MXPA97006014A - Derivatives of xanteno and acridina and its emp - Google Patents

Abstract

The invention relates to new and known tricyclic dione derivatives of the general formula (I), wherein W represents hydrogen or lower alkyl, X represents lower alkyl, Y represents an oxygen atom or NR1, R1 represents hydrogen, lower alkyl, alkoxycarbonyl lower or lower alkoxycarbonyl-lower alkyl; Z represents aryl or heteroaryl optionally substituted with one or more substituents halogen, cyano, nitro, lower alkyl, halogen-lower alkyl, lower alkoxy, halogen-lower alkoxy, COR2, OCOR2, CO2R2, OR2, S (O) nR 2, NR 2 R 3, N (R 4) COR 5, Ar, Ar-lower alkyl, Het or Het-lower alkyl and / or in the adjacent carbon atoms with lower alkylenedioxy; R 2, R 3, R 4 and R 5 each represent individually substituents hydrogen, lower alkyl, Ar, Ar-lower alkyl, Het or Het-lower alkyl, or R2 and R3 together represent the group -CH = CH-CH = CH-or-CH = N-CH = CH-; Ar represents aryl optionally substituted with one or more its halogen, lower alkyl, lower alkoxy or nitro; Het represents heteroaryl optionally substituted with one or more halogen substituents, lower alkyl, onyx lower alkoxy, and represents 0.1, and its salts, which are inhibitors of herpes virus thymidine kinase simplex, in the treatment and prophylaxis of infections caused by the herpes virus simpl

Description

DERIVATIVES OF XANTENO AND ACRIDINA AND THEIR EMPLOYMENT DESCRIPTION OF THE INVENTION The present invention relates to xanthene and acridine derivatives and to their use, of general formula wherein w represents hydrogen or lower alkyl; X represents lower alkyl; Y represents an oxygen atom or NR1; R1 represents hydrogen, lower alkyl, lower alkoxycarbonyl or lower alkoxycarbonyl-lower alkyl; Z represents aryl or heteroaryl optionally substituted with one more substituent halogen, cyano, nitro, lower alkyl, halogen-lower alkyl, lower alkoxy, halogen-lower alkoxy, COR2, OCOR2, C02R2, OR2, S (0) nR2, NR2R \ N (R4) CORs, Ar, Ar-lower alkyl, Het or Het-lower alkyl and / or on the adjacent carbon atoms with lower alkylenedioxy, - R2, R3, R4 and Rs each represents individually substituents hydrogen, lower alkyl, Ar, lower aralkyl, Het or lower alkyl Het, or R2 and R3 together represent the group -CH = CH-CH = CH- or -CH = N-CH = CH-; Ar represents aryl optionally substituted with one or more halogen, lower alkyl, lower alkoxy or nitro substituents; Het represents heteroaryl optionally substituted with one or more halogen, lower alkyl, lower alkoxy or nitro substituents; and n represents 0, 1 or 2 and the salts thereof. A number of compounds falling within formula I are described here, among which are those described in US Pat. Nos. 3,414,587, 3,454,577 and 3,539,590, European Patent Publications Nos. 524 041, 369 762, 539154 and 539153, German Public Information Report No. 2,003,148, PCT Patent Publication No. WO 9408966 and B. Loev et al., J. Med. Chem., 1974, 17 (9), 956-965, in which it is reported that they have activity as anthelmintics, antibacterials, antihypertensives or agents for the treatment of urinary incontinence. No mention is made in these references regarding the inhibition of thymidine kinase (TK) of the herpes simplex virus (HSV). It has surprisingly been discovered according to the present invention, that the compounds of formula I inhibit the HSV TK and can therefore be used for the treatment and prevention of infections caused by the herpes simplex virus. Accordingly, the invention relates in a first aspect to the use of the compounds of formula I mentioned herein, in the treatment and prophylaxis of infections caused by the herpes simplex virus and, respectively, for the production of the corresponding medicaments. As used herein, the term "aryl" means a monocyclic or polycyclic aromatic group, preferably containing up to 14 carbon atoms, especially phenyl or naphthyl and particularly phenyl. The term "heteroaryl" means a 5- or 6-membered heteroaromatic group containing N-, S- or 0-, which can be fused with a benzene, e.g. ex. pyridyl, thienyl, furyl, pyrimidinyl, quinolyl, benzofuranyl and the like. As used herein, the term "lower" means that the group qualified with said term contains up to 7, preferably up to 4, carbon atoms. The lower alkyl and lower alkoxy groups can be straight chain or branched chain, such as methyl, ethyl, n-propyl, isopropyl, n-butyl and terebutyl and, respectively me-toxyl, ethoxy, n-propoxy, isopropoxy, n-butoxyl and tert.butoxyl. Trifluoromethyl is an example of a halogeno-lower alkyl group and trifluoromethoxy is an example of a halogeno-lower alkoxy group. Methylenedioxyl and ethylenedioxyl are examples of lower alkylenedioxyl groups. Lower alkoxycarbonyl can be for example methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopro-poxycarbonyl and the like. The term "halogen" means fluorine, chlorine, bromine or iodine. In the aforementioned use of the compounds of formula I, those compounds in which W and X represent methyl are preferred. Also preferred in the aforementioned use are compounds of formula I in which Y represents NR1 wherein R1 represents hydrogen, as well as those in which Z represents aryl or heteroaryl substituted with: i) two or more halogen, cyano, nitro substituents , lower alkyl, halogen-lower alkyl, lower alkoxy, halogen-lower alkoxy, COR2, OCOR2, C02R2, OR2, S (0) nR2, NR2R3, N (R4) C0R5, Ar, Ar-lower alkyl, Het or Het-alkyl lower, and / or on adjacent carbon atoms with lower alkylenedioxyl; or with ii) a substituent of OHet, O-lower alkyl-Het, N (R4) COHet and NR2'R3 'in which R2' and R3 'together represent -CH = CH-CH = CH- OR -CH = N -CH = CH-. In a particularly preferred embodiment Z represents phenyl substituted with Ar, OR2 or S (0) nR2 in meta position and with halogen, cyano or nitro in the para position, particularly with phenyl, benzyloxy, phenoxy, pyridyloxy, phenylthio or pyridylthio in the meta position and with chlorine, bromine, fluorine, cyano or nitro e position for. In another especially preferred version Z represents monosubstituted phenyl, preferably in the meta position, with OHet, O-lower alkyl-Het or NHCOHet in which Het represents pyridyl. The invention relates in another aspect to compounds of formula I and their salts per se which are still new. These are compounds of formula I in which W, X, Y, R 1, R 2, R 3, R 4, R 5, Ar, Het and n are defined above and Z represents aryl or heteroaryl substituted with: i) two or more halogen substituents, cyano, nitro, lower alkyl, halogen-lower alkyl, lower alkoxy, halogen-lower alkoxy, COR2, OCOR2, C02R2, OR2, S (0) nR2, NR2R3, N (R) C0Rs, Ar, Ar-lower alkyl , Het or Het-lower alkyl, and / or on adjacent carbon atoms with lower alkylenedioxyl; or with ii) a substituent of OHet, O-lower alkyl-Het, N (R) COHet and NR2'R3 'in which R2' and R3 'together represent -CH = CH-CH = CH- OR -CH = N-CH = CH-; with the proviso that: a) when and X represent methyl and Y represents an oxygen atom, then Z does not represent 2,4-dihydroxy-phenyl, 3,4-dimethoxy-phenyl, 4-benzyloxy-3,5-dimethoxy -phenyl, 4-hydroxy-3, 5-dimethoxy-phenyl, 3-hydroxy-4-methoxy-phenyl, 3,5-di-chloro-2-hydroxy-phenyl, 4-hydroxy-3-methoxy-phenyl , 3,4-methylenedioxy-phenyl or 2,4,4,5-trimethoxy-phenyl; and b) when and X represent methyl and Y represents NR1 in which R1 represents hydrogen, then Z does not represent 2,5-dibenzyloxy-4-methyl-phenyl or 2,5-dihydroxy-4-methyl-phenyl. Preferred new compounds of formula I are those in which W and X represent methyl. Also preferred are those in which Y represents NR1 wherein R1 represents hydrogen as well as those in which Z represents phenyl substituted with Ar, OR2 or S (0) nR2 in the meta position and by halogen, cyano or nitro in the para position. , particularly with phenyl, benzyloxy, phenoxy, pyridyloxy, phenylthio or pyridylthio in the meta position and with chlorine, bromine, fluorine, cyano or nitro in the para position. In another especially preferred version Z represents monosubstituted phenyl, preferably in the meta position, with OHet, O-lower alkyl-Het or NHCOHet in which Het represents pyridyl. Basic compounds of formula I can form salts with inorganic acids, e.g. ex. hydrocidal acids such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with organic acids p. ex. formic acid, acetic acid, citric acid, fumaric acid, malic acid, maloic acid, succinic acid, tartaric acid, salicylic acid, methanesulfonic acid or p-toluenesulfonic acid. Acid reaction compounds of formula I can form salts with metals, e.g. ex. alkali metal salts such as sodium or potassium salts or alkaline earth metal salts such as calcium or magnesium salts, with organic bases, e.g. ex. salts with amines such as N-ethylpiperidine, procaine or dibenzylamine, or salts with basic amino acids such as the salts with arginine or lysine. These salts can be obtained and isolated by methods well known in the art. Examples of particularly preferred novel compounds of formula I are: 9- (4-chloro-3-phenoxyphenyl) -3,4,6,7,9,1-hexahydro-3,6,6-tetramethyl-1, 8 (2H, 5H) -acridinedione; 9- (4-chloro-3-phenylthiophenyl) -3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione; 9- (6-chloro-3-biphenyl) -3,4,6,7,9,1-hexahydro-3,6,6,6-tetramethyl-1,8 (2H, 5H) -acridindione; 9- [4-chloro-3- (4-pyridyloxy) phenyl] -3,4,6,7,8,10-hexahydro-3,3,6,6-tetramethyl-l, 8 (2H, 5H) - acridindione; 25 9- [4-chloro-3- (4-pyridylthio) phenyl] -3,4,6,7,8,1-hexahydro-3,3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione; and 9- (3-benzyloxy-4-nitrophenyl) -3,4,6,7,8,10-hexahydro-3,3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione.

The invention also relates to a process for the preparation of the aforementioned new compounds, which process comprises: a) for the preparation of a compound of formula I in which Y represents an oxygen atom, reacting an aldehyde of general formula Z-CHO (II) wherein Z has the meaning already indicated. with a cyclohexanedione derivative of the general formula wherein W and X have the meanings already mentioned, or b) for the preparation of a compound of formula I in which Y represents NR1 and R1 represents hydrogen, by reacting an aldehyde of formula II or an acetal or hemiacetal thereof with an derivative of cyclohexanedione of formula III and aqueous ammonia, or c) for the preparation of a compound of formula I in which Y represents NR1 and R1 represents hydrogen, lower alkyl or lower alkoxycarbonyl-lower alkyl, by reacting an aldehyde of formula II or an acetal or hemiacetal thereof with a cyclohexenone derivative of the general formula wherein W and X have the meanings indicated above and R6 represents hydrogen, lower alkyl or lower alkoxycarbonyl-lower alkyl, or d) for the preparation of a compound of formula I in which Y represents NR1 and R1 represents lower alkoxycarbonyl, reacting a compound of formula I in which Y represents NR1 and R1 represents hydrogen, with a lower alkyl chloroformate, or e) for the preparation of a compound of formula I in which Z contains an amino substituent or NHCOR5, reducing the corresponding compound of formula I in which Z contains a nitro substituent and, when necessary, acylating the resulting compound of formula I in which Z contains an amino substituent and if desired, forming a salt. The reaction of an aldehyde of formula II with a cyclohexanedione derivative of formula III according to version a) of the process can be carried out in a manner in itself already known, p. ex. as described in the USA patents noß 3414587, 3454577 and 3539590. Thus, for example, the reaction can be carried out in an inert organic solvent, e.g. ex. a lower alkanol, such as methane or ethanol, an aromatic hydrocarbon, such as benzene or toluene, or a carboxylic acid, e.g. ex. acetic acid, suitable at an elevated temperature, e.g. ex. the reflux temperature of the reaction mixture. When a non-acid solvent is employed, it is desirable that an acid catalyst, e.g. ex. a sulfonic acid, such as p-toluenesulfonic acid. Version b) of the process can also be carried out in a known manner, e.g. ex. as described by Martin et al., in Heterocyclic Chem. 1995, vol. 32, p. 235. For example, the reaction can be carried out in an inert organic solvent at elevated temperature, preferably at the reflux temperature of the reaction mixture. Among the suitable solvents are those cited in connection with version a) of the process. Also known methods, described p. ex. by Greenhill in Chem. Soc. (C) 1971, p. 2699, for the reaction according to the c) of the procedure. The reaction is suitably carried out in an inert organic solvent at an elevated temperature, especially at the reflux temperature of the reaction mixture. Typical solvents are those mentioned above in connection with the version a) of the process. The reaction is conveniently carried out in the presence of an acid, especially a hydrocidal acid, especially hydrochloric acid, when a non-acidic solvent is used. Version d) of the process is carried out in a manner known per se, conveniently by deprotonation of a solution of the compound of formula (I) in an inert organic solvent, e.g. ex. a formamide, such as dimethylformamide, with an alkali metal hydride, especially sodium hydride, at elevated temperature, e.g. ex. at the reflux temperature of the mixture, and then the reaction with the desired lower alkyl chloroformate, p. ex. methyl chloroformate, the ambient temperature being approximately. The known methods per se can be used to carry out version e) of the procedure. For example, the reduction can be carried out using hydrogen in the presence of an appropriate catalyst, e.g. ex. a palladium catalyst such as Pd / C, and in an inert organic solvent, e.g. ex. a lower alkanol such as ethanol. Again, for example, the subsequent acylation can be effected by condensation of the amine with a conventional acylating agent, e.g. ex. an acid or a reactive derivative thereof such as an acid halide, preferably in an inert organic solvent in the presence of a conventional condensing agent or an acid-binding agent. The compounds of formulas (II), (III) and (IV) used as starting materials in the process provided by the invention insofar as they are unknown compounds or analogs of known compounds, can be prepared as described in the following examples or in analogy to them. The pharmacological activity of the compounds of formula I can be demonstrated on the basis of the following test procedure for the inhibition of HSV-1 and HSV-2 thymidine kinase (TK): In this test procedure, the test mixture contains 50 mmoles of Tris.HCl, pH 8, 5 mmoles of magnesium chloride, 5 mmoles of ATP, 0.3 mmoles of 3H-thymidine (50 Ci / mmoles), a conveniently diluted enzyme preparation and various concentrations of test compounds in a total volume of 100 ml. The assays are incubated at 37 ° C for 30 minutes and the reaction is stopped by immersion in a boiling water bath for 2 minutes. Subsequently, 85 ml aliquots of each assay are dried on DEAE cellulose paper discs and the non-phosphorylated 3H-thymidine is removed by washing in 4 mmoles of ammonium formate. Next, the radioactivity that remains attached to the discs is measured by scintillation spectrophotometry. The degree of inhibition at each concentration of the test compound is expressed as a percentage of the control reaction (100%) after subtracting a measured value from the control, which represents the amount of radioactivity bound to the disk from a control. reaction that contains enzymes inactivated by heat. Next, the ICS0 value is calculated, ie the concentration of the test compound that inhibits the enzymatic activity by 50%. The results obtained in the cited test using representative compounds of the formula I are indicated in the following table: Table A = 9- (4-chloro-3-f-enoxyphenyl) -3, 4, 6, 7, 9, 10-hexahydro-3,3,6,6-tetramethyl-l, 8 (2h, 5h) -acridinedione . B = 9- (4-chloro-3-phenylthiophenyl) -3,4,6,7,9,1-hexahydro-3,3,6,6-tetramethyl-l, 8 (2h, 5h) -acridindione. C = 9- (6-chloro-3-biphenyl) -3,4,6,7,9,9-hexahydro-3,3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. D = 9- [3,4-dichlorophenyl) -3,4,6,7,9,9-hexahydro-3,3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. E = 9- (4-chloro-3-f luorofenyl) -3, 4, 6, 7,, 10-hexahydro-3, 3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. F = 9 - [4-chloro-3 - (lH-pyrrol-1-yl) -f-enyl] -3,4,6,7,9, 10-hexahydro-3,6,6-tetramethyl-l 8 (2H, 5H) - acridindione.

G = 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9- (3-phenoxy-phenyl) -1,8 (2H, 5H) -acridindione. H = 9- [4-bromophenyl] -3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. I 9 - [4-chloro-3- (4-pyridyloxy) -f-enyl] -3,4,6,7,8,10-hexahydro-3,6,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. J = 9- (3-benzyloxy-4-nitrophenyl] -3,4,6,7,8,10-hexahydro-3,6,6,6-tetramethyl-l, 8 (2H, 5H) -acridinedione. 9 - [4-chloro-3- (4-pyridyl-thio) -f-enyl] -3,4,6,7,8,1-hexahydro-3,6,6,6-tetramethyl-l, 8 (2H , 5H) -acridinedione The compounds of formula I have an activity in the inhibition of HSV-1 TK and HSV-2 TK which is comparable with that of the pyrimidine nucleosides described in PCT Patent Publication No. WO 9603259, as p. ex. 2'5'-dideoxy-5-ethyl-5 '- [(9-xanthenyl) carboxamido] uridine, which has an IC 50 (nmol) of 4.2 against HSV-1 TK and an ICSO (nmol) of 0.34 versus HSV-2 TK in the assay described above. However, the compounds of formula I have the advantage over these pyrimidine nucleosides that they can be prepared more easily and cheaply. The compounds of formula I can be used as medicaments in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. ex. in the form of tablets, lacquered tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. Administration can also be carried out by rectal route, p. ex. in the form of suppositories, or parentally, p. ex. in the form of solutions for injection. The compounds of formula I can be processed with pharmaceutically inert, organic or inorganic fillers, for the production of pharmaceutical preparations. As such fillers, for example lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used for the manufacture of tablets, coated tablets, dragees and hard gelatine capsules. Suitable fillers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; however, because of the nature of the active ingredient, no charge is usually required in the case of soft gelatine capsules. Suitable fillers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable fillers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may still contain other substances of therapeutic value. Medicaments containing a new compound of formula I are also subject of the present invention, as well as a process for the production of said medicaments, the which method comprises the conversion of one or more new compounds and, if desired, one or more other therapeutically valuable substances, into a galenic administration form together with a pharmaceutically compatible charge. The dosage at which the compounds of formula I can be administered can vary within wide limits and, of course, must be adapted to the individual needs of each particular case. In general, in the case of administering to adults, a daily dose of about 1 mg to 1000 mg, preferably about 5 mg to 500 mg, should be appropriate. The daily dose can be administered as a single dose or in divided doses. The following examples illustrate the preparation of the novel compounds of formula I: Example 1 A solution of 1.39 g of 3-amino-5,5-dimethyl-2-cyclohexen-1-one and 793 mg of 4-fluoro-3 -chlorobenzaldehyde in 10 ml of absolute ethanol and 1 ml of 1 M aqueous hydrochloric acid was heated to reflux in a nitrogen atmosphere for 18 hours. The cooled mixture was filtered and the residue was washed with 25 ml of cold diethyl ether. Crystallization with absolute ethanol / water gave 302 mg of 9- (4-fluoro-3-chlorophenyl) -3,4,6,7,9, 10-hexahydro-3,6,6,6-tetramethyl-l, 8 (2H, 5H) -acridinedione as a pale yellow crystalline solid of melting point 274-275 ° C (decomposition). Example 2 A solution of 1.94 g of 5, 5-dimethyl-l, 3-cyclo- Hexanedione and 1.5 mL of a 25% aqueous solution of ammonia in 10 mL of absolute ethanol was heated to reflux in a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature and 1.588 g of 4-bromo-3-nitro-benzaldehyde was added. The mixture was then heated to reflux for a further 18 hours, cooled and filtered. The residue was washed with 25 ml of cold diethyl ether and crystallized with dimethylformamide / water to obtain 2.36 g of 9- (4-bromo-3-nitrophenyl) -3,4,6,7,9. hexahydro-3,6,6,6-tetramethyl-1,8 (2H, 5H) -acridinedione as a yellow crystalline solid of melting point > 300 ° C. Example 3 The reaction of 5,5-dimethyl-1,3-cyclohexanedione with 3,4-dimethylbenzaldehyde in a manner analogous to that described in example 2, gave 9- [3,4-dimethylphenyl] -3,4, 6, 7, 9, lO-hexahi-dro-3, 3, 6, 6-tetramethyl-l, 8 (2H, 5H) -acridindione in the form of a yellow solid of melting point >300 ° C. Example 4 The reaction of 5, 5-dimethyl-l, 3-cyclohexanedione with 4-methyl-3-nitrobenzaldehyde in a manner analogous to that described in example 2, gave 9- (4-methyl-3-nitrophenyl) -3.4, 6, 7, 9, 10-hexahydro-3, 3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with methanol gave a yellow solid of melting point > 300 ° C. Example 5 The reaction of 5,5-dimethyl-1,3-cyclohexanedione with 3,4-dichloro-benzaldehyde in a manner analogous to that described in example 2, gave 9- (3,4-dichlorophenyl) -3 , 4,6,7,9, 10-hexahydro- 3, 3, 6, 6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave a yellow crystalline solid of melting point > 300 ° C. Example 6 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3,4-dibromobenzaldehyde in a manner analogous to that described in example 1 gave the 9- (3, 4- dibromophenyl) -3, 4, 6, 7, 9, 10-hexahydro-3, 3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with absolute ethanol gave a pale yellow crystalline solid of melting point > 290 ° C (decomposition). Example 7 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-bromo-4-fluorobenzaldehyde in a manner analogous to that described in Example 1, gave 9- (3- bromo-4-fluorophenyl) -3,4,6,7,9, 10-hexahydro-3,6,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with absolute ethanol gave a pale yellow crystalline solid of melting point 260 ° C (decomposition). EXAMPLE 6 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3,4-difluorobenzaldehyde analogously to that described in example 1 gave the 9- (3, 4 difluorophenyl) -3,4,6,7,9, 10-hexahydro-3,6,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with absolute ethanol / water gave a pale yellow crystalline solid of melting point 270 ° C (decomposition). Example 9 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-chloro-3-fluorobenzaldehyde analogously to that described in example 1, gave 9- (4-chloro-3-fluorophenyl) -3,4,6,7,9, 10-hexahydro-3, 3.6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with absolute ethanol gave a yellow crystalline solid of melting point > 300 ° C (decomposition). Example 10 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-benzyloxy-4-chlorobenzaldehyde in a manner analogous to that described in example 1, gave 9- (3- benzyloxy-4-chlorophenyl) -3,4,6,7,9, 10-hexahydro-3,6,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave a pale yellow crystalline solid of melting point 243-244 ° C. EXAMPLE 11 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-chloro-3-phenoxybenzaldehyde analogously to that described in Example 1 gave the 9- (4- chloro-3-phenoxyphenyl) -3,4,6,7,9, 10-hexahydro-3, 3,6, é-tetramethyl-1,8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave a yellow crystalline solid of melting point 246-248 ° C. Example 12 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-chloro-3-phenylthiobenzaldehyde dimethyl acetal in a manner analogous to that described in Example 1, gave 9- ( 4-chloro-3-phenylthiophenyl) -3,4,6,7,9,10-hexahydro-3,6,6,6-tetramethyl-1, 8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave a yellow crystalline solid of melting point 202-204 ° C. The 4-chloro-3-phenylthiobenzaldehyde dimethyl acetal used as starting material was prepared as follows: A solution of 312 mg of thiophenol and 85 mg of sodium hydride (80% dispersion in mineral oil) in 10 ml of diglyme was stirred at 50 ° C under nitrogen atmosphere for 30 minutes. Next, 500 mg of 3-bromo-4-chlorobenzaldehyde dimethyl acetal and 500 mg of copper bromide (I) were stirred and the mixture was stirred at 155-160 ° C under nitrogen atmosphere for 3 days. The solvent was removed under reduced pressure and the residue was extracted with 30 ml of dichloromethane. The solution was washed with 10 ml of 1 M aqueous potassium hydroxide solution and 10 ml of brine and then dried with anhydrous magnesium sulfate. The solution was evaporated to dryness and the residue was purified by column chromatography on silica gel using hexane / ethyl acetate (96: 4) as eluent, to give 4-chloro-3-phenylthiobenzaldehyde dimethyl acetal as a colorless oil. Example 3 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 2-chloro-1,1'-biphenyl-5-carboxaldehyde analogously to that described in example 1, gave 9- (6-chloro-3- (1,1'-biphenyl)] -3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8 (2H) , 5H) -acridinedione Crystallization with dimethylformamide / water gave a yellow crystalline solid of melting point 301-302 ° C (decomposition) .The 2-chloro-l, 1'-biphenyl-5-carboxaldehyde used as the material starting was prepared as follows-.

(A) A solution of 5.63 g of 5- (bromomethyl) -2-chloro-1,1'-biphenyl in 60 ml of carbon tetrachloride was added dropwise over 10 minutes to a refluxing solution of 2 g. , 81 g of hexamethylenetetramine in 60 ml of carbon tetrachloride under anhydrous nitrogen atmosphere. The mixture was refluxed for an additional hour and then cooled. The resulting precipitate was separated by filtration and washed with petroleum ether (bp 40-60 ° C) to give 6.2 g of an off-white solid. (B) A solution of 6.2 g of the solid obtained in section (A) in 60 ml of 50% aqueous acetic acid was heated to reflux for 2 hours. Then, 8 ml of concentrated hydrochloric acid was added, and the mixture was heated to reflux for a further 10 minutes. The cooled mixture was extracted with four 50 ml portions of diethyl ether and the extracts together were washed with 50 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.49 g of a yellow oil. . Purification by column chromatography on silica gel using hexane / ethyl acetate (95: 5) as eluent gave 2-chloro-1,1 '-biphenyl-5-carboxaldehyde as a white crystalline solid, melting point 84 ° C. Example 14 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-cyano-4-fluorobenzaldehyde analogously to that described in Example 1, gave the 5- (2, 3,4,5,6,7,8,9, -octahydro-3,6,6,6-tetramethyl-l, 8-dioxo-lH-acridin-9-yl) -2-fluorobenzonitrile. Crystallization with ethanol gave a solid Pale yellow-green crystalline melting point 274-275 ° C.

The 3-cyano-4-fluorobenzaldehyde used as starting material was prepared from 2-fluoro-5-methylbenzonitrile in a manner analogous to that described in example 13 (A) and (B). Example 15 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-cyano-3-nitrobenzaldehyde in a manner analogous to that described in Example 1, gave 4- (2, 3, 4, 5, 6, 7, 8, 9-octahydro-3, 3, 3, 6,6-tetramethyl-l, 8-dioxo-lH-acridin-9-yl] -2-nitrobenzonitrile The crystallization with methanol gave a yellow crystalline solid of melting point 274-275 ° C. Example 16 A solution of 330 mg of 5,5-dimethyl-3- (methylamino) -2-cyclohexen-1-one and 300 mg of 4-chloro-3 phenoxybenzaldehyde dimethyl acetal in 10 ml of absolute ethanol and 1.5 ml of 1 M aqueous hydrochloric acid was refluxed under nitrogen for 18 hours.The mixture was evaporated to dryness and the residue was washed with hexane and diethyl ether. Recrystallization from ethyl acetate / methanol gave 9- (4-chloro-3-phenoxyphenyl) -3,4,6,7,9, 10-hexahydro-3, 3, 6, 6, 10-pentamethyl-1, 8 (2H, 5H) -acridinedione in the form of a yellow crystalline solid of melting point 183-185 ° C. The reaction of 5,5-dimethyl-1,3-cyclohexanedione with 2,4-dichlorobenzaldehyde in a manner analogous to that described in Example 2, gave 9- (2,4-dichlorophenyl) -3,4,6 , 7.9, 10-hexahydro- 3,3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave a pale green crystalline solid of melting point > 300 ° C. Example 18 The reaction of 5,5-dimethyl-1,3-cyclohexanedione with 3,5-dibromobenzaldehyde analogously to that described in Example 2, gave 9- (3, 5-dibromophenyl) -3,4 , 6,7,9, 10-hexahydro-3,3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave a yellow crystalline solid of melting point 288-290 ° C. Example 19 The reaction of 5,5-dimethyl-1,3-cyclohexanedione with 3,5-dichlorobenzaldehyde analogously to that described in Example 2, gave 9- (3,5-dichlorophenyl) -3,4 , 6,7,9, 10-hexahydro-3, 3, 6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave a yellow crystalline solid of melting point 288-290 ° C. Example 20 The reaction of 5, 5-dimethyl-1,3-cyclohexanedione with 2,4,6-trifluorobenzaldehyde analogously to that described in Example 2, gave 9- (2,4,6-trifluorophenyl) -3.4, 6, 7, 9, 10-hexahydro-3, 3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with methanol / water gave a yellow crystalline solid of melting point > 300 ° C. Example 21 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-chloro-3- (lH-pyrrol-1-yl) benzaldehyde in a manner analogous to that described in the example 1, gave 9- [4-chloro-3- (LH-pyrrol-1-yl) phenyl] -3,4,6,7,9,10-hexahydro-3,6,6,6-tetramethyl-1,8 (2H, 5H) -acridindione. This product was recrystallized with dimethylformamide / water and gave a yellow crystalline solid of melting point 282-283 ° C (decomposition). The 4-chloro-3- (lH-pyrrol-1-yl) benzaldehyde used as the starting material was prepared as follows: (A) 5.0 g of 4-chloro-3- (lH-pyrrol-1-yl) acid ) benzoic acid in 200 ml of dichloromethane were treated successively with 3.13 ml of triethylamine and 4.33 g of l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDAC.HCl). The mixture was allowed to warm to room temperature until it became clear and then cooled to 0 ° C and 2.21 g of N, 0-dimethylhydroxylamine hydrochloride was added. The mixture was allowed to warm on its own at room temperature and was stirred for a further 18 hours, washed with 1 M aqueous hydrochloric acid and with brine and then dried with anhydrous magnesium sulfate. Evaporation under reduced pressure gave 5.73 g of N-methoxy-N-methyl-4-chloro-3- (lH-pyrrol-1-yl) benzamide as a viscous oil. (B) A solution of 1.5 g of N-methoxy-N-methyl-4-chloro-3- (lH-pyrrol-1-yl) benzamide in 30 ml of anhydrous tetrahydrofuran was added dropwise over a period of 30 minutes to a solution previously cooled to 0-5 ° C of 237 mg of lithium aluminum hydride (98%) in 30 ml of tetrahydrofuran. The mixture was stirred at 0-5 ° C for a further 45 minutes and then the reaction was stopped by adding 25 ml of saturated aqueous solution of ammonium chloride and 25 ml of 50% aqueous hydrochloric acid. Next, the sample with three 100 ml portions of diethyl ether and the combined extracts were dried with anhydrous magnesium sulfate. The solvents were removed under reduced pressure and the residue was purified by an oromatographic column on silica gel using hexane / ethyl acetate (90:10) as eluent to give 0.84 g of 4-chloro-3- (1H-pyrrol- 1-yl) benzaldehyde in the form of a yellow oil; NMR (CDC13, 250 Mhz) dH 10.00 (CHO). Example 22 The reaction of 3-amino-5,5-imethyl-2-cyclohexen-1-one with 4-chloro-3-phenylsulfonylbenzaldehyde dimethyl acetal analogously to that described in example 1, gave the 9- [ 3- benzenesulfonyl-4-chlorophenyl] -3,4,6,7,9,10-hexahydro-3,6,6,6-tetramethyl-1,8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave a yellow crystalline solid of melting point 252-254 ° C (decomposition). The 4-chloro-3-phenylsulfonylbenzaldehyde dimethyl acetal employed as starting material was prepared as follows: A suspension of 500 mg of 4-chloro-3-phenylthiobenz-aldehyde dimethyl acetal (prepared as described in Example 12), 1.09 g of sodium metaperiodate and a catalytic amount of ruthenium trichloride were stirred at room temperature for 12 hours under nitrogen in a solvent composed of 4 ml of water, 2 ml of acetonitrile and 2 ml of of carbon tetrachloride. The mixture was partitioned between 25 ml of diethyl ether and 25 ml of water. The ether phase was washed with two 10 ml portions of saturated aqueous sodium bicarbonate solution followed by two 10 ml portions of brine and then dried with magnesium sulfate. anhydrous. The solution was concentrated under reduced pressure to give 388 mg of 4-chloro-3-phenylsulfonylbenzaldehyde dimethyl acetal as a clear oil. EXAMPLE 23 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3- (l-imidazolyl) -benzaldehyde dimethyl acetal in a manner analogous to that described in example 1, gave the , 4,6,7,9,10-hexahydro-9- [3- (1-imidazolyl) -phenyl] -3,3,6,6-tetramethyl -1,8 (2H, 5H) -acridindione. Crystallization with methanol / water gave a yellow crystalline solid of melting point 286-288 ° C. The 3- (l-imidazolyl) -benzaldehyde dimethyl acetal used as a starting material was prepared as follows: A solution of 296 mg of imidazole and 131 mg of sodium hydride (80% dispersion in mineral oil) in 2 g. my of anhydrous dimethylformamide, was stirred at room temperature for 1 hour under a nitrogen atmosphere. Then 1.0 g of 3-bromobenzaldehyde dimethyl acetal and 30 mg of copper powder were added and the mixture was stirred at 150-160 ° C under nitrogen for 36 hours. The cooled mixture was diluted with 20 ml of water and extracted with four 25 ml portions of dichloromethane. The combined extracts were washed with two 25 ml portions of 25% aqueous ammonia, followed by two 25 ml portions of brine and then dried with anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give 0.75 g of 3- (l-imidazolyl) -benzaldehyde dimethyl acetal in the form of a clear viscous oil.

Example 24 3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3- (4-pyridyloxy) -benzaldehyde dimethyl acetal analogously to that described in example 1 to give 3 , 4,6,7,9, 10-hexahydro-3, 3, 6,6-tetra-methyl-9- [3- (4-pyridyloxy) -phenyl] -1,8 (2H, 5H) -acridindione. fication by column chromatography on silica gel using dichloromethane / methanol (95: 5) as eluent gave a beige solid of melting point 186-188 ° C. The 3- (4-pyridyloxy) -benzaldehyde dimethyl acetal employed as starting material was prepared as follows: A solution of 1 g of 3-hydroxybenzaldehyde dimethyl acetal and 2 g of potassium tert-butoxide in 10 ml of anhydrous dimethylformamide, it was heated at 60 ° C under a dry nitrogen atmosphere for 1 hour. The mixture was then cooled to room temperature and 900 mg of 4-chloro-pyridinium hydrochloride was added in portions over a period of 20 minutes. The mixture was then heated at 160 ° C for 18 hours, cooled, 100 ml of water was added and the product was extracted with ethyl acetate. The combined extracts were washed with 1 M aqueous sodium hydroxide solution and with brine, and then dried with anhydrous magnesium sulfate. Evaporation to dryness left a brown oil which was fied by column chromatography on silica gel using hexane / ethyl acetate (gradient: 90:10 to 20:80) for elution, to give 3- (4-pyridyloxy) -benzaldehyde dimethyl acetal in the form of a light brown oil.

Example 25 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-chloro-3- (4-pyridyloxy) -benzaldehyde dimethyl acetal analogously to that described in example 1 , gave 9- [4-chloro-3- (4-pyridyloxy) -phenyl] -3,4,6,7,9, 10-hexahydro-3,6,6-tetramethyl-1, 8 (2H , 5H) -acridindione. Crystallization with dimethylformamide / water gave a yellow crystalline solid of melting point 242-244 ° C. The 4-chloro-3- (4-pyridyloxy) -benzaldehyde dimethyl acetal used as starting material was prepared analogously to that described in Example 24. The fication by chromatographic column on silica gel using ethyl acetate / hexane ( : 30) for the elution gave the product in the form of a light yellow oil. EXAMPLE 26 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3- (4-pyridylmethoxy) -benzaldehyde dimethyl acetal in a manner analogous to that described in example 1, gave the - [3- (4-pyridylmethoxy) -phenyl] -3,4,6,7,9, 10-hexahydro-3,6,6,6-tetramethyl-1,8 (2H, 5H) -acridindione. Crystallization with methanol / water gave a yellow crystalline solid of melting point 156-158 ° C. The 3- (4-pyridylmethoxy) -benzaldehyde dimethyl acetal used as a starting material was prepared analogously to that described in Example 24. fication by chromatographic column on silica gel using ethyl acetate / hexane (70:30) to elution, gave the product as a colorless oil.

Example 27 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3- (2-pyrazinyloxy) -benzaldehyde dimethyl acetal analogously to that described in example 1 gave the , 4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9 - [3- (2-pyrazinyloxy) phenyl] -1,8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave a pale brown crystalline solid of melting point 204-207 ° C. The 3- (2-pyrazinyloxy) -benzaldehyde dimethyl acetal used as a starting material was prepared as follows: A solution of 168 mg of 3-hydroxybenzaldehyde dimethyl acetal in 10 ml of anhydrous dimethylformamide was stirred under a nitrogen atmosphere and added 220 mg of potassium tert.butoxide. The mixture was heated at 60 ° C for 1 hour, then cooled to room temperature and 115 mg of 2-chloropyrazine was added in portions. The mixture was then heated at 160 ° C for 18 hours. After cooling 15 ml of water were added and the product was extracted with 50 ml of ethyl acetate. The extract was washed with 25 ml of 1 M aqueous solution of sodium hydroxide and 25 ml of brine., and then dried with anhydrous magnesium sulfate. After filtering and evaporating the filtrate the residual yellow oil was purified by column chromatography on silica gel using ethyl acetate / hexane (1: 1) for elution, to give the 3- (2-pyrazinyloxy) -benzaldehyde dimethyl acetal in the form of a yellow oil. Example 28 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3- (2-pyrimidinyloxy) -benzaldehyde dimethyl acetal, in a manner analogous to that described in Example 1, gave 3,4,6,7,9, 10-hexahydro-3,6,6-tetramethyl- 9 - [3- (2-pyrimidinyloxy) -phenyl] -1,8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave a pale yellow crystalline solid of melting point 220-221 ° C. The 3- (2-pyrimidinyloxy) -benzaldehyde dimethyl acetal used as the starting material was prepared as follows: A solution of 168 mg of 3-hydroxybenzaldehyde dimethyl acetal in 2 ml of anhydrous dimethylformamide was stirred under a nitrogen atmosphere and added 220 mg of potassium tert.butoxide. The mixture was heated at 60 ° C for 1 hour, then cooled to room temperature and 114 mg of 2-chloropyrimidine was added in portions. The mixture was heated at 150 ° C for 20 hours. After cooling, 20 ml of water were added and the product was extracted with ethyl acetate. The extracts were washed with 10 ml of 1 M aqueous sodium hydroxide solution and 5 ml of brine, and then dried with anhydrous magnesium sulfate. After filtering and evaporating the filtrate, the residual brown gum was purified by column chromatography on silica gel using ethyl acetate / hexane (1: 1) for elution, to give 3- (2-pyrimidinyloxy) -benzaldehyde dimethyl. Acetal in the form of a syrup. Example 29 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-nitro-3-benzyloxybenzaldehyde dimethyl acetal analogously to that described in example 1 gave the 9- [ 3- benzyloxy-4-nitrophenyl] -3,4,6,7,9-hexahydro-3,6,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with methanol / water gave a yellow crystalline solid of melting point 239-240 ° C. The 4-nitro-3-benzyloxybenzaldehyde dimethyl acetal used as the starting material was prepared as follows: A solution of 1.0 g of 4-nitro-3-hydroxybenzaldehyde dimethyl acetal and 212 mg of sodium hydride (80% dispersion) in mineral oil) in 10 ml of anhydrous dimethylformamide was stirred at 50 ° C under nitrogen for 1 hour. A solution of 1.20 g of benzyl bromide dissolved in 10 ml of anhydrous dimethylformamide was added dropwise, followed by 174 mg of tetrabutylammonium iodide and the mixture was stirred at 60 ° C under nitrogen for 48 hours. The cooled mixture was concentrated under reduced pressure and the yellow oily residue was dissolved in 150 ml of ethyl acetate, washed with four 25 ml portions of water, followed by two 25 ml portions of brine and then dried with sulfate. of anhydrous magnesium. The solution was evaporated to give 1.47 g of 4-nitro-3-benzyloxybenzaldehyde dimethyl acetal as a light yellow oil. Example 30 A solution of 57 mg of isonicotinic acid in 2.5 ml of anhydrous tetrahydrofuran was stirred under a nitrogen atmosphere and cooled to 5 ° C on ice. To this solution were added 48 mg of 4-ethylmorpholine, 150 mg of 3, 4, 6, 7, 9, 10-hexahydro-3, 3, 6, 6-tetramethyl-9- (3-aminophenyl) -1, 8 (2H, 5H) -acridindione, 57 mg of 1-hydroxybenzotriazole and 80 mg of hydrochloride of l- (3- slowly heat alone to room temperature and then stir for 18 hours. After evaporation of the solvent the residue was treated with 15 ml of water and extracted with ethyl acetate. The combined extracts were washed with saturated sodium bicarbonate solution and brine and then dried with anhydrous magnesium sulfate. Filtration followed by evaporation of the filtrate gave a solid which was purified by column chromatography on silica gel using methanol / dichloromethane 1: 9 for elution to give 3,4,6,7,9, 10-hexahydro-3, 3 , 6,6-tetramethyl-9- [3- [(4-pyridyl) -carboxamido] -phenyl] -1,8 (2H, 5H) -acridindione in the form of a pale yellow solid of melting point 295-297 ° C. 3,4,6,7,9,10-hexahydro-3,6,6,6-tetramethyl-9- (3-ami-nofenil) -1,8 (2H, 5H) -acridinedione used as starting material was prepared as follows: (A) The reaction of 18.4 g of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 10 g of 3-nitrobenzaldehyde analogously to that described in example 1 gave 3,4,6,7,9,10-hexahydro-3, 3,6,6-tetramethyl-9- (3-nitrophenyl) -1,8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave 22.6 g of pure material in the form of pale yellow crystals of melting point >280 ° C. (B) A solution of 10 g of 3,4, 6, 7, 9, 10-hexahydro-3,3,6,6-tetramethyl-9- (3-nitrophenyl) -1,8 (2H, 5H) - acridindione in 190 ml of ethanol and 100 ml of 1 M hydrochloric acid was hydrogenated at atmospheric temperature and pressure, in the presence of 0.5 g of the 10% palladium on carbon catalyst. When the absorption of rcrrrrr) hnhn p < - »< =! artr? . HÍ »fal -i m-i n? I heard pah a l i 7aH by filtration and the filtrate was evaporated. The residue was dissolved in water (20 ml) and the solution made alkaline by the addition of an excess of 1 M sodium carbonate solution. The precipitated solid was removed by filtration, washed with water and dried to obtain 9.0 g. of 3,4, 6, 7, 9, 10-hexahydro-3, 3, 6,6-tetramethyl-9- (3-aminophenyl) -1,8 (2H, 5H) -acridinedione in the form of a pale brown solid , - mass spectrum (ESP) m / e 365 [M + H] \ Example 31 The reaction of 3-amino-5,5-dimethyl-1-one with 3-fluoro-4-trifluoromethylbenzaldehyde, Analogous to that described in Example 1 gave 9- [3-fluoro-4-trifluoromethylphenyl] -3,4,6,7,9, 10-hexahydro-3, 3,6,6-tetramethyl-1 , 8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave a yellow crystalline solid of melting point 296-300 ° C. EXAMPLE 32 The reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-chloro-3- (4-pyridylthio) -benzaldehyde dimethyl acetal analogously to that described in the example 1 gave 9- [4-chloro-3- [4-chloro-3- (4-pyridylthio) -phenyl-3,4,6,7,9,10-hexahydro-3,6,6,6-tetramethyl) -l, 8 (2H, 5H) -acridindione. Mass spectrum (ESP) m / e 493 [M + H +]. The 4-chloro-3- (4-pyridylthio) -benzaldehyde dimethyl acetal used as starting material was prepared as follows: (A) To a stirred solution of 10.0 of 3-bromo-4-chlorobenzoic acid in 275 ml of anhydrous dichloromethane at 0 ° C was added 7.6 g of 1- (3-dimethylaminopropyl) -3- hydrochloride. ethylcarbodiimide and 5.5 ml of triethylamine followed by 3.9 g of N, 0-dimethylhydroxylamine hydrochloride. After stirring overnight at room temperature, the mixture was washed with 200 ml of water and then with 200 ml of a 1M solution of hydrochloric acid. The organic solution was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 10.7 g of 3-bromo-4-chloro-N-methoxy-N-methylbenzamide as a creamy solid. (B) A solution of 10.7 g of 3-bromo-4-chloro-N-methoxy-N-methylbenzamide in 100 ml of anhydrous tetrahydrofuran was added dropwise to 43 ml of a 1 M solution of aluminum hydride and lithium in tetrahydrofuran below 5 ° C and stirred for 1 hour. Then 100 ml of saturated ammonium chloride solution were added cautiously followed by 100 ml of a 1M solution of hydrochloric acid and the mixture was extracted twice with 400 ml of diethyl ether. The combined organic extracts were dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 6.8 g of 3-bromo-4-chlorobenzaldehyde in forin of a pale yellow solid. (C) A solution of 6.8 g of 3-bromo-4-chlorobenzaldehyde in 17 ml of trimethyl orthoformate was stirred with 6.9 g of Amberlyst resin at room temperature overnight. The mixture was filtered and the filtrate was evaporated to give 4.5 g of 3-bromo-4-chlorobenzaldehyde dimethyl acetal as a colorless oil, mass spectrum (El) m / e 266 [M +]. (D) A solution of 222 mg of 4-mercaptopyridine in 2 ml of anhydrous dimethylformamide was added dropwise to a sodium in mineral oil in 15 ml of anhydrous dimethylformamide below 5 ° C. After 50 minutes, a solution of 0.5 g of 3-bromo-4-chlorobenzaldehyde in 1 ml of anhydrous dimethylformamide was added dropwise and the mixture was heated at 150 ° C for 29 hours. The mixture was then cooled to below 5 ° C and 5 ml of a 1M solution of hydrochloric acid was carefully added. The mixture was diluted with 50 ml of water and then extracted twice with 100 ml of ethyl acetate. The combined organic extracts were dried with anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel using methanol / dichloromethane (5:95) as eluent to give 120 mg of 4-chloro-3- (4-pyridylthio) -benzaldehyde dimethyl acetal as a pale yellow oil , mass spectrum (Cl) m / e 296 [M +]. The following examples illustrate the preparation of other compounds of formula I: EXAMPLE 3 The 5,5-dimethyl-1,3-cyclohexapdione was reacted with l, 4-benzodioxan-6-carboxaldehyde analogously to that described in the example 2 to give 9- (1, 4-benzodioxan-6-yl) -3,4,6,7,9, 10-hexahydro-3,6,6,6-tetramethyl-1, 8 (2H, 5H ) -acridindiona. Recrystallization with dimethylformamide / water gave a yellow crystalline solid of melting point >300 ° C. EXAMPLE 34 3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-phenylbenzaldehyde analogously to that described in Example 1 to give 9- (3-biphenylyl) -3 , 4, 6, 7, 9,10-hexahydro-3,3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with ethanol gave a pale yellow crystalline solid of melting point 227-229 ° C. EXAMPLE 35 3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-phenoxybenzaldehyde in a manner analogous to that described in example 1 to give 3,4, 6, 7, 9 , 10-hexahydro-3,3,6,6-tetramethyl-9- (3-phenoxyphenyl) -1,8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave a yellow crystalline solid of melting point 205-207 ° C. Example 36 3-Amino-5, 5-dimethyl-2-cyclohexen-1-one was reacted with 3-phenylthiobenzaldehyde in a manner analogous to that described in Example 1 to give 3,4, 6, 7, 9, 10-hexahydro-3,3,6,6-tetramethyl-9- (3-phenylthiophenyl) -1,8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave a yellow crystalline solid of melting point 252-253 ° C. Example 7 3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3- (4-methylphenoxy) benzaldehyde analogously to that described in Example 1 to give 3, 4,6,7,9,10-hexahydro-3,6,6,6-tetramethyl-9- [3- (4-methylphenoxy) -phenyl] -1,8 (2H, 5H) -acridinedione. Crystallization with ethanol gave a yellow crystalline solid of melting point 202-203 ° C. EXAMPLE 38 3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3- (4-methoxyphenoxy) -benzaldehyde analogously to that described in example 1 to give 3.4 , 6,7,9,10-hexahydro-3.3.6.6-t? rampl-i 1 -9- l "í- íd-mot-nvi fonnví *? _ phenyl] -i, 8 (2H, 5H) -acridindione. Crystallization with ethanol / water gave a pale yellow crystalline solid of melting point 210-212 ° C. Example 39 3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3- (3,5-dichlorophenoxy) benzaldehyde analogously to that described in example 1 to give the 9- [3- (3,5-Dichlorophenoxy) -phenyl] -3,4,6,7,9,10-hexahydro-3,6,6,6-tetramethyl-1,8 (2H, 5H) -acridinedione. Crystallization with di-methylformamide / water gave a yellow crystalline solid of melting point 254-255 ° C. EXAMPLE 40 3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3- (4-chlorophenoxy) benzaldehyde in a manner analogous to that described in Example 1 to give 9- [3 - (4-chloro-phenoxy) -phenyl] -3,4,6,7,9, 10-hexahydro-3,6,6,6-tetramethyl-1,8 (2H, 5H) -acridinedione. Crystallization with dimethylformamide / water gave a beige crystalline solid of melting point 238-239 ° C. Example 41 5,5-Dimethyl-1,3-cyclohexanedione was reacted with 4-trifluoro-methoxybenzaldehyde analogously to that described in Example 2 with the exception that the reaction time after the addition of the aldehyde was of 5 days. This gave 9- [4-trifluoromethoxy-phenyl] -3,4,6,7,9,9-hexahydro-3,6,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione, which formed a yellow crystalline solid of melting point 234 ° C after crystallization with ethanol.

Example 42 The reaction of 5,5-dimethyl-1,3-cyclohexanedione with 4-cyanobenzaldehyde analogously to that described in Example 2 gave the 4- (2, 3, 4, 5, 6, 7, 8 , 9-Octahydro-3, 3, 6,6-tetra-methyl-1,8-dioxo-lH-acridin-9-yl) benzonitrile. Crystallization with dimethylformamide / water gave a green-yellow solid of melting point > 300 ° C (decomposition). EXAMPLE 43 3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 2-bromobenzaldehyde analogously to that described in Example 1 to give 9- (2-bromophenyl) -3,4,6,7,9, 10-hexahydro-3, 3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave a yellow powder of melting point > 285 ° C (decomposition). Example 44 3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-benzoyloxybenzaldehyde analogously to that described in Example 1 to give 9- (3-benzoyloxyphenyl) -3 , 4,6,7,9, 10-hexahydro-3, 3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with ethanol gave a pale yellow crystalline solid of melting point 274-275 ° C (decomposition). Example 45 3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-benzyloxybenzaldehyde analogously to that described in Example 1 to give 9- (3-benzyloxyphenyl) 3,4,6,7,9, 10-hexahydro-3,6,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione. Crystallization with ethanol gave a solid Cream-colored crystalline melting point > 300 ° C (decomposition). EXAMPLE 46 The reaction of 5,5-dimethyl-1,3-cyclohexanedione with naphthalene-2-carboxaldehyde in a manner analogous to that described in Example 2 gave 3, 4, 6, 9, 10-hexahydro-3, 3, 6, 6-tetramethyl-9- (2-naphthyl) -1,8 (2H, 5H) -acridindione. Crystallization with methanol gave a cream-colored powder of melting point > 300 ° C. EXAMPLE 47 3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with the pyridine-4-carboxaldehyde analogously to that described in Example 1 to give 3,4, 6,7 , 9, 10-hexahydro-3,3,6,6-tetramethyl-9- (4-pyridyl) -1,8 (2H, 5H) -acridindione. Crystallization with dimethylformamide / water gave a pale yellow crystalline solid of melting point 218-219 ° C (decomposition). EXAMPLE 48 3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 5-methyl-2-thiophenecarboxaldehyde analogously to that described in example 1 to give 3,4, 6 , 7.9, 10-hexahydro-3, 3,6,6-tetramethyl-9- (5-methyl-2-thienyl) -1,8 (2H, 5H) -acridindione. Crystallization with ethyl acetate gave a beige crystalline solid of melting point 266-268 ° C (decomposition). Example 49 3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 5-nitro-furfuraldehyde in a manner analogous to that described in example 1 to give 3,4, 6,7 , 9, 10-hexahydro- 3,3,6,6-tetramethyl-9- (5-nitro-2-furyl) -1,8 (2H, 5H) -acridindione. Crystallization with ethyl acetate / methanol gave a beige crystalline solid of melting point 248-250 ° C (decomposition). Example 50 A solution of 980 mg of 5,5-dimethyl-1,3-cyclohexanedione, 550 mg of 5-nitro-2-thiophenecarboxaldehyde and 7 mg of p-toluenesulfonic acid in 70 ml of toluene were heated to reflux for 90 minutes. The mixture was evaporated to dryness and the residue was crystallized from ethyl acetate to give 3,4,6,7,9,10-hexahydro-3,6,6,6-tetramethyl-9- (5-nitro) -thienyl) -lH-xanthene-1, 8 (2H) -dione as a yellow crystalline solid of melting point 298-300 ° C. Example 51 A suspension of 17 mg of sodium hydride (80% dispersion in mineral oil) in 10 ml of anhydrous tetrahydrofuran was stirred at room temperature under a dry nitrogen atmosphere and treated dropwise with a solution of 200 mg. 3,4,6,7,9, 10-hexahydro-3,3,6,6-tetramethyl-9- (4-nitro-phenyl) -l, 8 (2H, 5H) -acridindione in 5 ml of dimethylformamide. The mixture was then heated to reflux for 15 minutes, cooled to room temperature, treated with 44 ml of methyl chloroformate and stirred at room temperature under a dry nitrogen atmosphere for 18 hours. The solvents were removed under reduced pressure and the waxy residue was extracted with diethyl ether and the insoluble material was removed by filtration. The filtrate was then purified by column chromatography on silica gel using hexane / ethyl acetate (gradient: 80:20 to 50:50) as eluent to give 2, 3, 4, 5, 6, 7, 8, 9-octahydro-3, 3, 6,6-Tetramethyl-9- (4-nitrophenyl) -1,8-dioxo-lH-acridin-10-carboxylic acid methyl ester as a white crystalline solid of melting point 189-190 ° C. Example 52 A solution of 1.39 g of 3-amino-5,5-dimethyl-2-cyclohexen-1-one, 1.26 g of 5-methyl-cyclohexane-1,3-dione and 1.51 g of 4-bromobenzaldehyde in 18 ml of absolute ethanol and 6 ml of glacial acetic acid was heated to reflux under a nitrogen atmosphere for 12 hours. The sample was then cooled to room temperature and about 10 ml of water was added until the product precipitated. The product was separated by filtration and washed with three 50 ml portions of cold diethyl ether to give 9- (4-bromophenyl) -3,4,6,7,9, 10-hexahydro-3, 3,6 ( RS) -trimethyl-1, 8 (2H, 5H) -acridinedione in the form of a pale yellow solid. The product proved to be a 9: 1 mixture of diastereoisomers by HPLC and gave an ionic mass of 414 (FAB, [M + H] +). Example 53 The 5-methyl-cyclohexane-1,3-dione was reacted with 4-bromobenzaldehyde in a manner analogous to that described in Example 2 to give 9- (4-bromophenyl) -3,4,6,7. , 9, 10-hexahydro-3,6-dimethyl-l, 8 (2H, 5H) -acridinedione in the form of a white crystalline solid. The product showed by HPLC to be a mixture of 3 diastereoisomers and gave an ionic mass of 401 (FAB, [M + H] +).

Example 54 The 5-ethyl-cyclohexane-1,3-dione was reacted with 4-bromobenzaldehyde in a manner analogous to that described in Example 2 to give 9 (RS) - (4-bromophenyl) -3 (RS) , 6 (RS) -diethyl-3,4,6,7,9, 10-hexahydro-l, 8 (2H, 5H) -acridindione in the form of a white crystalline solid. The product showed by HPLC to be a mixture of 3 diastereoisomers and gave an ionic mass of 428 (FAB, [M + H] +). Example 55 The 5-isopropyl-cyclohexane-1,3-dione was reacted with 4-bromobenzaldehyde in a manner analogous to that described in example 2 to give 9 (RS) - (4-bromophenyl) -3 (RS) , 6 (RS) -diisopropyl-3,4, 6, 7, 9, 10-hexahydro-l, 8 (2H, 5H) -acridindione in the form of a white crystalline solid. The product showed by HPLC to be a mixture of 3 diastereoisomers and gave an ionic mass of 456 (FAB, [M + H] +). The following example illustrates a pharmaceutical preparation containing a compound of formula I. Example A Tablets containing the following ingredients can be obtained in a conventional manner: Compound of formula I 100 mg Lactose 70 mg Corn starch 70 mg Polyvinylpyrrolidone 5 mg Magnesium stearate 5 mq Weight per tablet 250 mg ***** It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (22)

1. CLAIMS Tricyclic dione derivatives of general formula characterized in that W represents hydrogen or lower alkyl, -X represents lower alkyl; Y represents an oxygen atom or NR1; R1 represents hydrogen, lower alkyl, lower alkoxycarbonyl or lower alkoxycarbonyl-lower alkyl, -Z represents aryl or heteroaryl optionally substituted with one more substituent halogen, cyano, nitro, lower alkyl, halogen-lower alkyl, lower alkoxy, halogen-lower alkoxy, COR2, OCOR2, C02R2, OR2, S (0) nR2, NR2R \ N (R) COR5, Ar, Ar-lower alkyl, Het or Het-lower alkyl and / or on the adjacent carbon atoms with lower alkylenedioxy, - R2 , R3, R4 and Rs each individually represent hydrogen, lower alkyl, Ar, lower alkyl, Het or lower alkyl, - or R2 and R3 together represent the group -CH = CH-CH = CH- or -CH = N-CH = CH -, - Ar represents aryl optionally substituted with one or more substituents halogen, lower alkyl, lower alkoxy, halogen-lower alkoxy or nitro, -Het represents heteroaryl optionally substituted with one or more halogen substituents, lower alkyl, lower alkoxy, halogen-lower alkoxy or nitro, - and n represents 0, 1 or 2 and the salts thereof, for use in the treatment and prophylaxis of infections caused by the herpes simplex virus and for the preparation of the corresponding medicines.
2. 2. The use according to claim 1, of compounds of formula I indicated in claim 1, wherein R2, R3, R4 and Rs each individually represent hydrogen, lower alkyl, Ar, Ar-lower alkyl, Het or Het-lower alkyl, or R2 and R3 together represent the group -CH = CH-CH = CH-.
3. 3. The use according to claim 1, of compounds of formula I indicated in claim 1 or claim 2 in which and X represents methyl.
4. 4. The use according to claim 1, of compounds of formula I indicated in any one of claims 1 to 3, wherein Y represents NR1 wherein R1 represents hydrogen.
5. 5. The use, according to claim 1, of compounds of formula I indicated in any one of claims 1 to 4, wherein Z represents aryl or heteroaryl substituted with: i) two or more halogen, cyano, nitro substituents, lower alkyl, halogen-lower alkyl, lower alkoxy, halogen-lower alkoxy, COR2, OCOR2, C02R2, OR2, S (0) nR2, NRR3, N (R4) COR5, Ar, Ar-lower alkyl, Het or Het- lower alkyl, and / or on adjacent carbon atoms with lower alkylenedioxyl; or with ii) a substituent of OHet, O-lower alkyl-Het, N (R4) C0Het and NR2'R3 'in which R2' and R3 'together represent -CH = CH-CH = CH- or -CH = N -CH = CH-.
6. 6. The use according to claim 1 of compounds of formula I indicated in claim 5, wherein Z represents phenyl substituted with Ar, OR2 or S (0) nR2 in the meta position and with halogen, cyano or nitro in the position for.
7. The use according to claim 1 of compounds of formula I indicated in claim 6, wherein Z represents phenyl substituted with phenyl, benzyloxy, phenoxy, pyridyloxy, phenylthio or pyridyldithium in the meta position and with chlorine, bromine, fluorine , cyano or nitro in the para position.
8. 8. The use according to claim 1 of compounds of formula I indicated in claim 5, in which Z represents phenyl monosubstituted with OHet, 0-lower alkyl-Het or NHCOHet in which Het represents pyridyl.
9. 9 -compounds of formula I indicated in claim 1, characterized in that - W, X, Y, R 1, R 2, R 3, R R, Ar, Het and n are as defined in claim 1 and Z represents aryl or heteroaryl substituted with: i) two or more substituents halogen, cyano, nitro, lower alkyl, halogen-lower alkyl, lower alkoxy, halogen-lower alkoxy, COR2, OCOR2, C02R2, OR2, S (0) nR2, NR2R3, N (R) CORs, Ar, Ar-lower alkyl, Het or Het-lower alkyl, and / or on adjacent carbon atoms with lower alkylenedioxy, - or with ii) an OHet substituent, O-lower alkyl-Het, N (R4) C0Het and NR2'R3 'in which R2' and R3 'together represent -CH = CH-CH = CH- OR -CH = N-CH = CH-; with the proviso that: a) when W and X represent methyl and Y represents an oxygen atom, then Z does not represent 2,4-dihydroxy-phenyl, 3,4-dimethoxy-phenyl, 4-benzyloxy-3,5- dimethoxy-phenyl, 4-hydroxy-3, 5-dimethoxy-phenyl, 3-hydroxy-4-methoxy-phenyl, 3,5-dichloro-2-hydroxy-phenyl, 4-hydroxy-3-methoxy-phenyl, 3, 4-methylenedioxy-phenyl or 2, 5-trimethoxy-phenyl; and b) when W and X represent methyl and Y represents NR1 in which R1 represents hydrogen, then Z does not represent 2, 5-dibenzyloxy-4-methyl-phenyl or 2,5-dihydroxy-4-methyl-phenyl-2.
10. 10. Compounds according to claim 9, characterized in that Z represents aryl or heteroaryl substituted with two or more substituents halogen, cyano, nitro, lower alkyl, halogen-lower alkyl, lower alkoxy, halogen-lower alkoxy, COR2, OCOR2, C02R2 , OR2, S (0) nR2, NR2R3, N (R4) C0Rs, Ar, Ar-lower alkyl, Het or Het-lower alkyl and / or on the adjacent carbon atoms with lower alkylenedioxyl; and R2, R3, R4 and Rs each individually represent hydrogen, lower alkyl, Ar, Ar-lower alkyl, Het or Het-lower alkyl, or R2 and R3 together represent the group -CH = CH-CH = CH-.
11. 11. Compounds according to claim 9 or claim 10, characterized in that W and X represent methyl.
12. 12. Compounds according to any one of claims 9 to 11, characterized in that Y represents NR1 in which R1 represents hydrogen.
13. 13. Compounds according to any one of claims 10 to 12, characterized in that Z represents phenyl substituted with Ar, OR2 or S (0) nR2 in the meta position, and with halogen, cyano or nitro in the para position.
14. 14. Compounds according to claim 13, characterized in that X represents phenyl substituted with phenyl, benzyloxy phenoxy, pyridyloxy, phenylthio or pyridylthio in the meta position and with chlorine, bromine, fluorine, cyano or nitro in the p: a position.
15. 15. Compounds according to any one of claims 9, 11 and 12, characterized in that Z represents phenyl monosubstituted with OHet, O-lower alkyl-Het or NHCOHet in which Het represents pyridyl.
16. 16. A compound of formula I according to claim 10 selected from the following: 9- (4-chloro-3-phenoxyphenyl) -3,4,6,7,, 10-hexahydro-3,3,6,6 -tetramethyl-1, 8 (2H, 5H) -acridindione; 9- (4-chloro-3-f-enyl thiofenyl) -3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione; and 9- (6-chloro-3-biphenylyl) -3, 4, 6, 7, 9, 10-hexahydro-3, 3, 6, 6-tetramethyl-l, 8 (2H, 5H) -acridindione.
17. 17. A compound of formula I according to claim 9, selected from the following: 9- [4-chloro-3- (4-pyridyloxy) phenyl] -3,4,6,7,8,1-hexahydro-3,3,6,6-tetramethyl-l, 8 (2H, 5H) - acridindione; 9- [4-chloro-3- (4-pyridylthio) phenyl] -3,4,6,7,8,1-hexahydro-3,3,6,6-tetramethyl-l, 8 (2H, 5H) - acridindione; and 9- (3-benzyloxy-4-nitrophenyl) -3,4,6,7,8,10-hexahydro-3,3,6,6-tetramethyl-l, 8 (2H, 5H) -acridindione.
18. 18. A process for the preparation of compounds of formula I claimed in any one of claims 9 to 17, characterized in that it comprises: a) for the preparation of a compound of formula I in which Y represents an oxygen atom, the reaction of an aldehyde of the general formula: Z-CHO (II) wherein Z has the meaning indicated in claim 9, with a cyclohexanedione derivative of the general formula. wherein W and X have the meaning given in claim 1, or b) for the preparation of a compound of formula I in which Y represents NR1 and R1 represents hydrogen, the reaction of an aldehyde of formula II or an acetal or hemiacetal thereof with a derivative of the cyclohexanedione of formula III and aqueous ammonia, or c) for the preparation of a compound of formula I in which Y represents NR1 and R1 represents hydrogen, lower alkyl or lower alkoxycarbonyl-lower alkyl, the reaction of an aldehyde of formula II or an acetal or hemiacetal thereof with a derivative of the cyclohexenone of general formula wherein W and X have the meanings given in claim 1 and R6 represents hydrogen, lower alkyl or lower alkoxycarbonyl-lower alkyl, or d) for the preparation of a compound of formula I in which Y represents NR1 and R1 represents lower alkoxycarbonyl, the reaction of a compound of formula I in which Y represents NR1 and R1 represents hydrogen with a lower alkyl chloroformate, or e) for the preparation of a compound of formula I in which Z contains an amino substituent or NHCOR5, the reduction of corresponding compound of formula I in which Z contains a nitro substituent, and if necessary, the acylation of the resulting compound of formula I in which Z contains an amino substituent, and if desired, the formation of a salt. 19 a rrBd arerrtD, catheterized because it contains an aa pussto according to any one of claims 1 to 8 and a pharmaceutically compatible filler for the treatment and prophylaxis of infections caused by the herpes simplex virus. twenty . Ui madicciiEntD, otetitr zpñ) prrqi-f *; Accept a duaud-db test with any one of claims 9 to 17 and a pharmaceutically compatible loading material. 21. Compounds according to any one of claims 9 to 17 for use as therapeutically active substances, especially for the treatment and prophylaxis of infections caused by the herpes simplex virus. 22. Compounds according to any one of claims 9 to 17, provided that they are prepared by the process claimed in claim 18 or by an obvious chemical equivalent thereof. SUMMARY OF THE INVENTION The invention relates to new and known tricyclic dione derivatives, of general formula: wherein W represents hydrogen or lower alkyl, - X represents lower alkyl, - Y represents an oxygen atom or NR1; R1 represents hydrogen, lower alkyl, lower alkoxycarbonyl or lower alkoxycarbonyl-lower alkyl; Z represents aryl or heteroaryl optionally substituted with one more substituent halogen, cyano, nitro, lower alkyl, halogen-lower alkyl, lower alkoxy, halogen-lower alkoxy, COR2, OCOR2, C02R2, OR2, S (0) nR2, NR2R3, N (R4) COR5, Ar, Ar-lower alkyl, Het or Het-lower alkyl and / or on the adjacent carbon atoms with lower alkylenedioxy, - R2, R3, R4 and Rs each represent each substituents hydrogen, lower alkyl, Ar , Ar-lower alkyl, Het or Het-lower alkyl, or R2 and R3 together represent the group -CH = CH-CH = CH- or -CH = N-CH = CH-, - Ar represents aryl optionally substituted with one or plus halogen, lower alkyl, lower alkoxy or nitro substituents, -Het represents heteroaryl optionally substituted with one or more halogen substituents, lower alkyl, lower alkoxy or nitro, - and n represents 0, 1 or 2 and its salts, which are inhibitors of thymidine herpes simplex virus kinase, in the treatment and prophylaxis of infections caused by the herpes simplex virus.