NO178261B - Substituted diaminophthalimides and analogs, pharmaceutical preparations containing them and their use in drugs - Google Patents

Abstract

Compounds of the formula I <IMAGE> in which Ar1, Ar2, A1, A2, R and X have the meanings given in the description, have useful pharmaceutical properties and are particularly active against diseases responsive to the inhibition of protein kinases, for example tumours. They are prepared in a manner known per se.

Description

The present invention relates to compounds of formula I

where A 1 and A 2 independently represent hydrogen, lower alkyl, lower alkenyl or lower alkanoyl; or where Ai and A2 together stand for -( CE2) 2~ eHer "(^2)3-; Ar^ and Ar2 stand independently of each other for phenyl, which is unsubstituted or substituted with one or more substituents from the group consisting of halogen, phenyl, phenyl lower alkyl, lower alkoxy, di lower alkylamino, cyano, nitro, amino and trifluoromethyl; or represents C3~Cg cycloalkyl; the group -C(=X) represents -C(=0) or -C(=S); and R stands for hydrogen or lower alkyl, or a salt thereof, if salt-forming groups are present, for the production of pharmaceutical preparations.

The terms used above and below have the following meaning in this application: The prefix "lower" denotes a residue with up to and including 7, preferably up to and including 4 and at least one or two carbon atoms.

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

Lower alkenyl has 2 to 7, preferably 2 to 4 carbon atoms and is, for example, allyl or crotyl.

Lower realkanoyl is preferably formyl, acetyl, propionyl, n-butyryl, pivaloyl or valeroyl, in particular acetyl. Aryl lower alkyl is preferably phenyl lower alkyl and in particular benzyl.

C3-C8 cycloalkyl is particularly Cs-Cy cycloalkyl, which should mean that it contains 3 to 8 and preferably 5 to 7 carbon ring atoms.

Halogen stands for fluorine, chlorine and bromine in particular, but can also be lead.

Salts of the compounds of the invention with salt-binding groups are primarily pharmaceutically usable, non-toxic salts. For example, compounds of formula I with basic groups can form acid addition salts, for example with inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid or with suitable organic carboxylic or sulphonic acids, for example acetic acid, fumaric acid or methanesulphonic acid or with amino acids, such as arginine or lysine.

Complexes of compounds with the formula I (Ai,Å2 = hydrogen) with transition metal ions, for example copper, cobalt or manganese also fall within salts of the compounds of the invention.

Pharmaceutically unsuitable salts, for example pyrrates and perchlorates, can also be used for isolation and purification. Only the pharmaceutically usable, non-toxic salts are therefore preferred for pharmaceutical use.

The compounds of the invention exhibit valuable, particularly pharmaceutically usable, properties. In particular, they show specific inhibition that is of pharmacological interest. Primarily, they act as protein tyrosine kinase inhibitors and show, for example, a strong inhibition of the tyrosine kinase activity of the receptors for the epidermal growth factor (EGF) and the c-erbB2 kinase. This receptor-specific enzyme activity plays a key role in signal transmission in many mammalian cells including human cells, in particular for epithelial cells, cells of the immune system and cells of the central and peripheral nervous system. The EGF-induced activation of the protein thyrokinase (RGF-R-PTK) which is bound to receptors is, in various cell types, a prerequisite for cell division and thus for reproduction in a cell population. By adding an EGF receptor-specific tyrosine kinase inhibitor, the proliferation of these cells was thereby inhibited.

The inhibition of EGF receptor specific protein thyrokinase (EGF-R-PTK) can for example be shown by the method of C. House et al., Europ. J. Biochem. 140, 363-367 (1984). The compounds of the invention inhibit the enzyme activity by 50# (IC50) at concentrations <1 pM. They also show, in micromolar amounts, for example, an inhibition of cell growth in an EGF-dependent cell line, such as the mouse epidermal keratinocyte cell line. To measure this inhibition of cell growth, the EGF-stimulated cell division of epidermal Balb/MK keratinocytes is used (description of the method in meyer, T. , et al, Int. J. Cancer 43, 851 (19S9). These cells are simultaneously dependent on EGF for proliferation (Weissmann, B.E., Aaronson, S.A, Cell 32,599 (1983). To perform the assay, the Balb/MK cells (10,000/well) are plated in 96-well microtiter plates and incubated overnight. The test substances (dissolved in DJJSO) were added in different concentrations (in dilution series) so that the final concentration in DMSO is not greater than 1%. After the addition, the plates are incubated for three days, during which time the control cultures without test substance have been able to pass through at least 3 cell division cycles. The growth of the MK cells was measured by means of methylene blue staining. IC5g values were defined as the concentration of each of the test substances first to a 505É reduction compared to the control cultures without inhibitor.

In addition to EGF-R-PTK, the compounds of the invention also inhibit other tyrosine kinases, which are involved in the transmission of signals through the tropic factor, for example the abl kinase, kinases from the src kinase family and the c-erbB2 kinase (HER-2), so as well as serine/threonine kinases, such as protein kinase C, all of which play a role in growth regulation and transformation for mammalian cells including human cells.

The inhibition of c-erbB2-tyrokinase (HER-2) can be shown, for example, analogously to the method used for EGF-R-PTK according to C. House et al., Europ. J. Biochem. 140, 363-367 (1984). The c-erbB2 kinase can be isolated according to a known method and its activity can be determined, for example according to T. Akiyama et al., Science 232, 1644 (1986).

Accordingly, the compounds of the invention are also suitable for the inhibition of certain and related thyrokinase mediated processes.

The compounds of the invention are therefore useful, for example, in the treatment of bony or malignant tumors. They are able to effect tumor regression and to prevent tumor metastasis formation and the growth of micrometastases. They are particularly useful in epidermal hyperproliferation (psoriasis), in the treatment of epidermal neoplasms, for example mammary carcinomas and leukaemia. Furthermore, they can be used in connection with the treatment of diseases of the immune system and of inflammation, to the extent that protein kinases are involved in these diseases. The compounds are also useful in the treatment of diseases of the central or peripheral nervous system, if signal transmission by protein kinases is involved.

The compounds of the invention can be used either alone or in combination with other pharmacologically active substances, for example together with (a) inhibitors for enzymes in polyamine synthesis, (b) inhibitors for protein kinase C, (c) inhibitors from other tyrosine kinases, (d) Cytokines, (e) negative growth regulators, for example TGF-β<-> or IFN-ε, (f) aromatase inhibitors, (g) antiestrogens or (h) cytostatics.

Particularly preferred are the compounds of formula I which were discussed in the previous section, where A± and A2 independently of each other stand for hydrogen or lower alkyl, the group -C(=X)- stands for -C(=0)-. -C(=S)- or -C(=CH2)- and R stands for hydrogen or lower alkyl and salts thereof.

Even more preferred are compounds of formula I where A 1 and A 2 independently of each other stand for hydrogen, lower alkyl, lower alkenyl or lower alkanoyl; or where A 1 and A 2 together mean C 1 -C 4 lower alkylene; where Ar^ and Ar2 independently stand for phenyl or naphthyl which is either unsubstituted or substituted with one or more substituents from the group consisting of lower alkyl, lower alkylene (bonded to two neighboring C atoms), hydroxy, phenyloxy, halogen, nitro , amino, lower alkylamino, dilower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-dilower alkylcarbamoyl, and cyano; pyridyl; pyrimidinyl; or C 3 -C 8 cycloalkyl; the group -C(=X)-stands for -C(=0)- or -C(=S)- and R stands for hydrogen, lower alkyl, phenyl lower alkyl, amino or hydroxy and salts thereof if salt-forming groups are present.

In the first place, the invention relates to compounds of formula I, where Ai and A2 independently of each other stand for hydrogen or methyl; or where A^ and A2 together stand for -(CH2)2- or -(0112)3-; ^rl°S ^r2 independently of each other represents phenyl, which is unsubstituted or substituted with one or more substituents from the group consisting of lower alkoxy, phenyl lower alkyl, nitro, amino, dilower alkylamino, halogen, trifluoromethyl, cyano; or for cyclopentyl or cyclohexyl; the group -C(=X)- stands for -C(=O)- or -C(=S)- and R stands for hydrogen or lower alkyl, and their pharmaceutically usable salts.

First and foremost, the invention relates to compounds of formula I, where Ai and A2 stand for hydrogen; Ar 1 and Ar 2 are independently phenyl if unsubstituted or substituted with trifluoromethyl, phenyl, lower alkoxy, benzyloxy, amino, dilower alkylamino, halogen or cyano; or cyclohexyl; the group -C(=X)- stands for -C(=O)- or -C(=S)- and R stands for hydrogen and their pharmaceutically usable salts.

The invention relates above all to the specifically described compounds and pharmaceutically usable salts thereof which are described in the examples, in particular 4,5-bis(aniline)phthalimide or 4,5-bis(4-fluoroaniline)phthalimide.

The compounds of formula I can be prepared in a known manner by, for example

(a) reacts a compound of formula II

where Ar^, Ar2. A^ and A2 have the meaning given under formula I and R3 and R4 independently of each other stand for aryl or lower alkyl, with a compound of formula III where R has the meaning given under formula I, or (b) reacts a compound of formula IV where Ar and A are as defined under formula I, with a compound of formula III

where R has the meaning given under formula I;

and/or converts an obtained compound of formula I into another compound of formula I, and/or converts an obtained salt into the free compound or into another salt, and/or converts an obtained four compound I into a salt and/or purifies the individual isomers from the resulting mixture of isomeric compounds of formula I.

In the following description of the method, the symbols Ar 1 , Ar 2 , A 2 , A 2 1 X, R, R 3 and R 4 have the meanings given under formulas I and II, unless otherwise stated.

Method (a): The reaction was carried out according to method (a) by a known aminolysis of the phthalic acid esters with ammonia or primary amine. The reaction takes place with activated phthalic acid diesters, for example the di(p-nitrophenyl) esters, normally at room temperature, with the dilover alkyl esters, on the other hand, mostly at higher temperatures. Preferably, the dimethyl esters are used. The reaction of the lower alkyl esters is preferably carried out in a solvent, preferably in an alcohol with a high boiling point, for example a diol, such as ethylene glycol, at temperatures from 100 to 150 °C, for example about 120 °C, or the reaction of the lower alkyl esters with ammonia or the relevant amine of formula III at the same temperature in the presence of a solvent, for example an alcohol, such as a lower alcohol, for example methanol or ethanol, or in the absence of a solvent in an autoclave at an elevated pressure.

The starting compound with formula II is prepared, for example, by reacting a cyclohexadiene with formula V

where Me stands for methyl, with an aniline of formula VI

where A preferably stands for hydrogen or lower alkyl, under acid catalysis [p. Matlin, Stephen A. and Barron, Kenneth, J. Chem. res. Synopsis. 8, 246-247 (1990)].

The preparation of the compound of formula V follows, for example, via a Diels-Alder reaction and is possibly described in the indicated literature.

For the preparation of unsymmetrical compounds of formula II, where Ai and A2 and/or Ar^ and Ar2 are different, for example compounds of formula V can be reacted with two different compounds of formula VI, for example stepwise, and the desired compound of formula II is isolated by means of chromatographic purification.

Furthermore, for example, compounds of formula II with Ai=A2=H can be reacted in a 1:1 ratio with a lower alkylating agent, for example methylene iodide, whereby unsymmetrical compounds of formula II with A^ = lower alkyl and A2 = H are obtained. the lower alkylating agent in excess, for example 10:1, symmetrical compounds of formula II with A^ = A<* = lower alkyl are obtained.

Method (b): The reaction according to method (b) follows the known aminolysis of phthalic anhydrides, for example with ammonia or primary amines, at elevated temperatures or with hexamethyldisilazane and methanol at room temperature [Davis, Peter D. and Bit, Eino A., Tetrahedron Easy. 31, 5201-5204 (1990)].

The starting compound of formula IV is prepared, for example, by reacting a compound of formula VII

with an acid anhydride of formula VIII, (R5C0)(R5* CO)0, where R5 and R5' independently of each other stand for hydrogen or lower alkyl, but not both for hydrogen.

The compounds of formula VII are available, for example, by hydrolysis, for example in acidic or alkaline medium, of an obtained compound of formula II.

The compound of formula I can be converted into other compounds of formula I in a known manner.

For example, a compound of formula I, where the group -C(=X)- stands for -C(=0)- can be reacted with a suitable reagent so that another compound of formula I, where the group -C(=X. )-stands for -C(=S)-, is obtained. A suitable reagent for the transfer of -C(=0=- into -C(=S)- is, for example, the Lawesson reagent (=2,4-bis-(4-methoxyphenyl)-2,4-dithioxo-1,3 ,2,4-dithiaphosphetane), where the reaction is carried out, for example, in a halogenated hydrocarbon, such as dichloromethane, at temperatures from 30° C to reflux temperature, preferably at reflux temperature. For the conversion of -C(=0)- into -CH2- is, for example the system LiAlB^/tetrahydrofuran or zinc amalgam/HCl/ethanol suitable.

Moreover, for example compounds of formula I, where R stands for hydrogen, can be transferred via alkylation, for example with lower alkyl halides after treatment with suitable bases, possibly sodium hydride or potassium tert-butoxide, to other compounds of formula I where R stands for lower alkyl.

Furthermore, for example, compounds of formula I, where A^ and/or A2 stand for hydrogen, can be transferred via conversion with appropriate reagents to other compounds of formula I, where A^ and/or A2 stand for lower alkyl, aryl, acyl, lower alkylsulfonyl or arylsulfonyl.

For the introduction of A^ and/or A2 = lower alkyl, treatment with the base LDA and subsequent reaction with a dilower alkyl ether or a lower alkyl halide is relevant, for example. During this treatment, a possibly present -N(-R)- = -NH- which is present in the molecule is alkylated only slightly or not at all.

For the introduction of A 1 and/or A 2 = lower alkylsulfonyl, the starting compound can, for example, first be reacted with LDA and then with an acylating agent, for example acetyl chloride.

Compounds of formula I, where Ar^ and Ar2 stand for phenyl substituted with halogen, preferably bromine, can be converted into the corresponding derivatives, where one or all of the halogen atoms present in the phenyl's Ar^ and/or Ar2 are replaced with cyano, for example by reaction with a transition metal cyanide salt, in particular CuCN, at temperatures between 50 and 150°C, preferably between 60 and 140°C, in an inert polar solvent, such as an N,N-dilower alkyl-lower alkane carboxylic acid amide, for example dimethylformamide, without or with the addition of a catalyst, for example a transition metal halide, such as ferric chloride, in aqueous solution (see also Rosenmund et al., Ber. 52, 1749 (1916); from Braun et al., Ann. 488, 111 ( 1931).

In compounds of formula I, with the residues Ar^ and/or Ar2, which stand for unsubstituted phenyl, can be independently nitrated by introducing one or more nitro groups, for example under normal conditions for introducing a nitro group in aromatics, for for example with concentrated or 100% nitric acid with temperatures between 0 and 100°C, preferably between 10 and 40°C, in an inert solvent, for example an organic acid anhydride, such as acetic anhydride. This results in several different products with different positions and numbers of nitro groups, which can be purified by conventional methods, for example column chromatography.

The nitro substituents in the residues Ar^ and/or Ar2 can be reduced to amino groups, for example by hydrogenation under normal conditions, for example by hydrogenation in the presence of suitable catalysts for the selective reduction of the nitro groups, such as Raney-Nickel, in an inert solvent, for example a cyclic or non-cyclic ether, such as tetrahydrofuran, under normal pressure or at an elevated pressure up to 5 bar.

Compounds of formula I with preferred hydroxy groups, for example with lower carboxylic acid residues as substituents on Ar^ and/or A2, can by ether cleavage be transferred to the corresponding hydroxy-substituted compounds of formula I. The ether cleavage takes place under known conditions, for example in the presence of hydrohalic acids, such as hydrogen bromide or hydrogen iodide, in the presence or absence of solvents, such as carboxylic acid, for example lower alkanecarboxylic acid, such as acetic acid, at temperatures between 20°C and the reflux cooling temperature of the reaction mixture, or preferably under running conditions with boron halides, especially boron tribromide, in an inert solvent, such as a chlorinated hydrocarbon, for example methylene chloride or chloroform, with temperatures between -80 and 0°C, preferably between -50 and -20<*>C.

Free compounds of formula I with salt-forming properties, which are formed during the process, can be transferred to their salts in a known manner.

The mixtures of isomers obtained according to the invention can be purified into the individual isomers in a known manner, racemates can for example be purified by forming salts with optically pure salt-forming reagents and purifying the obtained diastomer mixture for example by means of fractional crystallization.

The above-mentioned reactions can be carried out under known reaction conditions, absence or usually the presence of a solvent or diluent, preferably those that are inert to the reagents used and dissolve these, in the absence or presence of a catalyst, condensing agent or neutralizing reagents, depending on the type of reaction and/or the reaction is carried out at a lower, normal or elevated temperature, for example in the temperature range from about -80°C to about 200°C, preferably from about -20°C to about 150°C, for example at the boiling point of the solvent used, under atmospheric pressure or a closed vessel, optionally under pressure and/or in an inert atmosphere, for example under a nitrogen atmosphere.

Due to the close relationship between compounds of formula I in free form and in the form of salts, free compounds or their salts in this description shall in practice also be understood as corresponding salts or free compounds, as long as the compounds contain salt-forming groups, for example basic groups such as amino and imino groups, also those which do not contain more than one unsaturated carbon atom, such as the groups -NA^Ar^ and/or -NA2Ar2 as residues on the C atom in the central phenyl ring, where Ar^ and Ar2 and /or Ar2 and A2 are not bound to an unsaturated carbon atom.

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

In the method according to the invention, starting materials were preferably used which lead to the formation of the particularly valuable described compounds.

The invention also relates to those embodiments of the method where one starts from a desired method steps in from acquired compounds as intermediates and carries out the missing method steps, or those where a starting material is used which is formed under the reaction conditions or in the form of a derivative, for example a salt.

The invention also relates to pharmaceutical preparations, which contain one of the compounds of formula I as active substance. Particularly preferred are preparations for enteral, especially oral, as for parental delivery. The preparations contain the active substance alone or possibly together with a pharmaceutically usable carrier material. The dosage of the active substance is related to the disease to be treated, as well as the species, age, weight and individual condition, as well as the method of delivery.

Preferred is a pharmaceutical composition suitable for delivery to a warm-blooded, especially human, suffering from a disease affected by inhibition of a protein kinase, for example psoriasis or a tumor, comprising an amount of a compound of formula I or a salt of this, if there are salt-forming groups, which are effective for inhibiting the protein kinase, together with at least one pharmaceutically acceptable carrier material.

The pharmaceutical preparation contains from about 5 to about 95% of the active substance, where single dosed application forms preferably contain from 20 to about 90% and non-simply dosed application forms preferably contain from about 5 to about 2056 active substance. Dosage unit forms, such as dragees, tablets or capsules contain from about 0.05g to about 1g of the active substance.

The pharmaceutical preparations according to the invention were prepared in a known manner, for example by means of conventional mixing, granulation, coating, dissolving or lyophilization methods. Thus, pharmaceutical compositions for oral use can be obtained by mixing active substances with one or more solid carriers, possibly granulating the obtained mixture and processing the mixture or the granulate if desired, possibly by adding suitable excipients, to

tablets or dragon cores.

Suitable carriers are in particular fillers, such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparation and/or calcium phosphate, for example tricalcium phosphate or calcium hydrogen phosphate, for without a binder such as starch, for example corn, wheat, rice or potato starch . Further auxiliaries are primarily flow regulating and lubricating agents, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol or derivatives thereof.

The kite cores can be equipped with suitable gastric juice-resistant coatings, where one uses, among other things, concentrated sugar solutions containing possibly gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, varnish solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. The tablets or dragon coatings can be added with dyes or pigments, for example for identification or identification of different doses of active substance.

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

Further oral forms of application are, for example, in the usual way syrups containing the active ingredient, for example in suspended form and in a concentration of from 5% to 20%, preferably about 10% or another suitable concentration, such as for example in measures of 5 or 10 ml provides a suitable single dose. In addition, for example, powdery or liquid concentrates for the production of "Shakes", for example 1 milk, 1 consideration, also come. Such concentrates can also be taken in amounts for single doses.

As rectally applicable pharmaceutical preparations, for example, suppositories come into consideration, which consist of a mixture of the active substance in a suppository base. Natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycol or higher alkanols are suitable as suppository base material.

For parental delivery, primarily aqueous solutions of an active substance in water-soluble form are suitable, for example a water-soluble salt or aqueous injection suspensions, which contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran and any stabilizers. There, the active substance can optionally be present together with excipients, also in the form of a lyophilisate kit and be brought into solution for parental delivery by adding suitable solvents.

Solutions that are used, for example, for parental delivery, can also be used as infusion solutions.

The invention also relates to the use of a compound of formula I or a salt thereof, for the production of a drug against diseases affected by inhibition of protein tyrosine kinases or serine/threonine kinases. The compounds of formula I can be given prophylactically or therapeutically, preferably against the mentioned diseases, in an amount which is effective against the mentioned diseases in warm-blooded, for example humans, who need such treatment, where this is preferably used in the form of pharmaceutical preparations . Then, with a body weight of about 70 kg, a daily dose of about 0.1 g to about 5 g, preferably about 0.05 g to about 2 g, of a compound according to the invention is used.

The following examples illustrate the invention; the temperature is given in degrees Celsius. The following abbreviations are used: ether corresponds to diethyl ether; ethyl acetate corresponds to acetic acid ethyl ester; THF = tetrahydrofuran; DMF = N,N-dimethylformamide; RT corresponds to room temperature; MS corresponds to mass spectrum; FAB is equivalent to "Fast Atom Montbardment".

Example 1: 4. 5-bis(anllino) phthalimld

A suspension of 230 mg (0.7 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester in 23 ml of ethylene glycol was heated to 120°C; ammonia gas was passed through with stirring for 24 hours. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was then washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The evaporation residue was chromatographed with dichloromethane/methanol 40:1 on silica gel, the product fraction was combined and evaporated. The title compound was obtained as yellow crystals, mp 215-217°C, FAB-MS: 330[M<+>+E].

ouch 4 . 5-bis(trimethylsilvlox) cyclohexa-l. 4-diene-l. 2-dlcarbon<y>redimeth<y>lester

A solution of 7.1 g (50 mmol) of acetylene dicarboxylic acid dimethyl ester in 30 ml of toluene was added dropwise under an argon atmosphere to 12.5 g (50 mmol) of 2,3-bis(trimethylsilyloxy)-1,3-butadiene (95$) and then boiled for 19 hours at reflux. The reaction mixture was cooled, the solvent evaporated and the residue distilled in high vacuum (0.1 mbar, 124-127°C). The title compound was obtained as a highly viscous oil, <1>H-NMR (CDCl 3 ): S - 0.18 (s, 18E), 3.09 (s, 4H), 3.78 (s, 6H).

b) 4 . 5- bis(anllino) phthalic acid dlinet ester

A solution of 5.6 g (15 mmol) 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester and 5.5 ml (60 mmol) aniline in 60 ml glacial acetic acid was boiled in 4 hours with reflux cooling. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed successively in 20 ml 1N HCl, 50 ml saturated NaHCO 3 and twice in 20 ml water, dried over sodium sulfate and evaporated. The crude product was recrystallized from ethanol. The title compound was obtained as yellow crystals, mp 17S'C, FAB-MS: 377 [M<+>+H].

Example 2j 5 . 8- difenvl- 5 . 8- diaza- 5 . 6. 7 . 8- tetrahydro-naphthalene- 2. 3- dicarboxylic acid imide

Analogous to example 1, 40 mg (0.1 mmol) of 5,8-diphenyl-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxylic acid dimethyl ester in 4 ml of ethylene glycol was heated to 120°C, where it was passed through ammonia gas with stirring for 24 hours. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with dichloromethane/methanol 20:1 on silica gel, the product fractions were combined and evaporated. The title compound was obtained as yellow crystals, FAB-MS: 356[M<+>+E].

aj 5 , 8- diphenyl- 5. 8- diaza- 5. 6. 7. 8- tetrahydro- naphthalene- 2. 3- dicarbosvredlmet<y>ester

A solution of 2.24 g (6 mmol) 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid methyl ester (Example 1a) and 5.1 g (24 mmol) N,N' -diphenylethylenediamine in 24 ml of glacial acetic acid was boiled for two hours under reflux. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed with 20 ml of 1N HCl, 50 ml of saturated NaHCO 3 and twice with 20 ml of water, dried over sodium sulfate and evaporated. The crude product was chromatographed with hexane/ethyl acetate 3:1 on silica gel, the product fraction evaporated and the residue recrystallized from ethanol. The title compound was obtained as orange crystals, FAB-MS: 402[M<+>], 403[M<+>+H],

Example 3: 4. 5-bis(4-fluoroanllino) phthalimld

Analogously to example 1, 290 mg (0.7 mmol) of 4,5-bis(4-fluoroanllino)phthalic acid dimethyl ester in 22 ml of ethylene glycol was heated to 120°C and ammonia gas was passed through with stirring for 18 hours. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with hexane/ethyl acetate 1:1 on silica gel, the product fractions combined and evaporated. The title compound was obtained as orange crystals , melting point greater than 220°C, FAB-MS: 366 [M<+>+H].

a) 4. 5-bis(4-fluoroanilino) phthalic acid dimethyl ester

A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid methyl ester (Example 1a) and 2.3 ml (24 mmol) of 4-fluoroaniline in 60 ml of glacial acetic acid was boiled for 2 hours under reflux. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed respectively with 20 ml 1N HCl, 50 ml saturated NaHCO 3 and twice 20 ml water, dried over sodium sulfate and evaporated. The residue was chromatographed with ethyl acetate/hexane 2:1 on silica gel, the product fractions evaporated and recrystallized from ethyl acetate/hexane. The title compounds were obtained as yellow crystals, <1>H-NMR (CDCl 3 ): δ = 7.40 (S, 2E), 7.10-6.80 (m, 8H), 5.70 (br s, 2H), 3.83 (s, 6H).

Example 4: 4. 5-bis(4-benzyloxy-anilino) phthalimide

Analogous to example 1, 294.4 mg (0.5 mmol) of 4,5-bis(4-benzyloxy-anillno)phthalic acid dimethyl ester in 22 ml of ethylene glycol was heated to 120°C, and ammonia gas was passed through with stirring for 16 hours. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with dichloromethane/methanol 50:1 on silica gel, the product fractions were combined and evaporated. The title compound was obtained as red crystals, mp 187 to 189°C, FAB-MS: 542[M<+>+H].

a) 4 t5-bis(4-benzyloxy-anilino) phthalic acid dimethyl ester

A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 4.8 g (24 mmol) of 4-benzyloxyaniline in 24 ml of glacial acetic acid was boiled for 2 hours at reflux. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed in respectively 20 ml of 1N HCl, 50 ml of saturated NaHCO 3 and twice 20 ml of aqn, dried over sodium sulfate and evaporated. The residue was dissolved in hot ethyl acetate and filtered, then allowed to crystallize at 0°C. The crystalline residue was chromatographed with ethyl acetate/hexane 3:2 on silica gel, the product fractions evaporated and recrystallized from ethyl acetate/hexane. The title compound was obtained as beige crystals, FAB-MS: 589[M<+>+H].

Example 5: 4,5-bis[4-(N,N-diethylamino)-anilino]phthalimide bis<y>hydrochloride

Analogous to example 1, 294.4 mg (0.5 mmol) of 4,5-bis[4-(N,N-diethylamino)-anilino]phthalic acid dimethyl ester in 22 ml of ethylene glycol was heated to 120°C after which ammonia gas was passed through with stirring for 22 hours. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with dichloromethane/methanol 30:1 on silica gel, the product fractions were combined and evaporated. The red crystalline residue was dissolved in dichloromethane and made into 4.1 N HCl (g) in ether. The crystalline precipitate was filtered off and dried. The title compound was obtained as yellow crystals, mp 228 to 230°C, FAB-MS: 472 [M<+>+H].

a) 4.5-bisr4-N.N-diethylamino)-anllinolphthalic acid dimethyl ester

A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid methyl ester (Example 1a) and 3.94 g (24 mmol) of 4-(N, N-diethylamino)-aniline in 24 ml of glacial acetic acid was boiled for 2 hours under reflux. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed respectively with 50 ml of saturated NaHCO 3 and twice with 20 ml of water, dried over sodium sulfate and evaporated. The residue was chromatographed with dichloromethane/methanol 400:15 on silica gel, the product fractions evaporated and again chromatographed with ethyl acetate/hexane 1:1 on silica gel. The product fractions were evaporated. The title compounds were obtained as green crystals, FAB-MS: 518[M<+>], 519 [M<+>+H].

Example 6: 4. 5-bis(cyclohexylamino) phthalimide

Analogously to example 1, 194 mg (0.5 mmol) of 4,5-bis-(cyclohexylamino)phthalic acid dimethyl ester in 15 ml of ethylene glycol was heated to 120°C, then ammonia gas was passed through with stirring during 12 hours. The reaction mixture was cooled, extracted with saturated sodium chloride and with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residue was chromatographed with hexane/ethyl acetate 3:1 on silica gel, the product fractions were combined and evaporated. The title compound was obtained as orange crystals, mp 170 to 175°C, FAB-MS: 342[M<+>+H].

a) 4. 5- bis (cyclohexylamino) phthalic acid dimethyl ester

A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid methyl ester (Example 1a) in 21.5 ml (188 mmol) of cyclohexylamine and 4, 5 glacial acetic acid was boiled for 3.5 hours at reflux. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed respectively with 100 ml of 2N HCl, 50 ml of saturated NaHCO 3 and twice with 20 ml of water, dried over sodium sulfate and evaporated. The residue was chromatographed with ethyl acetate/hexane 5:12 on silica gel, the product fractions evaporated and again chromatographed with ethyl acetate/hexane 1:4. The title compound was obtained as a yellow oil, FAB-MS: 388 [M<+>].

As a by-product, 4-cyclohexylamino-phthalic acid dimethyl ester was obtained, which was converted analogously to example 6 into 4-cyclohexylamino-phthalimide. In this way a colorless powder was obtained: FAB-MS: 245 [M<+>], melting point 217-219<0>C.

Example 7: 4. 5-bis(4-methoxyanilino) phthalimide

Analogous to example 1, 393 mg (0.9 mmol) of 4,5-bis(4-methoxyanilino)phthalic acid dimethyl ester in 25 ml of ethylene glycol was heated to 120°C, and then ammonia gas was passed through stirring during 18 hours. The reaction mixture was cooled , saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with ethyl acetate/hexane 1:1 on silica gel, the product fractions were combined and evaporated. The compound in the title was obtained as yellow crystals, mp 191 to 193°C, FAB-MS: 390 [M<+>+H].

a) 4. 5- bis(4-methoxyanilino) phthalic acid dimethyl ester

A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 3.0 g (24 mmol) of 4-anisidine in 24 ml of glacial acetic acid was boiled for 2 hours under reflux. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed respectively with 20 ml 1N HCl, 50 ml saturated NaHCO 3 and 2 times 20 ml water, dried over sodium sulfate and evaporated. The residue was chromatographed with ethyl acetate/hexane 1:1 on silica gel and the product fractions evaporated. The title compound was obtained as a yellow foam, FAB-MS: 437 [M<+>+H].

Example 8: 4. 5-bis(2-iodanilino) phthalimide

Analogous to example 1, 1.48 g (2.36 mmol) of 4,5-bis(2-iodanilino)phthalic acid dimethyl ester in 25 ml of ethylene glycol was heated to 120°C and it was passed through ammonia gas with stirring for 19 hours. The reaction mixture was cooled, diluted with brine and extracted with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue obtained after evaporation was filtered with dichloromethane through silica gel and the product fractions were combined and evaporated. The residue obtained after evaporation was crystallized from boiling dichloromethane. The title compound was obtained as yellow crystals, mp 108-110°C, FAB-MS: 582 [M<+>+H].

a) 4. 5-bis(2-iodanilino) phthalic acid dimethyl ester

A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 5.3 g (24 mmol) of 2-iodaniline in 24 ml of glacial acetic acid was boiled for 2 hours under reflux. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed respectively with 20 ml 1N BCl, 50 ml saturated NaHCO 3 and twice 20 ml water, dried over sodium sulfate and evaporated. The residue obtained after evaporation was chromatographed with ethyl acetate/hexane 2:1 on silica gel and the product fractions evaporated. The title compound was obtained as a yellow foam: 1H-NMR (DMSO-d6):S - 7.91 (dxd, <J>1<=>8, J2=1, 2H), 7.39( dxdxd, J1=10, J2=8, J3=l, 2H), 7.32 (br s, 2H), 7.22-7.05(m, 2H), 7.01 (s, 2E), 6 .88 (txd, Jt=8, Jd=1.2H), 3.73 (s, 6E).

Example 9: 4. 5-bis(2-cyananilino) phthalimide

A solution of 581 mg (1 mmol) 4,5-bis(2-iodanilino)-phthalimide and 197 mg (2.2 mmol) copper (I) cyanide in DMF stirred for 6 hours at 130-140°C, whereby the the dark brown solution changes to a dark yellow suspension. The reaction mixture was cooled to 80°C and diluted with 8 ml of acetic acid. After further cooling to 60 to 70°C, a solution of 467 mg (2.88 mmol) of iron (III) chloride in 1.6 ml of water and 300 µl of concentrated hydrochloric acid was added dropwise and stirred for 30 minutes. To the reaction mixture was added 2 ml of water and Hyflo Super Cel®

(diatomaceous earth from the company Fluka, Buchs, Switzerland) and filtered through supergel and the phases were separated. The aqueous phase was extracted once with ethyl acetate, the combined organic phases were washed twice with water, once with saturated sodium bicarbonate solution and again twice with water, dried over magnesium sulfate and evaporated. The resulting oily brown crystal mixture was chromatographed with ethyl acetate/hexane 2:3 on silica gel. The product fractions were evaporated and crystallized from boiling dichloromethane. For-

the title compound was obtained as pale yellow crystals: FAB-MS: 330 (M<+>+E), mp 279-280°C.

5-anilino-4-(2-cyananilino)-phthalimide was obtained as a by-product in the form of yellow crystals: FAB-MS: 355 (M<+>+E), melting point 115-117°C.

Example 10: 4. 5-bis(2-nitroanilino) phthalamide. 4-( 4- nitro-anillno- 5-( 2. 4- dinitroanillno ) phthalimide and 4. 5- bls( 4- nitro-anillno) phthalimide

To a mixture of 12 mmol of acetic anhydride and 24 mmol of glacial acetic acid and 7.5 mmol of nitric acid (10056), 990 mg (3 mmol) of 4,5-bis(anilino)phthalimide was added at temperatures below 20°C. After stirring for 20 minutes, the reaction mixture was put on ice and extracted with glacial acetic acid. The organic phase was washed once with saturated NaHCO3 solution and once with water, dried over sodium sulfate and filtered. Chromatography twice on silica gel with a gradient of dichloromethane/acetic ester 1:1 to 3:1 gave the following amorphous compounds: 4,5-bis(2-nitroanilino)phthalimide in the form of a red-black powder: melting point 87 to 90°C; 4-(4-nitroanilino-5-(2,4-dinitroanilino)phthalimide in the form of a red-black powder: melting point 176 to 178° C, 1-E-NMR (DMS0-d6): 9.25 (br s , 2H), 8.85 (d, J=2.5, 1H), 8.16 (dxd, J1=8, J2=2.5, 1E) , 8.13 (d, j=9, 2H) , 7.88 (s, 1E), 7.75 (s, 1H), 7.17 (d, J=9, 2H), 6.96 (d, J=9.5, 1H); 4.5 -bis(4-nitroanilino )phthalimide in the form of a red glistening powder: melting point >250°C, zers from about 105°C, -*-E-NMR (DMS0-d6): 9.22 (br s, 2E ), 8.12 (d, J=9,1, 4E), 7.71 (s, 2E), 7.13 (d, J=9,1, 4E); <13>C-NMR (DMSO- d6): 168.9s, 149.8s, 139.6s, 138.2s, 128.2s, 125.9d, 116.2d, 115.6d.

Example 11: 4. 5-bis(4-aminoaniline) phthalimide

Solution of 38 mg (0.009 mmol) of 4,5-bis(4-nitroanilino)-phthalimide in 15 ml of THF was hydrogenated with 1056 Raney-Nickel as catalyst during 3 hours at normal pressure and RT. The catalyst was filtered from the reaction mixture which was evaporated. The title compound was obtained as a faint yellowish powder: mp 154 to 157°C, FAB-MS: 360

(M<+>+H).

Example 12: Analogously to the examples indicated in parentheses, the following was prepared: (a) 4,5-bis(4-iodanilino)phthalimide, FAB-MS: 582 (M<+>+H), melting point: 246-147°C ( analogous to example 8). (b) 4,5-bis(3-iodanilino)phthalimide, FAB-MS: 582 (M<+>+H), melting point: 244-245°C (analogous to Example 8). (c) 4,5-bis(2,6-dibromanilino)phthalimide, FAB-MS: 642 (M<+>+H), melting point: 235-237°C (analogous to Example 8). (d) 4,5-bis(3-methoxyanilinino)phthalimide, FAB-MS: 390 (M<+>+H), mp: 169 to 171°C (analogous to Example 7). (e) 4,5-bis(2-methoxyanilino)phthalimide, FAB-MS: 390 (M<+>+H), melting point: 227-228°C (analogous to Example 97). (f) 4,5-bis(4-trifluoromethylanilino)phthalimide, FAB-MS: 512 (M<+>+H), <i>H-NMR (CD30D): 7.7 (s, 2E), 7, 5 (d, 4H), 7.2 (d, 4H) (analogous to example 1), as by-product. (g) 4-cyanilino-5-trifluoromethylanilino-phthalimide, FAB-MS: 423 (M<+>+H), <i>H-NMR (CDCl 3 ): 7.7(d,2H), 7.6( d,4H),7,1(d,2H),7,0-(d,2H),6,2(s,1H),6,1(S,1H) (analogous to check example 1). (h) 4,5-bis(4-biphenylamino)phthalimide, FAB-MS: 482 (M<+>+H), melting point: 230-231°C (analogous to example 1). (i) 4,5-bis(4-cyanilino)phthalimide, FAB-MS: 380 (M<+>+H), melting point: >250°C, <1>H-NMR(DMS0-d6): 7, 1 (d, 4H), 7.6 (d, 4H), 7.7 (s, 2H) (analogous to Example 9).

(j) 4,5-bis(3-cyanilino)phthalimide, FAB-MS: 380 (M<+>+H), melting point: 225-227°C (analogous to Example 9).

Example 13: 4. 5-bis(N-methyl-N-phenylamino) phthalimide

Analogously to Example 1, 66 mg (0.16 mmol) of 4,5-bis(N-methyl-N-phenylamino)-phthalic acid dimethyl ester (Example 14A) was heated in 5 ml of ethylene glycol to 120°C and passed through ammonia gas with stirring for 18 hours . The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with hexane/ethyl acetate 1:1 on silica gel, the product fraction purified and evaporated. The title compound was obtained as pale yellow crystals, FAB-MS: 358 [M++H] , <1->H-NMR (CDCl 3 ): 3.05 (s, 6H).

Example 14: 4-(N-methyl-N-phenylamino)-5-anilinophthalimide

Analogous to example 1, 160 mg (0.41 mmol) of 4-(N-methyl-N-phenylamino)-5-aniline phthalic acid dimethyl ester in 12 ml of ethylene glycol was heated to 120<*>C and ammonia gas was passed through with stirring for 18 hours. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with hexane/ethyl acetate 1:1 on silica gel, the product fractions were combined and evaporated. The title compound was obtained as pale yellow crystals, FAB-MS: 344 [M<+>+H], 1 H-NMR (CDCl 3 ): 3.28 (s, 3H).

a .) 4, 5-bis(N-methyl-N-phenylamino)phthalic acid dimethyl ester (A) and 4-(N-methyl-N-phenylamino)-5-anllino- phthalic acid dimethyl ester (B)

A solution of 564 mg (1.5 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester (Example 1b) in 5 ml of acetonitrile was heated with 0.93 ml (15 mmol) of methyl iodide and 442 mg (3.2 mmol) of anhydrous potassium carbonate in a bomb tube for 16 hours at 80°C. The reaction mixture was evaporated to dryness, the residue dissolved twice in dichloromethane, filtered and the filtrate evaporated. Multiple chromatography with hexane/ethyl acetate on silica gel afforded the title compound as a faint yellowish powder. (A): FAB-MS: 405[M<+>+E]; (B): FAB-MS: 391 [M<+>+E].

Example 15: 4. 5-bis(anillno)-N-methylphthalimide

Analogously to Example 1, 376 mg (1 mmol) of 4,5-bis(ani1ino)-phthalic acid dimethyl ester in 33 ml of ethylene glycol was heated to 120°C and methylamine was passed through with stirring for 18 hours. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with hexane/ethyl acetate 1:1 on silica gel, the product fractions were combined and evaporated. The title compound was obtained as pale yellow crystals FAB-MS: 344[M<+>+H], mp 195-196°C.

Example 16: 4. 5-bis(anilino)-thiophthalimide f=5. 6- bis-( anilino )- isoindol- l- on- 3- thione~ l

To a solution of 100 mg (0.3 mmol) of 4,5-bis(anilino)phthalimide (Example 1) in 15 ml of dichloromethane was added 138 mg (0.36 mmol) of Lawesson's reagent [=2,4-bis-( 4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiaphosphate] and refluxed for 4 hours. The reaction mixture was evaporated and directly chromatographed with hexane/ethyl acetate 2:1 on silica gel. The product fractions were evaporated. The title compound was obtained as yellow crystals, FAB-MS: 346 [M<+>+H].

Example 17: 4. 5- bis(anilino)- N^ >N5— propane- 1, 3- divlphthalimide

In an autoclave, 457 mg (1 mmol) of 4,5-bis(anilino)-N<4>,N<5->propane-1,3-diyl-phthalic acid dimethyl ester in 5 ml of methanol were dissolved and 15 ml of ammonia was added for amide formation . This closed autoclave was heated to 120°C for 24 hours, then cooled, opened and the ammonia with nitrogen stripped off. The residue was flushed with ethyl acetate, filtered and the filtrate chromatographed on silica gel with hexane/ethyl acetate 3:1. The product fractions were evaporated and crystallized from hexane/-acetic ester The title compound was obtained as yellow crystals, FAB-MS: 370 [M<+>+E].

a) 4. 5- bis(anillnol- N^-. N^— propanedivl- phthalic acid dimethyl ester and 4. 5- bis( N- allylanllino) phthalic acid dimethyl ester

A solution of 3.76 g (10 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester (Example 1b) in 15 ml of HMPT (hexamethylphosphoric acid triamide) or DMPU was added at room temperature under argon to 0.6 g (15.4 mmol ) sodium amide and heated to 60°C for 30 minutes. The deep red solution was cooled to room temperature and evacuated for 5 minutes (1 torr). Then a solution of 1.5 ml (15.2 mmol) 1-bromo-3-chloropropane in 2 ml TEF was added dropwise and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was poured onto ice water, extracted with glacial acetic acid, the organic phases combined and thoroughly washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel with hexane/acetic ester 5:1. The compounds of the title were thus obtained: 4,5-bis(anilino)-N<4>,N<5->propanediylphthalic acid dimethyl ester in the form of colorless crystals, FAB-MS; 457[M<+>+E].

Example 18: Analogous to examples 13 to 17, the following was prepared: (a) 4-(N-acetyl-N-phenyl)amino-5-anilino-phthalimide, FAB-MS: 372[M<+>+E], ifl -NMR (DMS0-d6): 2.05 (s, 3E) analogous to example 14). (b) 4,5-bis(N-allylanilino)phthalimide, FAB-MS: 410 (analogous to Example 17).

Example 19: 5000 capsules were prepared, each containing 0.25 g of active substance, for example one of the compounds that were prepared in examples 1 to 16: Procedure: The powdered substances were sieved through a sieve with a mesh size of 0.6 mm and mixed. Portions each of 0.33 g of the mixture using a capsule filling machine filled into gelatin capsules.

Example 20: 4-anilino-5-(4-hydroxyvanillino)phthalimide

To a solution of 359.4 mg (1 mmol) of 4-anilino-5-(4-methoxy-anilino)phthalimide in 5 ml of chloroform was added dropwise at -40° C. to -30° C. to a solution of 186 µl ( 2 mmol) boron tribromide in 5 ml chloroform. The reaction mixture was stirred for 5 hours at -30°C and then quenched with 5 ml of water at -30°C. The reaction mixture was warmed to room temperature and the phases were separated. The organic phase was washed twice with water, dried over magnesium sulfate and evaporated. The residue was chromatographed with ethyl acetate/hexane 1:1 on a silica gel column cooled with ice water, the product fractions combined and evaporated. The title compound was obtained as yellow crystals, FAB-MS: 346[M<+>+H].

a) 4-anilino-5-(4-methoxy-anilino) phthalimide

0.7 g (1.7 mmol) of 4-anilino-5-(4-methoxy-anilino)phthalic acid dimethyl ester in 20 ml of ethylene glycol was analogously to example 1 heated to 120°C, after which ammonia gas was passed through during 18 hours under stirring. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed twice with water and once with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The rest

was chromatographed with ethyl acetate/hexane 1:1 on silica gel, the product fractions combined and evaporated. The title compound was obtained as yellow crystals, mp 266 to 267°C, FAB-MS: 360[M<+>+H].

b) 4- anilno- 5-( 4- methoxy- anilino) phthalic acid dimethyl ester and 4. 5- bis ( 4- methoxyoxy-anilino) phthalic acid dimethyl ester

A solution of 4.8 g (12 mmol) 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-dyne-1,2-dicarboxylic acid methyl ester (Example 1a), 2.6 g (24 mmol) p-anisidine and 2.2 ml (24 mmol) of aniline in 48 ml of glacial acetic acid was refluxed for 2 hours. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in ethyl acetate and the solution washed respectively with 40 ml 1N HCl, 100 ml saturated NaHCO 3 and twice 100 ml water, dried over magnesium sulfate and evaporated. The residue was chromatographed with ethyl acetate/hexane 1:3 on silica gel and the product fraction evaporated. From the first product reaction, 4,5-bis(4-methoxyanilino)phthalic acid dimethyl ester was thus obtained in the form of a yellow foam: FAB-MS: 437[M<+>+H]. The residue in the subsequent product fraction was recrystallized from ethyl acetate/hexane and 4-anilino-5(4-methoxy-anilino)phthalic acid dimethyl ester was obtained as yellow crystals, mp 122 to 124°C, FAB-MS: 407[M<+>+H ].

Claims (5)

1. Chemical compound, characterized in that it has formula I, where Ai and ţ independently stand for hydrogen, lower alkyl, lower alkenyl or lower alkanoyl; or where Ai and Ag together stand for -(CHg^- or -(CHg^-; Ar! and Ar2 independently stand for phenyl, which is unsubstituted or substituted with one or more substituents from the group consisting of halogen, phenyl , phenyl lower alkyl, lower alkoxy, di lower alkylamino, cyano, nitro, amino and trifluoromethyl; or represents C3~C3 cycloalkyl; the group -C(=X) represents -C(=0) or -C(=S); and R represents for hydrogen or lower alkyl, or a salt thereof, provided salt-forming groups are present. 2. Compound according to claim 1, characterized in that it is 4,5-bis(anilino)phthalimide. 3. Compound according to claim 1, characterized in that it is 4,5-bis(4-fluoroaniline)phthalimide. 4. Pharmaceutical preparation, characterized in that it contains a compound of formula I or a salt thereof, according to claims 1 to 3, and possibly at least one pharmaceutically usable carrier material. 5. Use of a compound of formula I or a salt thereof, according to one of claims 1 to 3, for the production of a medicament for use in the treatment of diseases which are affected by inhibition of protein tyrosine kinases or serine/threonine kinases.