hydroxy-lower alkanes, such as methanol, ethanol, ethylene glycol or glycerol, or aryl alcohols, such as phenols, for example phenol, or in dimethyl sulfoxide, in the absence or presence of water, preferably in the absence of water. The reaction in alcohols, such as the last-mentioned hydroxy-lower alkanes, is especially preferred.

The reaction can also be carried out by way of the free base the base 4-amidino-l-indanone-2'-amidinohydrazone which is prepared, for example, by converting the acid salt, used as starting material, of said base with an acid that does not fall within the definition of an acid selected from N-cyclohexylsulfamic acid and lactic acid, with the aid of a base, for example a hydroxy base, such as an alkali hydroxide, for example NaOH or KOH, in aqueous solution in the presence or absence of an organic solvent, such as defined under a), into the free base; the subsequent conversion of the free base is carried out, for example, as described under Process a).

The base 4-amidino-l-indanone-2'-amidinohydrazone and the acids selected from N-cyclohexylsulfamic acid and lactic acid are used in the mentioned reactions in suitable molar ratios, or the acid is used in excess. The individual components are used preferably in the molar ratio corresponding to the ratio of the molarity of the base and the acid in the acid addition salts according to the invention.

Additional process measures Isomeric mixtures obtainable according to the invention can be separated in a manner known per se into the individual isomers. For example, racemates can be separated by the formation of salts with optically pure salt-forming reagents and separation of the diastereoisomeric mixture so obtainable, for example by means of fractional crystallisation or by chromatography on optically active column materials.

In the process of the present invention, it is preferable to use those starting materials that lead to the acid addition salts described at the beginning as being especially valuable.

The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example a salt, thereof.

Pharmaceutical compositions: The present invention relates also to pharmaceutical compositions that comprise as active ingredient one of the pharmacologically active acid addition salts of the base 4-amidino-l-indanone-2'-amidinohydrazone with an acid selected from N-cyclohexylsulfamic acid and lactic acid. Compositions for enteral, especially oral, and parenteral administration are especially preferred. The compositions comprise the active ingredient alone or, preferably, together with at least one pharmaceutically acceptable carrier. The dose of the active ingredient depends on the disorder to be treated and on the species and its age, weight and individual condition, and also on the method of administration.

The pharmaceutical compositions comprise from approximately 0.1 % to approximately 95 % active ingredient, single dosage forms of administration comprising preferably from approximately 1 % to approximately 90 % and non-single dosage forms of administration comprising preferably from approximately 0.1 % to approximately 20 % active ingredient. Unit dose forms, such as dragees, tablets or capsules, comprise from approximately 1 mg to approximately 500 mg of the active ingredient.

The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. For example, pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with one or more solid carriers, optionally granulating a resulting mixture, and processing the mixture or granules, if desired or necessary after the addition of further excipients, to form tablets or drag6e cores.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.

Further excipients are especially flow-conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.

Dragee cores may be provided with suitable enteric or non-enteric coatings, there being used, inter alia, concentrated sugar solutions that may contain gum arabic, talc, polyvinyl- pyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acerylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate. Colourings or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient.

Orally administrable pharmaceutical compositions are also dry-filled capsules consisting of gelatin, and also soft sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders and/or glidants, such as talc or magnesium stearate, and optionally stabilisers. 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, to which stabilisers may also be added.

Further oral forms of administration are, for example, syrups prepared in customary manner that comprise the active ingredient, for example, in suspended form and in a concentration of approximately from 0.1 % to 10 %, preferably approximately 1 % or in a similar concentration that, for example, on measuring off 5 or 10 ml, gives a suitable individual dose. Also suitable are, for example, pulverulent or liquid concentrates for the preparation of shakes, for example in milk. Such concentrates can also be packed in amounts for individual doses.

Suitable rectally administrable pharmaceutical compositions are, for example, suppositories that consist of a combination of the active ingredient and a suppository base.

Suitable as suppository base are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

Suitable for parenteral administration are especially aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, or aqueous injection suspensions containing viscosity-increasing substances, for example sodium carboxy-methylcellulose, sorbitol and/or dextran and optionally stabilisers. The active ingredient, optionally together with excipients, may also be in the form of a lyophilisate and may be dissolved before parenteral administration by the addition of suitable solvents. An isotonic solution for infusion can be prepared especially by the addition of suitable salts, such as NaCl, buffers, such as phosphate buffers, for example with sodium as counter-ion, and/or sugar alcohols, such as mannilol, it being optionally possible for others of the mentioned excipients also to be present.

Solutions, as used, for example, for parenteral administration, may also be used in the form of infusion solutions. : The invention also relates to a pharmaceutical composition for treating the above-mentioned diseased states, caused especially by a lack of S-adenosylmethionine decarboxylase-inhibition, which respond to treatment with an inhibitor of S-adenosylmethionine decarboxylase. The acid addition salts of the present invention may be administered prophylactically or therapeutically, especially in amounts that are suitable for inhibiting S-adenosylmethionine decarboxylase, and they are used preferably in the form of pharmaceutical compositions. In the case of a body weight of approximately 70 kg, a daily dose, especially one that is effective against the mentioned diseases, of from approximately 1 mg to approximately 1000 mg, preferably approximately from 25 to 100 mg in the case of oral administration or approximately from 2 to 50 mg in the case of parenteral administration, of an acid addition salt of the present invention is administered, for example to a warm-blooded animal, such as a human, that is in need of such treatment because it is suffering from a protozoa infection or from tumours.

The invention relates also to a pharmaceutical composition that is suitable for administration to a mammal, for example a human, for the prevention or treatment of a disease that responds to treatment with an inhibitor of S-adenosylmethionine decarboxylase, especially a tumour disease or a protozoa infection, which composition comprises an amount of an acid addition salt of the base 4-amidino-l-indanone-2'-amidinohydrazone with an acid selected from N-cyclohexylsulfamic acid and lactic acid that is effective in the inhibition of S-adenosylmethionine decarboxylase, and a pharmaceutically acceptable carrier.

Starting Compounds: The protic acids selected from N-cyclohexylsulfamic acid and lactic acid are known, can be prepared in accordance with processes known per se or are commercially available.

The starting compound 4-amidiho-l-indanone-2'-amidinohydrazone is prepared in accord- ance with processes known per se, for example as follows: (i) a compound of formula II as defined under Process a) is condensed with an amine of formula III as defined under Process a), or (ii) in a compound of formula IV as defined under Process c), the radical W3 is converted into the group X, and, if desired, a resulting salt of 4-amidino-l-indanone-2'-amidinohydrazone is converted into the free compound or into a different salt, and/or, if desired, the resulting free 4-amidino-l-indanone-2'-amidinohydrazone is converted into a salt.

In the following more detailed description of Processes i)-ii), each of the symbols A and X is as defined for a compound of formula II, unless otherwise indicated.

Process (i): There may be mentioned as functionally modified or protected carbonyl CWJW2, for example: di-lower alkoxymethyl, Q-Qalkylenedioxymethyl, dihalomethyl, di-lower alkylthiomethyl or Cj -Chalky lenedithiomethyl.

The group N W2 m me compounds of formula II is preferably in the form of free carbonyl.

The condensation reaction according to Process a) is carried out under the conditions known per se for the formation of hydrazones. It is preferably catalysed by an acid. In compounds of formula II, suitable protected carbonyl groups CWjW2 are those that pass over into free carbonyl under the conditions of the condensation reaction.

The intermediates of formula I wherein X is amidino are obtained, for example, by first converting a compound of formula V into the corresponding thiocarboxamide [-C(=S)-NH2] by treatment with hydrogen sulfide. The thiocarboxamide can also be obtained by other methods starting from the analogous carboxamide [-C(=0)-NH2]> f°r example by reaction with Lawesson's reagent [2,4-bis(4-methoxyphenyl)-2,4-dithioxo-l,3,2,4-dithiadiphosphetane]. The thiocarboxamides are S-alkylated, for example, with lower alkyl iodide or tri-Iower alkyloxonium tetrafluoro-borate, and thus converted into imino-lower alkylthiol ester hydroiodides [-C(=NH)S-alkyl · HI] or tetrafluoroborates, respectively, which can be readily converted into the desired carboximidamides of formula I by reaction with ammonia [see S. Patai (Ed.), The Chemistry of Amidines and Imidates, Wiley, London etc. 1975, p. 303-304].

The preparation of the carboxamides of formula II from the cyano compounds of formula V takes place analogously to the preparation, described below in connection with Process (ii), of carboxamides of formula I from cyano compounds of formula IV and is described in detail there.

Another possible method of preparing the compounds of formula II is to treat a compound of formula V, wherein the group CWjW2 is as defined under formula II, for example with ethanol and hydrochloric acid in, for example, chloroform or diethyl ether, to form the corresponding iminoethyl ester hydrochloride which can be converted into the desired carboximidamide of formula II, for example, by reaction with ammonia and, for example, methanol.

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

The compounds of formula V can be prepared, for example, by intramolecular Friedel-Crafts acylation of ω-phenyl-lower alkanoic acids of formula VI, wherein W4 is cyano or a cyano precursor, or acid derivatives thereof, for example acid chlorides or acid anhydrides. There may be used as catalysts in the case of free acids, for example, polyphosphoric acid, and, in the case of acid chlorides or acid anhydrides, for example A1C13.

In that reaction it is preferable to use compounds of formula VI wherein W4 is not cyano but a precursor of cyano, for example halogen, especially bromine, or protected amino, for example acetylamino. After the cyclisation step, the cyano precursors can be converted into cyano in a manner known per se, for example: bromine can be converted by reaction with copper(I) cyanide, or acetylamino can be converted by removal of the acetyl-protecting group, diazotisation and reaction with copper(I) cyanide.

Compounds of formula V wherein the group CWjW2 is carbonyl can also be prepared, for example, by oxidation, for example with chromium trioxide (Cr03), from the corresponding non-carbonyl compounds of formula VII wherein W4 is cyano or a cyano precursor as defined above. If a cyano precursor is used, it is again to be converted, after completion of oxidation, into cyano, for example as indicated above.

Another possible method of preparing the compounds of formula V wherein the group CW1W2 is carbonyl is to start from compounds of formula II wherein X is hydrogen and to introduce the cyano group, for example, by a reaction sequence analogous to US Patent 3 956 363, Example 10, which comprises nitration, reduction of the nitro group to amino, diazotisation and reaction with copper(I) cyanide (Sandmeyer reaction).

The preparation of amino-guanidines of formula III is known p_er se.

Process (ii): In the intermediates of formula IV, W3 is, for example, free or functionally modified carboxy, especially halocarbonyl, cyano, imino-lower alkoxycarbonyl, imino-lower alkyl-thiolcarbonyl or thiocarbamoyl.

In the preparation of amidines of formula II, the group W3 in a compound of formula IV may be, for example: an acid addition salt of an imino-lower alkyl ester ( = imino-lower alkyl ether) or imino-lower alkylthiol ester, for example -€(=ΝΗ)-0(¾Η5 · HC1 or -C(=NH)-SC2H5 · HI, respectively, or cyano.

By reacting an imino-lower alkyl ester of formula IV (in the form of a salt) with ammonia, the unsubstituted amidine, 4-amidino-l-indanone-2'-amidinohydrazone is obtained. Cyano compounds of formula IV can be converted, for example, by reaction with an alkali metal amide, for example KNH2> mto an unsubstituted or mono- or di-substituted amidine 4-amidino- l-indanone-2 '-amidinohydrazone.

The carboxylic acid ester imides are obtained, for example, by acid-catalysed addition of alcohols to the nitriles of formula IV. The amides are obtained from the ester imides in the manner of a Pinner cleavage by thermal decomposition of the ester imide salts at temperatures above approximately 80°C.

Compounds of formula IV wherein W3 is cyano can be prepared, for example, by reacting a compound of formula V with a compound of formula ΠΙ in accordance with Process ii). The other compounds of formula IV wherein W3 is free carboxy or carboxy functionally modified in another manner can be prepared from compounds of formula IV wherein W3 is cyano in a manner known per se or as described above. 4-Amidino-l-indanone-2'-amidinohydrazone can also be obtained by reacting compounds of formula IV wherein W3 is a radical -C(=S)-NH2, with S-alkylation, for example with tri-lower alkyloxonium tetrafluoroborate, and by subsequent reaction with ammonia or a corresponding ammonium salt, for example the chloride.

Free 4-amidino-l-indanone-2'-amidinohydrazone can be converted in a manner known p_er se into its salts: for example, by treatment with acids, either with the protic acids selected from N-cyclohexylsulfamic acid and lactic acid themselves or preferably with other protic acids, for example organic acids that do not fall within the definition of an acid selected from N-cyclohexylsulfamic acid and lactic acid, such as formic acid, acetic acid and methanesulfonic acid, or inorganic acids, such as sulfuric acid, hydrohalic acids, such as HF, HC1, HBr or HI, also hydrazoic acid or phosphoric acid. Hydrohalic acids are especially preferred. The reaction takes place, for example, analogously to Process a) for the preparation of acid addition salts according to the invention.

The acid addition salts of the base 4-amidino-l-indanone-2'-amidinohydrazone, especially those with protic acids other than those selected from N-cyclohexylsulfamic acid and lactic acid, can also be converted into the free compounds. That can be effected, for example, by conversion into the free base, for example by reaction of the salt of 4-amidino-l-indanone-2'-amidinohydrazone used as starting material with a hydroxy base, such as an alkali metal hydroxide, for example NaOH or OH, in aqueous solution in the presence or, preferably, absence of an organic solvent, as defined under a), also by dialysis, using ion exchangers or by gel chromatography.

The preparation of starting compounds of formulae II, III and IV is carried out as indicated in the more detailed description of Processes i) and ii).

Owing to the close relationship between 4-amidino-l-indanone-2'-amidinohydrazone, the compounds of formulae II, III, IV and also V, VI and VII in free form and, insofar as the mentioned compounds contain salt-forming groups, in the form of salts, hereinbefore and hereinafter the free compounds and their salts are also to be understood as being the corresponding salts, for example acid addition salts or also salts with bases, and the free compounds, respectively, where appropriate and where the context so allows.

The preparation of salts, for example of the compounds of formulae II, III and IV having salt-forming groups, is carried out analogously to the preparation of salts of the the base 4-amidino-l-indanone-2'-amidinohydrazone (Process a)).

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

The above reactions given under Process i) or ii) can be carried out under reaction conditions known per se, in the absence or, generally, presence of solvents or diluents, preferably those that are inert towards the reagents used and dissolve those reagents, in the absence or presence of catalysts, condensation agents or neutralising agents, depending on the type of reaction and/or the reactants at reduced, normal or elevated temperature, for example in a temperature range of from approximately -70°C to approximately 190°C, preferably from approximately -20°C to approximately 150°C, for example at room temperature or at the boiling point of the solvent used in the reaction mixture concerned, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under a nitrogen atmosphere.

The preparation of some starting compounds of formula I is described below for purely illustrative purposes. Temperatures are given in degrees Celsius. The following abbreviations are used: abs. = absolute (anhydrous); D20 = deuterised water; DMF = N,N-di-methylformamide; DMSO-d6 = perdeuterised dimethyl sulfoxide; ether = diethyl ether; ethyl acetate = acetic acid ethyl ester; IR = infrared spectroscopy; m.p. = melting point; THF = tetrahydrofuran; MS (FAB) = mass spectrum ("Fast Atom Bombardment"). 1) Starting Compound A: 4-Amino-l-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, with stirring, a solution of 5.85 g (27.8 mmol) of 4-amidino-l-indanone hydrochloride in 200 ml of methanol is added over the course of 30 min. The reaction mixture is boiled under reflux for 24 h and, after cooling, is concentrated to dryness by evaporation. The residue is suspended in 50 ml of ethanol, filtered, washed with ethanol and ether and dried to yield the title compound which contains 1 mol of water of crystallisation, m.p. >330°; MS(FAB): (M+H)+=231; ^-NMR (D20): 6=8.08 (d,lH); 7.75 (d,lH); 7.58 (t,lH); 3.35 (m,2H); 2.96 (m,2H).

The precursors are prepared as follows: (a) 4-Thiocarbamoyl-l-indanone A solution of 12.1 g (77 mmol) of 4-cyano-l-indanone [Coll. Czechoslov. Chem.

Commun. 43, 3227 (1978)] in 220 ml of pyridine and 10.6 ml (77 mmol) of triethylamine is saturated for 3 h at 40° with hydrogen sulfide and stirred for a further 16 h at that same temperature. After cooling, the reaction mixture is concentrated to dryness by evaporation and 300 ml of water are added to the residue. The yellow product which crystallises out is filtered off with suction, washed with water, dried and recrystallised from ethyl acetate to yield the title compound, m.p. 197° (decomposition). (b) 4-Amidino-l-indanone hydrochloride 10.8 g (54 mmol) of triethyloxonium tetrafluoroborate are added at room temperature and under argon to a solution of 9.8 g (51.3 mmol) of 4-thiocarbamoyl-l-indanone in 500 ml of abs. methylene chloride. After 16 h, a mixture of 4.2 g of potassium carbonate and 4.2 ml of water is added to the reaction solution. The reaction mixture is then stirred briefly and filtered and the filtrate is washed with water. The organic phase is dried over magnesium sulfate, filtered and concentrated by evaporation. The resulting crude ethylthioimino ether is dissolved in 160 ml of abs. ethanol; 3.3 g (60 mmol) of ammonium chloride are added and the reaction mixture is heated under reflux for 20 h. After cooling, it is concentrated to dryness by evaporation and the title compound is purified by chromatography on 1000 ml of Amberlite® ER-180 resin (water as eluant) and recrystallised from ethanol/ether, m.p. 215-218° (decomposition).

Further processes for the preparation of Starting Compound A) (4-amidino-l-indanone-2 -amidinohydrazone dihydrochloride): Analogously to the process described for Starting Compound A under 1 b), 4-thio-carbamoyl-l-indanone-2'-amidinohydrazone hydrochloride (Starting Compound D, see below) is reacted with triethyloxonium tetrafluoroborate and ammonium chloride to yield Starting Compound A, m.p. >330°; MS (FAB): (M+H)+ = 231; H-NMR (D20): 6=8.08 (d,lH); 7.75 (d,lH); 7.58 (t,lH); 3.35 (m,2H); 2.96 (m,2H).

Starting Compound D: 4-Thiocarbamoy[-l-indanone-2'-amidinohydrazone hydrochloride 1.36 g (10 mmol) of aminoguanidine hydrogen carbonate and 10 ml of 2N hydrochloric acid are added to a solution of 1.9 g (10 mmol) of 4-thiocarbamoyl-l-indanone (prepared as described under Starting Compound A, 1 a)) in 50 ml of ethanol and the reaction mixture is heated under reflux for 24 h. After cooling, it is concentrated to dryness by evaporation to yield the tide compound.

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

Temperatures are given in degrees Celsius (°C). If no temperature is indicated, the reaction concerned is carried out at room temperature. If concentration by evaporation is carried out, a rotary evaporator is used unless otherwise indicated.

The values for proton nuclear magnetic resonance spectroscopy are given in ppm ("parts per million") based on tetramethylsilane (δ = 0) as the internal standard, d = doublet, s = singlet, t = triplet, m = multiplet.

In the case of elemental analyses, the empirical formula, the molecular weight, and calculated and found analysis values are indicated.

The shortened forms and abbreviations used have the following meanings: elemental analysis calculated dideuterium oxide completely deuterised dimethyl sulfoxide proton nuclear magnetic resonance spectroscopy melting point with decomposition Example 1: 4-Amidino-l-indanone-2'-amidinohvdrazone dicyclamate A solution of 717 mg (4 mmol) of N-cyclohexylsulfamic acid in 20 ml of methanol is added to a solution of 460 mg (2 mmol) of 4-amidinoindanone-l-amidinohydrazone in 80 ml of methanol and the batch is concentrated to dryness by evaporation. The residue is dissolved in ethanol and crystallised by the addition of diethyl ether to yield the title compound, m.p. 210° (decomp.); Ή-ΝΜΙΙ (D20): δ 7.97 (d,lH); 7.64 (d,lH); 7.47 (t,lH); 3.25 (m,2H); 2.9 (m,4H); 1-2 (m,20H); anal, for C^H^NgOgSz (588.75): calc. 46.92% C, 6.85% H, 19.03% N, found 46.5% C, 6.9% H, 19.0% N.

The starting material is prepared as follows: a) 4-Amidino-l-indanone-2,-amidinohydrazone 9.63 g (30 mmol) of 4-amidino-l-indanone-2'-amidinohydrazone dihydrochloride (Starting Compound A, prepared in accordance with one of the processes described under "Starting Compounds", for example in accordance with 16)) are dissolved in 900 ml of distilled water heated to 70-80°C and cooled to 10°C. 30 ml of 2N sodium hydroxide solution are added dropwise to the resulting solution with stirring. The product which separates out is filtered off with suction, washed with a small amount of ice-water and dried to yield the title compound, m.p. 250° (decomp.).

Example 2: 4-Amidino-l-indanone-2,-amidinohydrazone dilactate Analogously the Example given hereinbefore, 4-amidino-l-indanone-2'-amidinohydrazone is converted into the title compound using lactic acid.

Example 3: Capsules, each containing 0.25 g of active ingredient, for example one of the acid addition salts of Examples 1 or 2, can be prepared as follows: Composition ("for 5000 capsules) active ingredient 1250 g talc 180 g wheat starch 120 g magnesium stearate 80 g lactose 20 g The pulverulent substances are forced through a sieve having a mesh size of 0.6 mm and mixed. 0.33 g portions of the mixture are introduced into gelatin capsules by means of a capsule-filling machine.

Example 4: 10 000 tablets, each comprising 5 mg of active ingredient, for example one of the acid addition salts prepared in Examples 1 or 2, are prepared: Composition: active ingredient 50.00 g lactose 2535.00 g corn starch 125.00 g polyethylene glycol 6000 150.00 g magnesium stearate 40.00 g purified water quantum satis Method: All of the pulverulent constituents are passed through a sieve having a mesh size of 0.6 mm. The active ingredient, the lactose, the magnesium stearate and half of the starch are then 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 the polyethylene glycol in 260 ml of water. The resulting paste is added to the powder mixture and granulated, where appropriate with the addition of more water. The granules are dried overnight at 35°C, forced through a sieve having a mesh size of 1.2 mm and compressed to form tablets having a breaking notch.

Claims

103448/ 3 - 22 - 4-18815/A What is claimed is:

1. An acid addition salt of the base 4-Amidino-l-indanone-2'-amidinohydrazone with an acid selected from N-cyclohexylsulfamic acid and lactic acid.

2. 4-Amidino-l-indanone-2'-amidinohydrazone dicyclamate according to claim 1.

3. 4-Amidino-l-indanone-2'-amidinohydrazone dilactate according to claim 1.

4. A pharmaceutical composition comprising an acid addition salt according to any one of claims 1 to 3 and at least one pharmaceutically acceptable carrier.

5. The use of an acid addition salt according to any one of claims 1 to 3 for the preparation of a pharmaceutical composition^ substantially as described in the Specification .