HIV-INHIBITING BENZENEACETAMIDE DERIVATIVES

Abstract: A compound for use as a medicine having formula (I), a pharmaceutically acceptable acid addition salt form or a stereochemically isomeric form thereof, wherein R<1> and R<2> each independently are hydrogen, C1-6alkyl or C3-6cycloalkyl; or R<1> and R<2> taken together with the nitrogen atom bearing said R<1> and R<2> may form a pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or 4-C1-4alkylpiperazinyl group; X is O or S; R<3> is hydrogen or C1-6alkyl; R<4>, R<5> and R<6> each independently are hydrogen, halo, C1-6alkyl, C1-6alkyloxy, nitro, trifluoromethyl, cyano, aminomethyl, carboxyl, C1-4alkyloxycarbonyl, C1-4alkyl-carbonyl, aminocarbonyl or hydroxy; R<7> is hydrogen or halo; and R<8>, R<9> and R<10> each independently are hydrogen, halo, C1-6alkyl, C1-6alkyloxy, nitro, hydroxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (trifluoromethyl)carbonyl, aminocarbonyl, (cyclopropyl)carbonyl or a radical C1-6alkyl-(C=Y)- wherein =Y represents =O, =N-OH, =N-OCH3, =N-NH2 or =N-N(CH3)2; provided that (1) R<1> is other than n-propyl when R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<9> and R<10> represent hydrogen, R<8> represents 4-ethoxy and X represents oxygen, and (2) X is other than sulfur, when R<1>, R<2>, R<3>, R<6>, R<7>, R<8>, R<9> and R<10> represent hydrogen and R<4> and R<5> represent 3,4-dimethoxy. Novel compounds, pharmaceutical compositions containing said compounds of formula (I), and processes for preparing said compositions.

Description: HIV-INHIBΓΠNG BENZENEACETAMIDE DERIVATIVES Background of the invention In US-4,246,429 corresponding to EP-A-0,006,713 there are described a number of benzeneacetamides and thioamides being useful as intermediates in the preparation of phytopharmaceutical compounds. Unexpectedly, it has now been found that some of these intermediates effectively inhibit the replication of HTV and consequently may be useful for the treatment of individuals infected by HIV. Moreover, closely related, but hitherto undisclosed compounds were found to inhibit the replication of the retrovirus even better. Further, in GB- A- 1 ,423,430 there are disclosed benzenethioacetamide compounds , more specifically α-(phenylamino)-3,4-dimethoxybenzenethioacetamide, said compounds having anti-secretory activity. In Archives Internationales de Pharmacodynamie et de Therapie, 1966, 164(2), 321- 330 there are disclosed alkoxybenzene acetamide derivatives, in particular α-[(4-ethoxy- phenyl)amino]-M-propylbenzeneacetamide, said compounds having analgesic properties. Description of the invention The present invention is concerned with compounds for use as a medicine having the formula the pharmaceutically acceptable acid addition salt forms and the stereochemically isomeric forms thereof, wherein R 1 and R 2 each independently are hydrogen, Cj.galkyl or C3_6cycloalkyl ; or R- and R 2 taken together with the nitrogen atom bearing said R-* and R 2 may form a pyrrolidinyl, piperidinyl, moipholinyl, piperazinyl or 4-C-j galley lpiperazinyl group; X is O or S; R*-- is hydrogen or C^galkyl; R 4 , R5 and R^ each independendy are hydrogen, halo, Cj.galkyl, C^alkyloxy, nitro, trifluoromethyl, cyano, aminomethyl, carboxyl, Cj^alkyloxycarbonyl, Ci^alkyl- carbonyl, aminocarbonyl or hydroxy; R7 is hydrogen or halo; and R*-*, R9 and R-*0 each independently are hydrogen, halo, Ci.galkyl, C^alkyloxy, nitro, hydroxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (trifluoromethyl)carbonyl, aminocarbonyl, (cyclopropyl)carbonyl or a radical wherein =Y represents =0, =N-OH, =N-OCH 3 , =N-NH2 or =N-N(CH 3 ) 2 ; provided that (1) R 1 is other than n-propyl when R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R9 and R- Q represent hydrogen, represents 4-ethoxy and X represents oxygen, and (2) X is other than sulfur, when R 1 , R 2 , R 3 , R6, R7, 8 5 R 9 an d R 10 represent hydrogen and R 4 and R**-" represent 3,4-dimethoxy. The compounds of formula (I) wherein at least one of R- and R 2 is hydrogen may also exist in their tautomeric form. Said form although not explicitly indicated herein- above is intended to be included within the scope of the present invention. In the foregoing definitions the term halo defines fluoro, chloro, bromo and iodo; Cι_4_dkyl defines straight and branched saturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2*-methylpropyl and 1,1-dimethylethyl; Ci-^alkyl defines Cι- 4 alkyl and the higher homologs thereof having 5 or 6 carbon atoms; C3^cycloalkyl defines cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Pharmaceutically acceptable addition salts as mentioned hereinabove comprise the therapeutically active non-toxic addition salt forms which the compounds of formula (I) are able to form. Said salt forms can conveniendy be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohaUc acid, e.g. hydrochloric, hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-l,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be convened by treatment with alkali into the free base form. The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and die like. Particular compounds are those compounds of formula (I) as defined hereinabove wherein R 4 , R and R each independentiy are hydrogen, halo, Ci^alkyl, C j .βalkyloxy , nitro or hydroxy; R 7 is hydrogen, R 8 , R 9 and R-® each independendy are hydrogen, halo, Cj^alkyl, C^galkyloxy, nitro, hydroxy, trifluorome oxy, 2,2,2-trifluoroethoxy, (trifluoromethyl)carbonyl, aminocarbonyl, (cyclopropyl)carbonyl, or a radical Cι.5alkyl-C(=Y)- wherein =Y represents =0, =NOH, =NOCH 3 , or =N-N(CH3>2. Interesting compounds for use in the method according to the present invention are those compounds of formula (I) wherein R- and R 2 are each independently hydrogen; and/or X is oxygen; and/or R 4 , R-5 and R are each independently hydrogen, halo, .^alkyloxy or nitro; and/or R 7 is hydrogen; and/or R 8 , R 9 and R-® are eac h independendy hydrogen, halo, Cj.5aU.yl, Cj^alkyloxy, nitro, trifluoromethoxy or Cl-5aUcylcarbonyl. More interesting compounds are those interesting compounds wherein R- and R 2 are each independendy hydrogen; and/or R 3 is hydrogen; and/or R 4 , R-- 5 and R-*** are each independendy hydrogen, halo, memoxy or nitro; and/or R 8 , R 9 and R\- are each independendy hydrogen, halo, methyl, methoxy, nitro, trifluoromethoxy or methylcarboπyl. Particularly interesting compounds are those interesting compounds wherein R 1 and R 2 are hydrogen; R 4 represents 2-chloro or 4-methoxy, R 5 , R 6 and R 7 being hydrogen; or R 4 and R 5 represent 2,6-dichloro, 2,4-dichloro or 3,4-dimethoxy, R 6 and R 7 being hydrogen; or R 4 , R 5 and R 6 represent 2,6-dichloro-3-nitro or 2,3,6-trichloro; R 7 being hydrogen; or R 4 , R 5 , R 6 and R 7 represent 2,3,6-trichloro-4-trifluoromethyl; and/or R 8 represents hydrogen, chloro, methyl, methoxy, nitro, trifluoromethoxy or methyl- carbonyl, R 9 and R 10 being hydrogen; or R 8 and R 9 represent 2,4-dimethyl, 2,5-di- methyl, 2,4-dichloro, 2,6-dichloro, 3,5-dichloro, 2-hydroxy-5-chloro, 2-methoxy-5- chloro, 2-nitro-5-chloro, 2-nitro-5-methyl, 2-methoxy-5-methyl, 2-methylcarbonyl-5- methyl, 2-methylcarbonyl-5-chloro, 2-methylcarbonyl-5-fluoro or 2-chloro-4-nitro, R-® being hydrogen. The most interesting compounds widiin the present invention are those wherein R 4 and R*- * represent 2,6-dichloro, R-**- and R 7 being hydrogen; or R 4 , R** 5 and R**-* represent 2,3,6-trichloro; R 7 being hydrogen; R 8 represents 2-med oxy, 2-nitro, 2-methyl- carbonyl, 2-trifluoro-methoxy, 3-methyl, R 9 and R-® being hydrogen; or R 8 and R 9 represent 2-methoxy-5-methyl, 2-nitro-5-chloro, 2-nitro-5-methyl, 2-methoxy-5-chloro, 2-methy lcarbonyl-5-methyl, 2-methy lcarbonyl-5-fluoro or 2-methylcarbonyl-5-chloro, R- Q being hydrogen. Preferred compounds are (-)-α-[(2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-α-[(5-methyl-2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-α-[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-α-[(2-acetyl-5-methylphenyl)amino]-2,6-dichlorobenzeneacetamide, α-[(2-acetyl-5-chlorophenyl)amino]-2,6-dichlorobenzeneacetamide, α-[(5-chloro-2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, and α-[(2-acetyl-5-fluorophenyl)amino]-2,6-dichlorobenzeneacetamide. An additional feature of the present invention comprises the fact that a number of the compounds of formula (I) are deemed novel and have especially been developed for use in die method according to the present invention. An interesting subgroup of novel compounds is formed by die compounds of formula die phaπmaceuticaUy acceptable acid addition salt forms and die stereochemically isomeric forms thereof, wherein R 4 represents halo, Ci-6alkyl, Cι_5alkyoxy or nitro; R 5 and R 6 each independently represent hydrogen, halo, Ci.galkyl, C^alkyloxy, nitro, trifluoromethyl, cyano, aminomethyl, carboxyl, carbonyl, aminocarbonyl or hydroxy; R 7 represents hydrogen or halo; R 8 represents Ci-6alkyloxy, nitro, trifluoromemoxy, 2,2,2-trifluoroedιoxy, (trifluoromethyl)carbonyl, aminocarbonyl, (cyclopropyl)carbonyl or a radical Cι.6alkyl-(C=Y)- wherein =Y represents =0, =N-OH, =N-OCH , =N-NH 2 or =N-N(CH 3 ) 2 , and R 9 and R-® each independendy are hydrogen, halo, C^alkyl, Ci^alkyloxy. nitro, hydroxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (trifluoromethyl)carbonyl, aminocarbonyl, (cyclopropyl)carbonyl or a radical Cι_6alkyl-(C=Y wherein =Y represents =0, =N-OH, =N-OCH 3 , =N-NH 2 or =N-N(CH 3 ) 2 ; provided that R 8 is otiier than 2-memoxy when R 4 is chloro, R*- 5 is 6-chloro, R-*- 1 , R 7 and R 9 are hydrogen and R-® is hydrogen or 5-medιyl. An interesting subgroup of novel compounds is formed by die compounds of formula (I) or of formula (I-a) wherein the asymmetric carbon atom bearing the amide group has me same absolute configuration as in (- α-[(2-nitrophenyl)amino]-2,6-dichloro- benzeneacetamide. Anodier subgroup of novel compounds is formed by the compounds of formula (I) or of formula (I-a) wherein the asymmetric carbon atom bearing the amide group has die reversed absolute configuration as in (-)-α-[(2-nitrophenyl)amino]-2,6-dichloro- benzeneacetamide. Novel compounds of particular interest are those novel compounds wherein R 4 is halo or Ci-6alkyl; R** 5 and R*> arc hydrogen, halo or Ci-6alkyl; R 7 is hydrogen or chloro; R 8 is Ci-6alkyloxy, trifluoromethoxy, nitro or Ci-6alkylcarbonyl; R 9 and R-® are hydrogen, halo or Ci-6alkyl. The most interesting novel compounds are diose wherein R 4 is chloro or methyl; R 5 is hydrogen, chloro or mediyl; R-*> is hydrogen or chloro; R 7 is hydrogen, R 8 is methoxy, trifluoromethoxy, nitro or methylcarbonyl; R 9 is hydrogen, chloro, fluoro or mediyl; and R-® is hydrogen. Preferred novel compounds are diose wherein R 4 is chloro; R 5 is 6-chloro or 6-methyl; R 6 is hydrogen or 3-chloro; R 7 is hydrogen; R 8 is methoxy, trifluoromethoxy, nitro or methylcarbonyl; R 9 is hydrogen, 5-chloro, 5-fluoro or 5-methyl; and R 10 is hydrogen. The most preferred novel compounds are (-)-α-[(2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-α-[(5-methyl-2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-α-[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-α-[(2-acetyl-5-med ylphenyl)amino]-2,6-dichlorobenzeneacetamide, α-[(2-acetyl-5-chlorophenyl)amino]-2,6-dichlorobenzeneacetamide, α-[(5-chloro-2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, and α-[(2-acetyl-5-fluorophenyl)amino]-2,6-dichlorobenzeneacetamide. The compounds of formula (I) and die compounds of formula (I-a) can generally be prepared following art-known procedures such as, for example, the procedures described in US-4,246,429 and alternative procedures known in the art. The most interesting processes are described hereinbelow in more detail for the compounds of formula (I). Obviously, similar process for the preparation of die novel compounds of formula (I-a) are intended to be included thereby. The compounds of formula (I) can generaUy be prepared by alkylating an appropriate aniline derivative of formula (II) or a salt thereof, with an alkylating reagent of formula (III) foUowing art-known H-a cylation procedures. In formula (HI) and hereinafter W represents a reactive leaving group such as, for example, halo, e.g. chloro, bromo or iodo, a sulfonyloxygroup, e.g. methanesulfonyl- oxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, 4-methylbenzenesulfonyloxy, naphdialenesulfonyloxy and d e like reactive leaving groups. In formula (II). R^ represents hydrogen or Ci-6alkyl and may also represent formyl (-CHO). Said formyl derivatives are particularly useful for preparing salt forms of the intermediates of formula (II). In the subsequendy obtained for ylated end-products of formula (I) the formyl group may be replaced by hydrogen by hydrolysis or alternatively may be reduced to methyl following conventional reduction procedures. Said H-alkylation reaction can conveniently be carried out by stirring die reactants, optionaUy in a reaction-inert solvent such as, for example, water, an aromatic solvent, e.g. benzene, methylbenzene, dimethylbenzene, chlorobenzene, metiioxybenzene and d e like; a C^alkanol, e.g. methanol, edianol, 1-butanol and die like; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone and die like; an ester, e.g. ethyl acetate, γ-butyro- lactone and the like; an ether, e.g. l.l'-oxybisethane, tetrahydrofuran, 1,4-dioxane and die like; a dipolar aprotic solvent, e.g. Hvti-dimethylformamide, M,M-dimetiιyl- acetamide, dimediylsulfoxide, pyridine, l,3-dimediyl-3,4,5,6-tetrahydro-2(lH)- pyrimidinone, l,3-dimedιyl-2-imidazolidinone, 1,1,3,3-tetramed ylurea, l-methyl-2- pyrrolidinone, nitrobenzene, acetonitrile and die like; or a mixture of such solvents. The addition of an appropriate base such as, for example, an alkali metal or an earth alkaline metal carbonate, hydrogen carbonate, hydroxide, oxide, carboxylate, alkoxide, hydride or amide, e.g. sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium medioxide, sodium hydride, sodium amide and the like, or an organic base such as, for example, an amine, e.g. ____• diethyletiianamine, ϋ-(l-methylethyl)-2-propanamine, 4-edιylmorpholine, l,4-diazabicyclo[2.2.2]octane, pyridine and the like, may optionally be used to pick up the acid which is formed during die course of die reaction. Usually, it is advantageous to convert d e formylated intermediate of formula (II) first into a suitable salt form thereof such as, for example, an alkali, eartii alkaline metal salt, by reacting (II) with an appropriate base as defined hereinabove, and subsequendy using said salt form in the reaction with the alkylating reagent of formula (HI). Said alkali, earth alkaline metal can be for example, sodium, potassium, lithium, calcium, and die like. In some instances die addition of a iodide salt, preferably an alkali metal iodide, or a crown ether, e.g. 1,4,7,10,13,16-hexaoxacyclooctadecane and die like, may be appropriate. Stirring and elevated temperatures enhance the rate of the reaction; more in particular the reaction may be conducted at d e reflux temperature of the reaction mixture. Additionally, it may be advantageous to conduct said alkylation under an inert atmosphere such as, for example, oxygen-free argon or nitrogen gas. Alternatively, said alkylation may be carried out by applying art-known conditions of phase transfer catalysis reactions. Said conditions comprise stirring die reactants, with an appropriate base and optionally under an inert atmosphere as defined hereinabove, in the presence of a suitable phase transfer catalyst such as, for example, a trialkylphenyl- methylammonium, tetraalkylammonium, tetraalkylphosphonium, tetraarylphosphonium halide, hydroxide, hydrogen sulfate and d e like catalysts. Elevated temperatures may be appropriate to enhance the rate of die reaction. An efficient alternative for the foregoing M-alkylation reactions comprises heating an intermediate of formula (HI) in an excess of the aniline derivative of formula (II) in die absence of any solvent The reaction is conducted by stirring and heating die mixture to a temperature effecting complete dissolution of d e reagents. In all of the foregoing and in die following preparations, die reaction products may be isolated from the reaction mixture and, if necessary, further purified according to methodologies generally known in the art. The compounds of formula (I) wherein R- and R 2 are hydrogen, said compounds being represented by formula (I-b) when X is O and by formula (I-c) when X is S, can be prepared by reacting a nitrile of formula (IV) with a reagent H 2 X (V), namely water or hydrogen sulfide, under appropriate conditions. 8 The hydrolysis of die nitrile (IV) to the corresponding amide (I-b) wherein X is O, can easily be carried out following art-known procedures. Preferably said hydrolysis is carried out at room temperature in a concentrated strong acid, e.g. concentrated sulfuric acid, hydrochloric acid, hydrobromic acid, formic acid saturated widi hydrochloric acid and die like, optionally in the presence of a smaU amount of water. The nitrile (TV) can conveniendy be converted into the tiiioamide (I-c) wherein X is S by reaction widi hydrogen sulfide in an appropriate solvent, e.g. pyridine, a mono-, di- σr trimediylated pyridine and die like solvents, and in the presence of an appropriate base such as an amine, e.g. H . _S-diethylethanamine, 1-methylmorpholine, N-(l-methylethyl)- 1-methyledιanamine and the like. This latter reaction can conveniendy be conducted at room temperature and in some instances even at lower temperatures such as, for example, between about 0°C and room temperature. The tiiioamide compounds of formula (I-c) can conveniendy be converted into the corresponding amides of formula (I-b) by reaction widi an oxidizing reagent such as, for example, hydrogen peroxide in water, optionally in admixture with a reaction-inert organic co-solvent. The compounds of formula (I) wherein wherein X is O and at least one and possibly several of R 8 , R 9 and R * -" represent electron-widdrawing groups such as, for example, halo, nitro or Ci-6alkyloxy, said compounds being represented by formula (I-d) , may be prepared by -ar lating an intermediate of formula (VI) widi an appropriate benzene derivative of formula (VII). (vi) (vπ) In formula (VII) W-* represents a reactive leaving group, such as, for example, halo, Ci-6alkyloxy, aryloxy, (Ci-5alkyl or aryl)sulfonyloxy, (Ci-6alkyl or aryl)sulfonyl, Ci-6alkyldιio or nitro, preferably fluoro, chloro, nitro, 4-medιylbenzenesulfonyloxy, methoxy or methyldiio. Said arylation reaction can conveniendy be carried out following die procedures described hereinbefore for die alkylation reaction of intermediate (II) with intermediate (HI). More in particular, the reactants may be stirred, preferably at a somewhat elevated temperature and in particular at the reflux temperature, in the presence of a base as defined in die above-mentioned alkylation reaction, in an appropriate solvent such as, for example, a dipolar aprotic solvent, e.g. ££ Ji-dimediylformamide, £Lϋ-dimethylacetamide, dimediylsulfoxide, l-methyl-2-pyrrolidinone, acetonitrile, pyridine, hexamethylphosphor triamide; an alcohol, e.g. 1-butanol; an etiier, e.g. tetrahydrofuran, l,l'-oxybisethane, 1,4-dioxane and the like; and mixtures of such solvents. Phase transfer catalysis conditions may equally weU be employed in the above arylation reaction. Further, the compounds of formula (I) wherein X is O, said compounds being represented by formula (I-e), may also be obtained by amidation of die corresponding carboxylic acids or suitable reactive functional derivatives thereof, of formula (Vm). In (Vπi) L may represent hydroxy, Ci^aU yloxy, phenoxy (optionally further substi¬ tuted), lH-imidazolyl, (Cι.6alkyl orphenyl)oxycarbonyloxy, halo, and the like reactive leaving groups. Said preparation of the amides of formula (I-e) can conveniendy be carried out following art-known amidation and transamidation reactions. For example, said amides can be prepared by reacting an appropriate carboxylic acid (L is OH) with an amine (DC) in the presence of a reagent capable of promoting amidation reactions. Typical examples of such reagents are for example, dicyclohexylcarbodiimide, 2-chlσro-l-methylpyri- dinium iodide, phosphorus pentoxide, l,l'-carbonylbis[lH-imidazole], l.l'-sulfonyl- bis[lH-imidazole] and die like reagents. Alternatively, said carboxylic acids may be converted into a suitable reactive functional derivative thereof such as, for example, an acyl halide, symmetric or mixed anhydride, ester, amide, acyl azide and die like derivatives, before reaction widi the amine HNR-^R 2 . Said reactive functional derivatives may be prepared foUowing art known methods, for example, by reacting die carboxylic acid widi a halogenating reagent such as, for example, thionyl chloride, phosphorous trichloride, polyphosphorous acid, phosphoryl chloride, oxalyl chloride and the like, or by reacting said carboxylic acid widi an acyl halide such as acetyl chloride, ediyl chloroformate and me like. A particularly interesting method for preparing the amides wherein R 3 is hydrogen comprises reacting a suitable carboxylic acid derivative with a carbonate forming reagent such as, for example, carbonoic dichloride, trichloromethyl chloroformate, l, -carbonylbis[lH-imidazole], di(Ci-6alkyl)carbonate and die like, thus yielding a cyclic anhydride of formula (VHI-a), and subsequendy reacting said cyclic anhydride widi the amine R R 2 NH. Said reactive functional derivatives of die carboxylic acids may be generated in situ, or if desired, be isolated and further purified before reacting diem widi die amine HNR--R 2 . Amidation of said reactive functional derivatives can conveniendy be carried out by stirring the reactants, optionaUy in a suitable reaction-inert solvent such as, for example, a halogenated hydrocarbon, e.g. dichloromediane, trichloromediane and die like; an aromatic hydrocarbon, e.g. benzene, methylbenzene and die like ; an ether, e.g. l,l'-oxybisethane, tetrahydrofuran and die like ; or a dipolar aprotic solvent, e.g. H-dimethylformamide, ϋ-M-dimediylacetamide, pyridine and the like. In some instances it may be appropriate to employ an excess of one of die reagents as solvent. The water, acid, alcohol or amine which may be liberated during d e course of die reaction can be removed from the reaction mixture by art-known procedures such as, for example, azeotropical distiUation, complexation, salt formation and the like metiiods. In some instances particularly the addition of a suitable base such as, for example, an amine, e.g. H, -diethylethanamine, 4-ethylmorpholine, pyridine or H » H-dimethyl- 4-pyridinamine, may be appropriate. Further, in order to enhance the rate of the reaction, said amidation reaction may advantageously be conducted at a somewhat elevated temperature, in particular die reflux temperature of the reaction mixture. The compounds of formula (I) can also be converted into one anodier following art- known functional group transformation reactions. For example, the compounds wherein one of R , R 9 or R 10 represents a radical wherein Y represents =N-OH, =N-OCH 3 , =N-NH or =N-N(CH 3 ) 2 , can be prepared following art-known procedures from the corresponding compounds wherein Y represents =0 by reaction with hydroxylamine, Q-methylhydroxylamine, hydrazine or di(medιyl)hydrazine or a suitable addition salt form thereof. The compounds of this invention have at least one asymmetric carbon atom in dieir structure, namely the carbon atom bearing the amide or tiiioamide group. Said chiral center and any odier chiral center which may be present, can be indicated by die stereochemical descriptors R and S. Pure stereochemicaUy isomeric forms of die compounds of formula (I) may be obtained by die application of art-known procedures. Diastereoisomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g. counter current distribution, liquid chromatography and die like; and enantiomers may be separated from each other foUowing art-known resolution methods, for example, by die selective crystallization of dieir diastereomeric salts widi chiral acids. Pure stereochemicaUy isomeric forms may also be derived from die corresponding pure stereochemicaUy isomeric forms of the appropriate starting materials, provided that die reactions occur stereospecifically. Preferably, if a specific stereoisomer is desired, said compound wUl be syndiesized by stereospecific methods of preparation. These methods wiU advantageously employ enantiomericaUy pure starting materials. StereochemicaUy isomeric forms of the compounds of formula (I) are obviously intended to be included widiin the scope of die invention. The compounds of formula (I) as prepared in the above described processes are generaUy racemic mixtures of enantiomers which can be separated from one another foUowing art-known resolution procedures. The racemic compounds of formula (I) which are sufficiendy basic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequendy separated, for example, by selective or fractional crystaUization and die enantiomers are liberated therefrom by alkaline or acidic hydrolysis. A preferred manner of separating die enantiomeric forms of the compounds of formula (I) involves Uquid chromatography using a chiral stationary phase such as suitably derivatized ceUulose, for example, tri(dimethylcarbamoyl)ceUulose (Chiracel OD®) and simUar chiral stationary phases. As an alternative to the above-mentioned resolution of die compounds of formula (I), there should be mentioned also the resolution of racemic intermediates. Particularly useful intermediates for this purpose are the aminoacids of formula which can easdy be obtained from the corresponding benzene(thio)acetamide compounds of formula (I) by acidic or, preferably, alkaline hydrolysis, for example, by treatment with an aqueous solution of a base such as sodium or potassium hydroxide, in admixture widi a suitable organic solvent such as, for example, an alkanol, e.g. methanol, edianol and d e like. The thus obtained aminoacids of formula (Vlll-b) can conveniendy be resolved by formation of the corresponding diastereomeric salt forms by reaction with a suitable chiral base such as phenylethanamine, naphthyledianamine, cinchonine and otiier alkaloid bases. Obviously, said aminoacids may also be resolved by Uquid chromatography using an appropriate chiral stationary phase. The enantiomeric forms of the aminoacids of formula (Vlll-b) are converted into die enantiomeric forms of die benzene(tiιio)acetamide compounds of formula (I) according to die procedures described hereinbefore for converting die intermediates of formula (Vπi) into the compounds of formula (I). Other interesting, novel intermediates or derivatives of the racemic compounds of formula (I) for resolution by liquid chromatography are, for example, the iminoethers of formula (VIII-c) and the derivatives of formula (VlH-d) Some of the intermediates of formula (VIII-c) and (Vlll-d) are particularly interesting due to their relatively greater solubUity thus allowing one to load more racemic material on die chiral stationary phase. The intermediates of formula (VIII-c) can be prepared from the nitriles of formula (IV) by alcoholysis with an alcohol ROH wherein R represents Chalky! or phenyl, in die presence of dry hydrochloric acid. After resolution by Uquid chromatography, die separated enantiomers of formula (VIII-c) are converted into die corresponding enantiomeric amides of formula (I-b), by hydrolysis of die iminoether in an aqueous acidic medium to the carboxyUc acid and further conversion as described hereinabove. In the intermediates of formula (Vm-d) X represents a radical of formula -CH 2 OH or -CH N(CH 3 ). Said intermediates can easUy be prepared from the amides of formula (I-b) by reaction with formaldehyde or [(CH 3 )2N=CH2] + C1" following art-known procedures. Thermolysis of the separated enantiomers yields the corresponding enantiomeric amides of formula (I-b). A number of the intermediates and starting materials employed in the foregoing preparations are known compounds which can be prepared according to art-known methodologies ofpreparing said or siπύlar compounds. Some intermediates are less common or are novel, and a number of preparation metiiods wiU therefore be described hereinafter in more detaU. The intermediates (HI) wherein X is O, may be obtained from α-hydroxy benzeneacetic acid derivatives of formula (X) by reaction with a halogenating reagent such as, for example, phosphorus pentachloride, phosphoryl chloride, phosphorous trichloride, phosphorous tribromide, diionyl chloride and die like, or anodier activating reagent such as, for example, a sulfonylhalide. Said reaction can be conducted at an elevated temperature, in particular the reflux temperature of the reaction mixture, in an excess of the halogenating reagent as solvent, which may optionaUy be diluted widi a suitable reaction-inert solvent such as an aromatic hydrocarbon, a halogenated hydrocarbon, an etiier and die like solvents. The tiius obtained benzeneacetyl halide is conveniendy converted into the desired benzeneacetamide by pouring the reaction mixture into an aqueous or alcoholic solution comprising an amine of formula HNR--R 2 (DC). The intermediates of formula (IV-a) can be prepared by reacting an appropriate benzaldehyde (XII) with an anUine of formula (XI) in the presence of a cyanide salt and a suitable solvent. As examples of cyanide salts there may be mentioned alkaU metal and earth alkaline metal cyanides, e.g., sodium and potassium cyanide. Suitable solvents comprise, for example, water, alkanols, e.g. methanol, ethanol and die like, carboxylic acids, e.g. acetic acid, particularly glacial acetic acid, propanoic acid and die like; or a mixture of such solvents. Said reaction is conveniendy carried out by stirring at room temperature and, if desired, sUghtly heating the reactants, for example between 40°C and 60°C, in particular at about 50°G In some instances it is advantageous to carry out said reaction in die presence of a metal salt such as, for example, anhydrous zinc chloride and the like, in a non-aqueous solvent, particularly glacial acetic acid, as described in Chem. Ber., 98, 3902 (1965). Alternatively, the intermediates of formula (IV-a) can also be prepared by converting a N-arylbenzamide (XIII) into an imidoyl chloride (XIV) with a halogenating reagent, reacting said imidoyl haUde widi a cyanide salt and reducing die thus obtained α-iminonitrile (XV). Said imidoyl haUde can be prepared by reacting (XIII) with a halogenating reagent such as, for example, phosphorus pentachloride, phosphoryl chloride, phosphorous trichloride, phosphorous tribromide, tiiionyl chloride and die like, in a suitable solvent, such as for example, a halogenated hydrocarbon, e.g. dichloromethane, trichloro- methane; an ether, e.g. tetrahydrofuran, l,l'-oxybisethane, 1,4-dioxane and the like; or a mixture of such solvents; or in an excess of the halogenating reagent, optionally in admixture with one or more of the cited solvents. The substitution reaction of halo by cyano can be carried out in a reaction-inert solvent with a cyanide salt such as described hereinabove in the preparation of (TV-a) from the aldehyde (XII). Preferably said substitution is carried out under phase-transfer catalysis conditions in a two-phase solvent system as described in Synthesis 1978, p. 894. The dius obtained intermediate (XV) then is reduced to (IV-a) in the presence of an appro¬ priate reducing agent such as, for example, sodium borohydride, litiiium borohydride, sodium cyanoborohydride, Uthium aluminum hydride and die like reducing agents. A number of the intermediates of formula (TV) are deemed novel. An interesting subgroup of novel intermediates of formula (IV) is formed by die intermediates of formula and the stereochemicaUy isomeric form thereof, wherein R 4 represents halo, Cι_6alkyl, C^alkyloxy, nitro or hydroxy; R 5 and R^ each independently represent hydrogen, halo, C^galkyl, C^alkyloxy, nitro, trifluoromethyl, cyano, aminomethyl, carboxyl, Cι.4alkyloxycarbonyl, C^alkyl- carbonyl, aminocarbonyl or hydroxy; R 7 represents hydrogen or halo; R 8 represents Ci-6aUcyloxy, nitro, trifluoromemyloxy, 2,2,2-trifluoroethoxy, (trifluoromethyl)carbonyl, aminocarbonyl, (cyclopropyl)carbonyl or a radical C 1 .6alkyl-(C=Y)- wherein =Y represents =0, =N-OH, =N-OCH , =N-NH 2 or =N-N(CH 3 ) 2 , and R 9 and R**0 each independendy are hydrogen, halo, C^alkyl, Ci^alkyloxy, nitro, hydroxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (trifluoromethyl)carbonyl, aminocarbonyl, (cyclopropyl)carbonyl or a radical wherein =Y represents =0, =N-OH, =N-OCH 3 , =N-NH 2 or =N-N(CH 3 ) 2 ; provided that R 8 is other than 2-methoxy when R 4 is chloro, R$ is 6-chloro, R-*\ R 7 and R 9 are hydrogen and -® is hydrogen or 5-metiιyl. The intermediates of formula (VI) can conveniendy be prepared from a suitable carboxyUc acid derivative wherein L is as defined in (VIII) by reaction with an amine HNRlR 2 (DC). (xrv) Alternatively, die intermediates (VI) wherein R- and R 2 are hydrogen can be prepared by hydrolysis of ah intermediate (XV) foUowing die procedures described hereinbefore for the preparation of compound (I-b). An alternative metiiod for converting die intermediates of formula (XV) into the intermediates of formula (Vl-a) comprises stirring the intermediate of formula (XV) in an alkanol such as methanol, in die presence of a ketone such as acetone or cyclohexanone (R(C=0)-R) and a catalytical amount of a base such as sodium methoxide and the like. The dius obtained cycUc intermediate (XVI), which may rearrange to an intermediate of formula (XVH) is then hydrolysed to an intermediate of formula (Vl-a) by heating in water. Obviously, the intermediates of formula (XV) can easUy be obtained from benzaldehydes of formula (XH) by reaction widi an appropriate amine R3-NH 2 and cyanide as described hereinbefore for the preparation of the intermediates (IV-a). A number of the amlines of formula (XI) are novel and have especially been prepared for use in die present invention. For example, die intermediates of foπnula (Xl-a) wherein R 8 represents Cι_5alkyl-C(=0)- can be prepared from a nitrile (XVIII-a) or carboxylic acid of formula (XVIII-b), via die acyl chloride (XDC) which is reacted with an organometaUic reagent such as C^alkyl magnesium halide or a dialkyl-2-Cι_^alkyl-l,3-propanedioate magnesium salt. The latter yields a malonic ester derivative which is converted into (XX) by acid hydrolysis and concomitant decarboxylation. Reduction of the nitro group yields intermediate (Xl-a). Intermediates of formula (Xl-b) wherein R 8 represents (cyclopropyl) carbonyl can be prepared from a 2-fluorobenzenenitirile (XXI) by reaction with the Grignard reagent derived from cyclopropane bromide, foUowed by nucleophUic aromatic substitution of fluoro and hydrogenolysis of the benzyl group. The aldehydes of formula (XII) can generaUy be prepared from the corresponding toluene derivatives (XXII) by bromination, hydrolysis and oxidation. The compounds of formula (I) show antiretroviral properties, in particular against Human Immunodeficiency Virus (HTV), also known as LAV, HTLV-m or ARV, which is the etiological agent of Acquired Immune Deficiency Syndrome (AIDS) in humans. The HTV virus preferentiaUy infects human T-4 ceUs and destroys them or changes their normal function, particularly die coordination of die immune system. As a result, an infected patient has an everdecreasing number of T-4 cells, which moreover behave abnormaUy. Hence, the immunological defense system is unable to combat infections and neoplasms and the HTV infected subject usually dies by opportunistic infections such as pneumonia, or by cancers. Other conditions associated with HTV infection include thrombocytopaenia, Kaposi's sarcoma and infection of the central nervous system characterized by progressive demyeUnation, resulting in dementia and symptoms such as, progressive dysarthria, ataxia and disorientation. HIV infection further has also been associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL) and AIDS-related complex (ARC). Due to their antiretroviral properties, especiaUy their anti-HTV properties, die compounds of formula (I), dieir pharmaceutically acceptable salts and the stereo¬ chemicaUy isomeric forms diereof, are useful in die treatment of individuals infected by HTV and for the prophylaxis of individuals. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses whose existence is mediated by, or depends upon, the enzyme reverse transcriptase. Conditions which may be prevented or treated widi the compounds of die present invention, especially conditions associated with HTV and odier pathogenic retroviruses, include AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as, for example HTV mediated dementia and multiple sclerosis. Additionaly, it has been found that also die intermediates of formula (IV) show antiretroviral properties, in particular against HTV. In view of their pharmacological properties, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. Said pharmaceutical forms or compositions are deemed novel and consequendy constitute another aspect of the present invention. Also the preparation of said compositions constitutes a further aspect of the present invention. To prepare the pharmaceutical compositions of this invention, an effective amount of the active ingredient is combined in intimate admixture with a pharmaceuticaUy acceptable carrier. These pharmaceutical compositions are desirably in unitary dosage form suitable, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of die usual pharmaceutical media may be employed, such as, for example, water, glycols, oUs, alcohols and the Uke, in die case of oral Uquid preparations such as suspensions, syrups, elixirs and solutions; or soUd carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and die Uke in die case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form. For parenteral compositions, die carrier wiU usuaUy comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate Uquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, me carrier optionaUy comprises a penetration enhancing agent and or a suitable wettable agent, optionaUy combined widi suitable additives. It is especiaUy advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce die desired tiierapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, piUs, powder packets, wafers, injectable solutions or suspensions and die like, and segregated multiples thereof. The present invention is also related widi a method of treating viral diseases in warm- blooded animals suffering from said viral diseases by administering an effective antiviral amount of a compound of formula (I), a pharmaceutically acceptable acid addition salt or a stereoisomeric form thereof. Those of skiU in the treatment of HTV-infection could easUy determine die effective daily amount from the test results presented here. In general it is contemplated mat an effective daUy amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form. It is evident that said effective daUy amount may be lowered or increased depending on die response of the treated subject and/or depending on die evaluation of die physician prescribing the compounds of me instant invention. The effective daily amount ranges mentioned hereinabove are therefore guideUnes only and are not intended to Umit the scope or use of the invention to any extent. The foUowing examples are intended to Ulustrate and not to limit the scope of the present invention. Unless otherwise stated all parts therein are by weight. Experimental part A. Preparation of the intermediates Example 1 To a stirred mixture of 43.8 parts of 2,6-dichlorobenzaldehyde and 325 parts of acetic acid there were added dropwise 35.3 parts of 2-medιoxybenzamine. After 15 min, there was added dropwise a solution of 20.3 parts of potassium cyanide in 35 parts of water, keeping the temperature below 30°C. Stirring was continued for 20 hours at room temperature. The precipitate was filtered off and recrystaUized from 2-propanol (2x). The product was filtered off and dried, yielding 35.3 parts of 2-(2,6-dichlorophenyl)-2-[(2- methoxyphenyl)amino]acetonitrile; mp. 117.5°C (interm. 1). Example 2 To a stirred and cooled (ice-bath) mixture of 44 parts of 2,6-dichlorobenzaldehyde and 500 parts of acetic acid there were added 27.6 parts of 2-nitrobenzamine, 50 parts of zinc(H)chloride and 16.3 parts of potassium cyanide. Stirring was continued for 17 hours„ at 50°C. After cooling, the reaction mixture was poured into 1000 parts of water. The precipitate was filtered off and triturated widi 2,2'-oxybispropane. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 45.9 parts of 2-(2,6-di- chlorophenyl)-2-[(2-nitrophenyl)amino]acetonitrile; mp. 194.8°C (interm. 2). Example 3 A mixture of 8.75 parts of 2,6-dichlorobenzaldehyde, 5.4 parts of l-(2-aminophenyl)-l- ethanone and 105 parts of acetic acid was stirred for 1 2 hour at room temperature. There were added 3.26 parts of potassium cyanide and stirring was continued for 20 hours. The reaction mixture was diluted widi water. The precipitate was filtered off, washed with water and recrystaUized from acetonitrile. The product was filtered off and dried, yielding 9.1 parts (71.3%) of (+)-α-[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetonitrile; mp. 178.7°C (interm. 3). Example 4 a) A mixture of 2 parts of 4-ethyl-2-nitrobenzenecarbonitrile, 31.6 parts of ethanol, 27.8 parts of hydrogen peroxide (30%) and 1.7 ml of sodium hydroxide 6N was stirred for 1 hour at room temperature. The reaction mixture was dUuted widi water and die product was extracted widi dichloromethane (3x). The combined extracts were washed with water, dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybis- propane. The product was filtered off and dried, yielding 1.3 parts (60.9%) of 4-ethyl-2- nitrobenzamide; mp.l75.0°C (interm. 4). b) To a stirred and heated (80°C) mixture of 29.2 parts of intermediate 4 and 234 parts of sulfuric acid (75%) there were added portionwise 53 parts of sodium nitrite. The whole was stirred at room temperature for 10 min and was then diluted with water. The precipitate was filtered off, washed widi water and dried, yielding 26 parts (88.8%) of 4- edιyl-2-nitrobenzoic acid; mp. 111.2°C (interm. 5). c) A mixture of 25.5 parts of intermediate 5 and 259.2 parts of tiiionyl chloride was stirred for 5 hours at reflux temperature. The reaction mixture was evaporated and the residue was co-evaporated widi methylbenzene (2x), yielding 27.8 parts (100%) of 4-ethyl-2-nitrobenzenecarbonyl chloride (interm. 6). d) To a stirred mixture of 3.4 parts of magnesium turnings, 2.0 parts of ethanol and 2.2 parts of tetrachloromethane there were added dropwise 35.5 parts of l,l'-oxybisethane. At reflux temperature, there were added dropwise a mixture of 22.4 parts of diethyl 1,3-propanedioate, 11.9 parts of ethanol and 10.7 parts of l.l'-oxybisethane and, after 3 hours, a solution of 27.8 parts of intermediate 6 in 10.7 parts of l.l'-oxybisethane. Stirring at reflux temperature was continued for 1 hour. After cooling, diere were added dropwise 91.4 parts of H 2 Sθ4 (8%). The organic layer was separated and the aqueous layer was extracted with metiiylbenzene (2x). The combined organic layers were washed with water, dried, filtered and evaporated. The residue was refluxed for 2 hours in a mixture of 84 parts of acetic acid, 18.4 parts of sulfuric acid and 45 parts of water. After cooling, the whole was dUuted widi water and extracted widi 2,2'-oxybispropane (2x). The combined extracts were washed with NaOH (10%) and water, dried, filtered and evaporated, yielding 22 parts (87.6%) of l-(4-ethyl-2-nitrophenyl)ethanone (interm. 7). e) A mixture of 22 parts of intermediate 7, 2 parts of a solution of thiophene in methanol 4% and 316 parts of methanol was hydrogenated at normal pressure and 50°C in the presence of 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, die catalyst was filtered off and die filtrate was evaporated. The residue was purified by column chromatography (sUica gel ; CH2CI2 / hexane 80:20). The eluent of the desired fraction was evaporated, yielding 16 parts (89.1%) of l-(2-amino-4-ethylphenyl)ethanone (interm. 8). f) A mixture of 5.25 parts of (2,6-dichlorophenyl)medιanone, 4.08 parts of intermediate 8 and 105 parts of acetic acid was stirred for 2 hours at room temperature. There were added 1.96 parts of potassium cyanide and stirring was continued for 20 hours. The reaction mixture was poured into water and die product was extracted widi dichloro¬ methane. The extract was washed widi NaOH (10%) and water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CH2CI2 / hexane 80:20). The eluent of the desired fraction was evaporated and the residue was crystaUized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 4.28 parts (49.3%) of (±)-α-[(2-acetyl-5-ethylphenyl)amino]-2,6-dichlorobenzene- acetonitrile; mp. 111.3°C (interm. 9). Example 5 a) To a solution of 117 parts of (4-trifluoromethylphenyl)methanone in 136 parts of medianol there were added portionwise 13.1 parts of sodium tetrahydroborate under a nitrogen atmosphere, whUe cooling on ice. After stirring for 18 hours at room temperature, me reaction mixture was poured into water which was acidified with HC1 (20%). The product was extracted with 2,2'-oxybispropane (2x) and the combined extracts were washed widi water, dried, filtered and evaporated, yielding 130 parts (100%) of 4-(trifluoromethyl)benzenemethanol (interm. 10). b) A mixture of 125 parts of intermediate 10 and 821 parts of l-methyl-2-pyrrolidinone was hydrogenated at normal pressure and room temperature in the presence of 3 parts of paUadium-on-charcoal catalyst 10%. After die calculated amount of hydrogen was taken up, die catalyst was filtered off and the filtrate was evaporated. The residue was distiUed (U0 5 Pa, 90-100°C), yielding 75 parts (66.0%) of l-trifluoromethyl-4-methylbenzene (interm. 11). c) A mixture of 29.4 parts of intermediate 11 and 4.1 parts of antimony trichloride was stirred for 6 hours at 60°C, while chlorine was bubbled through. The reaction mixture was diluted with 50 parts of water and stirred for another 15 min at 60°C. The product was extracted with 2,2'-oxybispropane and the extract was washed with water, dried, filtered and evaporated. The residue was taken up in hexane and the whole was filtered and evaporated. The residue was distiUed (1.3.10 3 Pa, 100-105°C), yielding 29 parts (61.1%) of l,3,4-trichloro-5-trifluoromethyl-2-methylbenzene (interm. 12). d) A mixture of 29 parts of intermediate 12, 30 parts of M-bromosuccinimide, 2.5 parts of benzoylperoxide and 795 parts of tetrachloromethane was stirred for 6 hours at reflux temperature. The reaction mixture was washed with water (2x), dried, filtered and evaporated. The residue was boded in hexane and die whole was filtered and evaporated, yielding 40 parts (100%) of 2-bromomediyl-l,3,4-trichloro-5-trifluoromethylbenzene (interm. 13). e) A mixture of 40 parts of intermediate 13, 600 parts of water and 27.6 parts of potassium carbonate was stirred for 21 hours at reflux temperature. After cooling, die precipitate was filtered off and recrystaUized from hexane. The product was filtered off and dried, yielding 15 parts (48.8%) of 2,3,6-trichloro-4-trifluoromethylbenzene- methanol (interm. 14). f) To a stirred mixture of 80 parts of water, 79.12 parts of sulfuric acid (cone.) and 1 part of benzyltriethylammonium chloride there were added 6.6 parts of potassium dichromate and dropwise a solution of 15 parts of intermediate 14 in 160 parts of dichloromethane. Stirring at room temperature was continued for 4 hours. The reaction mixture was dUuted with 400 parts of water and die product was extracted with dichloro¬ methane (2x). The combined extracts were washed with water, dried, filtered and evaporated, yielding 16 parts (100%) of [2,3,6-trichloro-4-(trifluoromethyl)phenyl]- methanone (interm. 15). g) A mixture of 4.1 parts of l-(2-aminophenyl)edιanone, 11 parts of intermediate 15 and 105 parts of acetic acid was stirred for 2 hours at room temperature. There were added 2.6 parts of potassium cyanide and stirring at room temperature was continued for 18 hours. The reaction mixture was poured into 500 parts of water. The product was extracted widi dichloromethane (2x) and die combined extracts were washed with Na2C03 (5%), dried, filtered and evaporated, yielding 16 parts (100%) of 2,3,6-tri- chloro-4-(trifluoromemyl)-α-[[2-(memylcarrx)nyl)phenyl]ammo]benzeneacetonitrile (interm. 16). Example 6 a) To a stirred mixture of 10 parts of magnesium and 72 parts of tetrahydrofuran there were added portionwise 50 parts of bromocyclopropane, keeping the temperature below 10°C. At reflux temperature, there was added a solution of 50 parts of 2-fluorobenzene- carbonitrile in 72 parts of tetrahydrofuran. Stirring at reflux temperature was continued until completion of die reaction. The reaction mixture was cooled on ice (0-5°C) and decomposed widi a mixture of ice, water and acetic acid. The product was extracted with trichloromethane (3x) and die combined extracts were washed widi water (2x), dried, filtered and evaporated. The residue was distiUed (1.33 Pa; 78-105°C) (2x), yielding 19.8 parts (29.4%) of cyclopropyl (2-fluorophenyl)methanone; bp. 100-103°C (at 1.3 Pa) (interm. 17). b) To a solution of 50 parts of intermediate 17, 34.5 parts of benzenemethanamine and 218 parts of methylbenzene there were added 45 parts of sodium carbonate. The whole was stirred for 5 days at reflux temperature. The reaction mixture was filtered and die organic layer was separated, washed widi water and NaCl(sat), dried, filtered and evaporated. The residue was triturated in metiianol, yielding 32 parts (41.6%) of cyclo¬ propyl [2-[(phenylmethyl)amino]phenyl]medιanone (interm. 18). c) A mixture of 23 parts of intermediate 18 and 223 parts of tetrahydrofuran was hydrogenated at ndrmal pressure and room temperature in the presence of 3 parts of paUadium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and die filtrate was evaporated. The residue was purified by column chromatography (siUca gel ; hexane / (C2H5)2θ 90: 10). The eluent of the desired fraction was evaporated, yielding 14.1 parts (95.6%) of (2-aminophenyl) cyclopropylmedianone (interm. 19). d) To a stirred solution of 5 parts of intermediate 19 in 105 parts of acetic acid diere were added 6.5 parts of (2,6-dichlσrophenyl)methanone and, after 1 1 2 hour, 2.4 parts of potassium cyanide. The whole was stirred for 41 hours at room temperature and then poured into water. The precipitate was filtered off and recrystaUized from a mixture of methanol and acetonitrile, yielding 8.5 parts (79.4%) of (±)-2,6-dichloro-α-[[2-(cyclo- propylcarbonyl)phenyl]amino]benzeneacetonitrile; mp. 144.1°C (interm. 20). B. Preparation of the final compounds Example 7 To 200 parts of a mixture of concentrated sulfuric acid and water (10: 1 by volume) mere were added portionwise 28.5 parts of intermediate (1). After stirring for 18 hours at room temperature, the reaction mixture was poured into 2000 parts of ice-water. The precipitate was filtered off and dissolved in ttichloromediane. This solution was washed widi water, dried, filtered and evaporated. The residue was crystaUized from 2-propanol. The product was filtered off and dried, yielding 17.2 parts of 2-(2,6-dichlorophenyl)-2-[(2-methoxy- phenyl)amino]acetamide; mp. 192°C (comp.4). Example 8 To a stirred and cooled (ice-bath) amount of 450 parts of concentrated sulfuric acid there were added portionwise 44 parts of intermediate (2), keeping die temperature below 15°C. The resulting solution was stirred for 3 hours at room temperature and was tiien poured into 1000 parts of ice- water. The precipitate was filtered off, washed with water, triturated with 2,2'-oxybispropane and recrystaUized from acetic acid. The product was filtered off and dried, yielding 24 parts of 2-(2,6-dichlorophenyl)-2-[(2-nitrophenyl)- aminojacetamide. DUution of the mother liquor with water caused a second fraction of product to precipitate. The product was filtered off, washed widi petroleumether and dried, yielding an additional 6.6 parts of 2-(2,6-dichlorophenyl)-2-[(2-nitrophenyl)- amino]acetamide. Total yield- 30.6 parts; mp. 182.4°C (comp. 15). Example 9 a) A mixture of 3 parts of intermediate (3) and 50.2 parts of a mixture of concentrated sulfuric acid and water (10/1 by volume) was stirred for 3 hours at room temperature. The reaction mixture was poured into ice-water. The precipitate was filtered off, washed with water and recrystaUized from acetonitrile. The product was filtered off and dried, yielding 1.9 parts (59.9%) of (±)-α-[(2-acetylphenyl)amino]-2,6-dichlorobenzene- acetamide; mp.203.9°C (comp.22). b) 0.9 Parts of compound 22 were resolved by column chromatography (Chiracel OD® ; hexanes / C2H5OH 80:20). The eluent of die desired fractions was evaporated and the residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 0.164 parts (18.2%) of (-)-α-[(2-acetylphenyl)amino]-2,6-dichlorobenzene- 20 acetamide; mp. 168.8°C; [α]J = -64.83° (cone. = 0.1% in CH3OH) (comp. 23). Example 10 To a stirred solution of 2 parts of compound 22 in 3.5 parts of 2-propanol there were added 0.59 parts of pyridine and 0.5 parts of hydroxylamine monohydrochloride. After stirring for 2 hours at reflux temperature, the reaction mixture was poured into water. The product was extracted with dichloromethane and die extract was washed with water (2x), dried, filtered and evaporated. The residue was successively triturated in petroleum ether and recrystaUized from acetonitrile. The product was filtered off and dried, yielding 1.2 parts (56.8%) of (±)-(E)-2,6-dichloro-α-[[2-[l-(hydroxyimino)ethyl]phenyl]amino]- benzeneacetamide; mp. 114.8°C (comp. 35). Example 11 To a stirred solution of 2 parts of compound 22 in 3.5 parts of 2-propanol there were added 0.59 parts of pyridine and 0.6 parts of metiioxyamine monohydrochloride. After stirring for 4 1/2 hours at reflux temperature and subsequent cooling, the reaction mixture was poured into water. The precipitate was filtered off, washed with water and crystallized from acetonitrile, yielding 1.2 parts (54.6%) of (+)-(E)-2,6-dichloro-α-[[2- [l-(me oxyimino)ethyl]phenyl]amino]benzeneacetamide; mp. 205.5°C (comp. 36). Example 12 To a stirred solution of 1.8 parts of compound 22 and 3.12 parts of 2-propanol there were added 0.52 parts of pyridine and 0.32 parts of hydrazine monohydrate. After stirring for 12 hours at reflux temperature, the reaction mixture was extracted widi dichloro¬ methane. The extract was washed widi water (2x), dried, filtered and evaporated. The residue was purified by column chromatography (sUica gel ; CH2CI2 / CH3OH 95:5). The eluent of the desired fraction was evaporated and die residue was successively triturated in l,l'-oxybisedιane and crystaUized from acetonitrile. The product was filtered off and dried, yielding 0.6 parts (32.2%) of (±)-(E)-2,6-dichloro-α-[[2-(l-hydrazino- ethyl)phenyl]amino]benzeneacetamide; mp. 175.7°C (comp. 43). Example 13 a) To a stirred and heated (60°C) solution of 120 parts of compound (15) in 2100 parts of acetic acid diere were added 252 parts of hydrochloric acid. Stirring was continued for 22 hours at 100°C. The reaction mixture was concentrated, the precipitate was filtered off and purified by column chromatography (HPLC; sUica gel ; CH2CI2 / CH3OH 99: 1 -→ 90:10). The eluent of die desired fraction was evaporated, yielding 48.8 parts (40.6%) of (+)-2,6-dichloro-α-[(2-nitrophenyl)amino]benzeneacetic acid (interm. 21). b) To a solution of 5.1 parts of intermediate 21 in 66.8 parts of tetrahydrofuran there were added 1.7 parts of £L£j[-diethyletiιanamine and dropwise 1.8 parts of ethyl chloroformate. After stirring for 20 min at room temperature, the reaction mixture was poured into 90 parts of NH4OH (cone). The solvent was evaporated and the residue was taken up in 298 parts of trichloromethane. The whole was filtered, washed with water (2x), dried, filtered and evaporated. The residue was crystalUzed from acetonitrile, yielding 1.8 parts (35.2%) of 2,6-dichloro-α-[(2-nitrophenyl)amino]benzeneacetamide (comp. 15). Example 14 a) Through a stirred solution of 5 parts of intermediate 20 and 2.2 parts of Hϋ-diethyl- ethanamine and 98 parts of pyridine diere was bubbled hydrogen sulfide gas until completion of the reaction and tiien nitrogen gas for 1 hour. The reaction mixture was poured into 200 parts of water and die product was extracted widi dichloromediane. The extract was dried, filtered and evaporated. The residue was taken up in ttichloromediane and die whole was washed widi HCl (dU.) and evaporated. The residue was crystallized from a mixture of methanol and acetonitrile. The product was filtered off and dried in vacuo at 70°C, yielding 4.3 parts (81%) of (±)-2,6-dichloro-α-[(2-cyclopropylcarbonyl)- phenyl]amino]benzeneethanethioamide; mp.222.0°C (comp. 58). b) To a stirred and cooled (0°C) solution of 1 part of compound 58 in 18.8 parts of H^-dimethylformamide were added 4 parts of a sodium hydroxide solution 2N and 1.3 parts of hydrogen peroxide 30%. After stirring overnight at room temperature, the precipitate was filtered off, washed widi water and crystaUized from acetonitrile. The product was filtered off and dried in vacuo at 70°C, yielding 0.56 parts (60%) of (±)-2,6^dichloro-α-[[2-(cyclopropylcarbonyl)phenyl]amino]benzeneacetamide; mp. 196.4°C (comp. 48). Example 15 a) To a solution of 3.7 parts of sodium hydrogen carbonate in 225 parts of water diere were added 154 parts of formaldehyde (35% aq.) and 102.0 parts of compound (15). After stirring for 5 hours at reflux temperature and subsequent cooling, die reaction mixture was dUuted widi 1000 parts of water. The whole was stirred for 1/2 hour at room temperature. The precipitate was filtered off, washed widi water (3x) and crystaUized from methanol. The whole was filtered while hot and the filtrate was stirred for 17 hours -28- at room temperature. The crystaUized product was filtered off, washed with metiianol (2x) and dried in vacuo at 40°C, yielding 76.2 parts (68.6%) of (±)-2,6-dichloro-N- (hydroxymedιyl)-α-[(2-mtrophenyl)amino]benzeneacetamide; mp. 175.0°C. b) The thus obtained derivative was resolved by liquid chromatography using a chiral stationary phase (Chiralcel OJ®). The chromatographic system was deaerated with edianol. The eluent consisting of edianol was warmed to a temperature of about 35°C and was pumped tiirough the system. The racemic compound was dissolved in a mininal amount of ethanol, warmed at 30-40°C and injected into the chromatographic system. The desired fractions were collected (UV detection 240 nm) and the solvent was evaporated, yielding die separated enantiomeric derivates. c) A suspension of 0.53 parts of the obtained residue and 4 parts of 4-methyl-2- pentanone was stirred first for 4 hours at reflux temperature and then for 18 hours at 25°C. The precipitated product was filtered off and the filtrate was further stirred at 25°C. After filtration, the precipitated product was combined widi die previous fraction and washed with 0.8 parts of 4-methyl-2-pentanone. The product was filtered off and dried in vacuo at 40°C, yielding a first fraction of 0.17 parts (34.9%) of (-)-2,6-dichloro-α-[(2- nitrophenyl)amino]benzeneacetamide. The filtrate was stirred in an ice batii and evaporated at 40°C, yielding a second fraction of 0.15 parts (30.8%) of (-)-2,6-dichloro- α-[(2-nitrophenyl)amino]benzeneacetamide. Total yield: 0.32 parts (65.7%) of (-)-2,6- dichloro-α-[(2-nitrophenyl)amino]benzeneacetamide (comp.25) (e.e. =100%). Example 16 a) To a stirred solution of 3.37 parts of iLM-N'^'-tetramediyldiaminomethane in 44 parts of methylbenzene was added dropwise a solution of 2.59 parts of acetylchloride in 26 parts of methylbenzene during 30 minutes at 20-25°C under nitrogen atmosphere. Upon completion, the reaction mixture was further stirred for 20 minutes. 10.21 Parts of compound 15 and 78 parts of methylbenzene were added to the previous mixture and stirred for 5 hours at 80°C. The reaction mixture was aUowed to cool to 20°C, the precipitated prodifist was filtered off and dried in vacuo at 40°C, yielding 11.66 parts (97.8%) of -[(dimedιylamino)medιyl] 2,6-dichloro-α-[(2-nitrophenyl)amino]benzene- acetamide. b) The thus obtained derivative was resolved by Uquid chromatography using a chiral stationary phase (Chiralcel OJ®). The chromatographic system was deaerated widi a mixture of hexane and edianol (80:20; v/v). The eluent consisting of a mixture of hexane and edianol (80:20; v/v) was warmed to a temperature of about 35°C and was pumped dirough die system. The racemic compound was dissolved in a mininal amount of edianol, warmed at 30-40°C and injected into die chromatographic system. The desired fractions were collected (UV detection 240 nm) and the solvent was evaporated, yielding die separated enantiomeric derivates. c) 0.2 Parts of the desired fraction and 8 parts of 4-methyl-2-pentanone was refluxed for 5 hours in an oU bath at 120°C. The reaction mixture was aUowed to cool to 20-25°C. The precipitated product was filtered off, washed widi 2.4 parts of 4-methyl-2-pentanone and dried in vacuo at 40°C. The filtrate was evaporated at 50°C, and purified by column chromatograhpy (HPLC; silicagel; CH2Cl2/CH 3 OH 99:1 → 90:10) yielding 0.1 parts (58.8%) of (-)-2,6-dichloro-α-[(2-nitrophenyl)amino]benzeneacetamide (comp. 25) (e.e. = 82%). Example 17 a) To a stirred mixture of 585 parts of dichloromethane and 72 parts medianol, saturated with gaseous hydrochloride were added 96.66 parts of intermediate 2. The reaction mixture was stirred for 6.5 hours at 0-5°C while bubbUng dirough gaseous hydrochloric acid. After cooling to - 10°C, 240 parts of medianol and 260 parts of dichlorometiiane were added. The reaction mixture was neutralized and alkalized widi 365 parts of to pH 9. After evaporation in vacuo at 50°C, the residue was stirred in 668 parts of tetrahydrofuran. The precipitate was filtered off, washed with tetrahydrofuran and die filtrate was evaporated to dryness in vacuo at 50°C. The residue was boded in 280 parts of 2-propanol under nitrogen atmosphere. The product was aUowed to crystalUze (2 hours, 0-5°C), filtered off and washed widi 56 parts of 2-propanol, yielding 70.62 parts (66.5%) of (±)-Q-methyl 2,6-dichloro-α-[(2-nitro- phenyl)amino]benzeneethanimidate. b) The thus obtained derivative was resolved by Uquid chromatography using a chiral stationary phase (Chiralcel OJ®). The chromatographic system was dearrated with edianol. The eluent consisting of edianol was warmed to a temperature of about 35°C and was pumped dirough die system. The racemic compound was dissolved in a mininal amount of ethanol, warmed at 30-40°C and injected into the chromatographic system. The desired fractions were collected (UV detection 240 nm) and die solvent was evaporated, yielding die separated enantiomeric derivates. c) 0.1 Parts of die above residue were dissolved in 5.6 parts of dichloromethane at 20°C. The whole was heated to 45°C and a few drops of medianol, saturated widi gaseous hydrochloric acid (9.8N) were added. After stirring for 2 hours at reflux temperature (45-50°C), the reaction mixture was evaporated to dryness, yielding 0.085 parts (85%) of (-)-2,6-dichloro-α-[(2-nitrophenyl)amino]benzeneacetamide (comp. 25) (e.e. = 84%). Example 18 a) To a stirred and cooled (15°C) solution of 350 parts of 2,6-dichlorobenzaldehyde and 1600 parts of acetic acid was added dropwise a solution of 162.8 parts of potassium cyanide in water during 30 minutes at 15-20°C. After stirring for 16 hours at 20°C, 1300 parts of dichloromethane and 1000 parts of water were added. The separated aqueous layer was washed three times with dichloromethane. The combined organic layers were washed widi water, dried, filtered and evaporated at 40°C, yielding 396 parts of 2,6-dichloro-α-hydroxybenzeneacetonitrile. b) 396 Parts of the above product were combined widi 80 parts of methanol and stirred at 20°C. 800 Parts of methanol, saturated with ammonia were added and the whole was refluxed for 4 hours (40°C → 60°C). After evaporation in vacuo, the residue was taken up in 520 parts of dichloromethane and 200 parts of water. The separated organic layer was washed twice with 200 parts of water, dried and cooled to 10°C. The whole was acidified widi 280 parts of 2-propanol, saturated widi hydrochloric acid. The crystaUized product was filtered off, taken up in 390 parts of dichloromethane and 200 parts of water and saturated widi ammonia to pH >9. The separated organic layer washed widi 200 parts of water, dried, filtered and evaporated, yielding 245 parts of α-amino- 2,6-dichlorobenzeneacetonitrile. c) The thus obtained derivative was resolved by Uquid chromatography using a chiral stationary phase (Chiralcel OJ®). The chromatographic system was deaerated with a mixture of hexane and edianol (80:20, v/v). The eluent consisting of a mixture of hexane and edianol (80:20; v/v) was pumped through the system. The racemic compound was dissolved in a mininal amount of ethanol and injected into the chromatographic system. The desired fractions were coUected (UV detection 240 nm) and the solvent was evaporated, yielding the separated enantiomeric derivates. d) The separated enantiomeric derivate was stirred in 52 parts of dichloromethane at 10-15°C. 2-Propanol, saturated widi hydrochloric acid was added and after stirring for 1 hour at 20°C, die precipitated product was filtered off, washed widi 26 parts of dichloro¬ metiiane and taken up in 260 parts of dichloromethane and 100 parts of water. The solution was treated widi ammonia to pH >9. The separated organic layer was washed, dried and dissolved in 280 parts of dichloromethane. After cooUng to 0°C, 26.8 parts of sulfuric acid were added dropwise. The whole was stirred for 18 hours at 20°C and 100 parts of water were added. The reaction mixture was treated widi ammonium hydroxide at <20°C. The separated aqueous layer was extracted twice with dichloromethane. The combined dichloromethane layers were washed widi water, dried, filtered and evaporated at <45°C, yielding 8.1 parts (82.6%) of α-amino-2,6-dichlorobenzeneacetamide. e) A mixture of 0.092 parts of α-amino-2,6-dichlorobenzeneacetamide, 0.032 parts of 2-fluoronitrobenzene and 1 part of l,3-dimetyl-2-imidazoUdinone was stirred for 6 hours at 140°C. The product was extracted and die extract was dried, filtered and evaporated at 100°C and 133 - 266 Pa. The residue was purified by column chromatograhpy (HPCL; silica gel; CH2Cl2/CH 3 OH 99:1 → 90:10), yielding 0.12 pans of (-)-2,6-dichloro-α- [(2-nitrophenyl)amino]benzeneacetamide (e.e. = 90%). All other compounds in the following table were prepared foUowing the procedures described in Examples 7-18. Table 1 Co. R5 R6 R 8 R 9 RlO Physical data No. 45 6-Cl H 2-COCH 3 5-CH 3 H mp.203.6°C r 1 20 ■• "-■D 0.951 in CH30H +15.77° 46 6-Cl H 2-COCH 5-CH 3 H mp. 189.5°C r L α J ιD 20 1.046 in CH3OH = -14.34° 47 6-Cl H 2-COCH3 3-OCH 3 H mp. 201.6°C 48 6-Cl H 2 H H mp. 196.4°C 49 4-Br 6-Cl 2-COCH 3 H H 50 4-CN 6-Cl 2-COCH3 H H 51 4-COOH 6-Cl 2-COCH3 H H 52 4-COOCH3 6-Cl 2-COCH 3 H H 53 4-CONH 6-Cl 2-COCH 3 H H 54 4-COCH 3 6-Cl 2-COCH3 H H 55 4-CF 3 6-Cl 2-COCH3 H H 56 4-CH 2 NH 2 6-Cl 2-COCH 3 H H C* Pharmacological example Example 19 A rapid, sensitive and automated assay procedure was used for the in- vitro evaluation of anti-HTV agents. An HTV-1 transformed T4-cell Une, MT-4, which was previously shown (Koyanagi et al., Int. J. Cancer, __ , 445-451, 1985) to be highly susceptible to and permissive for HTV infection, served as the target ceU line. Inhibition of the HTV- induced cytopathic effect was used as the end point. The viabdity of both HTV- and mock-infected ceUs was assessed spectrophotometricaUy via the in-situ reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoUum bromide (MTT). The 50% cytotoxic dose (CD50 in μg/ml) was defined as the concentration of compound mat reduced the absorbance of the mock-infected control sample by 50%. The percent protection achieved by die compound in HTV-infected cells was calculated by die following formula : (Q Dτ ) mv - (Q -Dc ) fflv expressed in %, (OD C )MOCK - (OD C )fflV whereby (OD*Ϊ)HΓV - S me optical density measured widi a given concentration of die test compound in HIV-infected ceUs; (ODc)mv is the optical density measured for the control untreated HTV-infiected cells; (ODς^MOCK - S me optical density measured for the control untreated mock-infected ceUs; aU optical density values were determined at 540 nm. The dose achieving 50% protection according to die above formula was defined as the 50% effective dose (ED50 in μg ml). The ratio of CD50 to ED50 was defined as the selectivity index (SI). AU compounds of die table hereinabove were shown to have a selectivity index larger tiian 1, i.e. inhibit HIV-1 effectively at doses below die cytotoxic dose. Particular values are Usted in the table hereinbelow.

Claims: AIMS 1. A compound for use as a medicine having the formula a pharmaceuticaUy acceptable acid addition salt form or a stereochemicaUy isomeric form thereof, wherein R- and R 2 each independendy are hydrogen, C1.5a.kyl or C 3 _5cycloalkyl ; or R 1 and R 2 taken together with the nitrogen atom bearing said R- and R 2 may form a pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or 4-Cι_ alkylpiperazinyl group; X is O or S; R is hydrogen or Cι_5alkyl; R 4 , R-5 and R each independendy are hydrogen, halo, C1.5aU_.yl, Cι_5alkyloxy, nitro, trifluoromethyl, cyano, aminomethyl, carboxyl, Cι_4_dkyloxycarbonyl, C^alkyl- carbonyl, aminocarbonyl or hydroxy; R7 is hydrogen or halo; and R 8 , R 9 and R-® each independendy are hydrogen, halo, Ci^aUcyl, C .6aUc loxy, nitro, hydroxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (trifluoromethyl)carbonyl, aminocarbonyl, (cyclopropyl)carbonyl or a radical Cι_5alkyl-(C=Y)- wherein =Y represents =0, =N-OH, =N-OCH 3 , =N-NH or =N-N(CH 3 ) 2 ; provided that (1) R 1 is other than n-propyl when R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 and RIO represent hydrogen, R 8 represents 4-edιoxy and X represents oxygen, and (2) X is other than sulfur, when Rl, R 2 , R 3 , R6, R7, R8, R9 an R 10 represent hydrogen and R 4 and R-5 represent 3,4-dimedιoxy. 2. A compound as claimed in claim 1 wherein R- and R 2 are each independendy hydrogen; and or X is oxygen; and/or R 4 , R5 and Rβ are each independendy hydrogen, halo, Cι_5alkyloxy or nitto; and/or is hydrogen; and/or R 8 , R 9 and R -® are each independendy hydrogen, halo, Ci^alkyl, C^alkyloxy, nitro, trifluoromethoxy or Ci-6alkylcarbonyl. 3. A compound as claimed in claim 2 wherein R 1 and R 2 are each independendy hydrogen; and/or R is hydrogen; and/or R 4 , R*- 5 and Rβ are each independendy hydrogen, halo, methoxy or nitro; and/or R 8 , R 9 and R-® are each independendy hydrogen, halo, mediyl, metiioxy, nitro, trifluoromethoxy or methylcarbonyl. 4. A pharmaceutical composition comprising a pharmaceuticaUy acceptable carrier and as active ingredient a therapeutically effective amount of a compound as defined in any of claims 1 to 3. 5. A process ofpreparing pharmaceutical compositions as claimed in claim 4, characterized in that a therapeuticaUy effective amount of a compound as defined in any of claims 1 to 3 is intimately mixed with a pharmaceutical carrier. 6. A compound having the formula a pharmaceuticaUy acceptable acid addition salt form or a stereochemicaUy isomeric form thereof, wherein R 4 represents halo, Cι_6alkyl, Cι. alkyoxy or nitro; R-5 and Rβ each independendy represent hydrogen, halo, Cι_6alkyl, Cι_6alkyloxy, nitro, trifluoromethyl, cyano, aminomethyl, carboxyl, Ci^alkyloxycarbonyl, C .4_dkyl- carbonyl, aminocarbonyl or hydroxy; R 7 represents hydrogen or halo; R 8 represents Ci-6alkyloxy, nitro, trifluoromethoxy, 2,2,2-trifluoroethoxy, (trifluoromethyl)carbonyl, aminocarbonyl, (cyclopropyl)carbonyl or a radical Cι_6alkyl-(C=Y)- wherein =Y represents =0, =N-OH, =N-OCH 3 , =N-NH 2 or =N-N(CH 3 ) 2 , and R 9 and R each independendy are hydrogen, halo, Cι.6alkyl, Cι_6alkyloxy, nitro, hydroxy, trifluoromethoxy, 2,2,2-trifluoroedιoxy, (ttifluoromethyl)carbonyl, aminocarbonyl, (cyclopropyl)carbonyl or a radical wherein =Y represents =0, =N-OH, =N-OCH , =N-NH 2 or =N-N(CH 3 ) 2 ; provided that R 8 is other than 2-methoxy when R 4 is chloro, R 5 is 6-chloro, R 6 , R 7 and R 9 are hydrogen and R 10 is hydrogen or 5-methyl. 7. A compound according to claim 6 wherein R 4 is halo or Ci-6alkyl; R*- 5 and are hydrogen, halo or Ci-6alkyl; R 7 is hydrogen or chloro; R 8 is Cl-όalkyloxy, trifluoro¬ methoxy, nitro or Ci-6alkylcarbonyl; R 9 and R 10 are hydrogen, halo or Ci-6alkyl. 8. A compound according to claim 7 wherein R 4 is chloro or methyl; R 5 is hydrogen, chloro or methyl; R 6 is hydrogen or chloro; R 7 is hydrogen, R 8 is medioxy, trifluoromethoxy, nitro or mediylcarbonyl; R 9 is hydrogen, chloro, fluoro or methyl; and R*0 is hydrogen. 9. A compound having the formula a pharmaceuticaUy acceptable acid addition salt form or a stereochemicaUy isomeric form thereof, wherein R 4 represents halo, Cι_5alkyl, C^alkyloxy, nitro or hydroxy; Rβ and Rβ each independendy represent hydrogen, halo, C1.5a.lkyl, C ^alkyloxy, nitro, trifluoromediyl, cyano, aminomethyl, carboxyl, Ci^alkyloxycarbonyl, Ci^alkyl- carbonyl, aminocarbonyl or hydroxy; R 7 represents hydrogen or halo; R 8 represents Ci-5alkyloxy, nitro, trifluoromethyloxy, 2,2,2-trifluoroethoxy, (trifluoromethyl)carbonyl, aminocarbonyl, (cyclopropyl)carbonyl or a radical =N-NH 2 or =N-N(CH 3 ) 2 , ^ R 9 and R 0 each independendy are hydrogen, halo, Cι_5alkyl, C^alkyloxy, nitro, hydroxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (trifluoromethyl)carbonyl, aminocarbonyl, (cyclopropyl)carbonyl or a radical Cι_5alkyl-(C=Y)- wherein =Y represents =0, =N-OH, =N-OCH 3 , =N-NH 2 or =N-N(CH ) ; provided that R 8 is odier dian 2-methoxy when R 4 is chloro, R- 5 is 6-chloro, R-*\ R 7 and R 9 are hydrogen and R-® is hydrogen or 5-medιyl. 10. A process for preparing a compound as defined in any of claims 6 to 8 characterized bv a) reacting a nitrile of formula (TV) in a concentrated strong acid, optionaUy in the presence of a small amount of water, tiius yielding a compound of formula (I-b) b) reacting a nitrile of formula (IV) with hydrogen sulfide in an appropriate solvent and in die presence of a base, thus yielding a compound of formula (I-c), c) converting the tiiioamide of formula (I-c) into an amide of formula (I-b) by reaction with an oxidizing agent; d) N-arylating an intermediate of formula (VII) wherein W* represents a reactive leaving group, with a benzene derivative of formula (VD in a reaction-inert solvent in the presence of a base; e) amidating a carboxyUc acid or a reactive derivative thereof of formula VTΩ wherein L represents hydroxy, Ci^alkyloxy, phenoxy (optionally further substituted), IH-imidazolyl, (Cι_5alkyl or phenyl)oxycarbonyloxy or halo, with an amine of formula R - R 2 NH (IX), thus yielding a compound of formula f) preparing enantiomerically pure forms of the compounds of formula (I) by resolving the racemic compounds of formula (I) by Uquid chromatography on a chiral stationary phase; g) preparing enantiomerically pure forms of the compounds of formula (I-b) by resolving racemic derivatives of formula (VHI-c) or (Vϋl-d) (vm-c) ( vn^ wherein R represents Cι_5alkyl or phenyl; and wherein X represents a radical of formula -CH 2 OH or -CH N(CH 3 ); by Uquid chromatograhy on a chiral stationary phase and converting the thus obtained separated enantiomeric derivatives into the compounds of formula (I-b); and, optionaUy converting the compounds of formula (I) into one another following functional group transformation reactions; and, if desired, converting the compounds of formula (I) into a therapeuticaUy active non-toxic acid addition salt form by treatment with an acid; or conversely, converting the acid salt into the free base with alkali; and/or preparing stereochemicaUy isomeric forms tiiereof.

Inventors: BOSMANS JEAN-PAUL RENE MARIE A, JANSSEN PAUL ADRIAAN JAN, VAN DAELE GEORGES HENRI PAUL, VERDONCK MARC GUSTAAF CELINE, BOSMANS, JEAN-PAUL, RENE, MARIE, ANDRE, JANSSEN, PAUL, ADRIAAN, JAN, VAN DAELE, GEORGES, HENRI, PAUL, VERDONCK, MARC, GUSTAAF, CELINE
Applicants: JANSSEN PHARMACEUTICA NV, JANSSEN PHARMACEUTICA N.V.
Application year: 1991
Main classification: C07C327
IPC codes: A61K31, A61P31, C07C45, C07C49, C07C205, C07C237, C07C251, C07C255, C07C327, C07D295