FARNESYL PROTEIN TRANSFERASE INHIBITING (IMIDAZOL-5-YL)METHYL-2-QUINOLINONE DERIVATIVES

Abstract: This invention comprises the novel compounds of formula (I), wherein the dotted line represents an optional bond; X is oxygen or sulfur; R<1> is hydrogen, C1-12alkyl, Ar<1>, Ar<2>C1-6alkyl, quinolinylC1-6alkyl, pyridylC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, aminoC1-6alkyl, or a radical of formula -Alk<1>-C(=O)-R<9>, -Alk<1>-S(O)-R<9> or -Alk<1>-S(O)2-R<9>; R<2>, R<3> and R<16> each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar<1>, Ar<2>C1-6alkyl, Ar<2>oxy, Ar<2>C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl; R<4> and R<5> each independently are hydrogen, halo, Ar<1>, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl; R<6> and R<7> each independently are hydrogen, halo, cyano, C1-6alkyl, 4,4-dimethyl-oxazolyl, C1-6alkyloxy or Ar<2>oxy; R<8> is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonylC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, carboxyC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, imidazolyl, haloC1-6alkyl, C1-6alkyloxyC1-6alkyl, aminocarbonylC1-6alkyl, or a radical of formula -O-R<10>, -S-R<10>, -N-R<11>R<12>; R<17> is hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxycarbonyl, Ar<1>; R<18> is hydrogen, C1-6alkyl, C1-6alkyloxy or halo; R<19> is hydrogen or C1-6alkyl; having farnesyl transferase inhibiting activity; their preparation, compositions containing them and their use as a medicine.

Description: Farnesyl protein ransferase inhibiting (imidazol-5-yl)methyl-2-quinolinone derivatives The present invention is concerned with novel (imidazol-5-yl)methyl-2-quinolinone derivatives, the preparation thereof, pharmaceutical compositions comprising said novel compounds and the use of these compounds as a medicine as well as methods of treatment by administering said compounds. Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non- transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer. A particular group of oncogenes is known as ras which have been identified in mammals, birds, insects, mollusks, plants, fungi and yeasts. The family of mammalian ras oncogenes consists of three major members ("isoforms") : H-ras, K-ras and N-ras oncogenes. These ras oncogenes code for highly related proteins generically known as p21 , . Once attached to plasma membranes, the mutant or oncogenic forms of p21 rαϊ will provide a signal for the transformation and uncontrolled growth of malignant tumor cells. To acquire this transforming potential, the precursor of the p21 rαs oncoprotein must undergo an enzymatically catalyzed farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Therefore, inhibitors of the enzyme that catalyzes this modification, famesyl protein transferase, will prevent the membrane attachment of p21 rαy and block the aberrant growth of rαs-transformed tumors. Hence, it is generally accepted in the art that famesyl transferase inhibitors can be very useful as anticancer agents for tumors in which ras contributes to transformation. Since mutated, oncogenic forms of ras are frequently found in many human cancers, most notably in more than 50 % of colon and pancreatic carcinomas (Kohl et al., Science, vol 260, 1834 - 1837, 1993), it has been suggested that famesyl tranferase inhibitors can be very useful against these types of cancer. In EP-0,371,564 there are described (lH-azol-1-ylmethyl) substituted quinoline and quinolinone derivatives which suppress the plasma elimination of retinoic acids. Some of these compounds also have the ability to inhibit the formation of androgens from progestines and/or inhibit the action of the aromatase enzyme complex. Unexpectedly, it has been found that the present novel compounds, all having a phenyl substituent on the 4-position of the 2-quinoIinone-moiety and wherein the imidazole moiety is bound via a carbon atom to the rest of the molecule, show famesyl protein transferase inhibiting activity. The present invention encompasses compounds of formula (I) the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; R 1 is hydrogen, Ci-πalkyl, Ar 1 , Ar 2 Cj.-6alkyl, quinolinylCj-galkyl, pyridylCi-6alkyl, hydroxyC ι-6alkyl, mono- or aminoCι-6alkyl, or a radical of formula -Alki-C^-R 9 , -Alk ! -S(O)-R 9 or -Alk 1 -S(0) 2 -R 9 , wherein Alk 1 is Cι-6alkanediyl, R 9 is hydroxy, Cι-6alkyl, Cj-6alkyloxy, amino, Ci-salkylamino or Ci-salkylamino substituted with Cι-6alkyloxycarbonyl; R 2 , R 3 and R 16 each independently are hydrogen, hydroxy, halo, cyano, Cι-6alkyl, Ci-6alkyloxy, hydroxyC] -6alkyloxy, Ci-6alkyloxyCι-6alkyloxy, aminoCι-6alkyloxy, mono- or di(Ci-6alkyl)aminoCi-6alkyloxy, Ar 1 , Ar 2 C]-6alkyl, Ar 2 oxy, Ar 2 Ci-6alkyloxy, hydroxycarbonyl, Cι-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, 4,4-dimethyloxazolyl; or when on adjacent positions R 2 and R 3 taken together may form a bivalent radical of formula -O-CH2-O- (a-1), -O-CH2-CH2-O- (a-2), -O-CH=CH- (a-3), -O-CH2-CH2- (a-4), -O-CH2-CH2-CH2- (a-5), or -CH=CH-CH=CH- (a-6); R 4 and R 5 each independently are hydrogen, halo, Ar 1 , Cι-6alkyl, hydroxyCι-6alkyl, Cι-6alkyloxyCi-6alkyl , Ci-βalkyloxy, Cι-6alkylthio, amino, hydroxycarbonyl, Ci-βalkyloxycarbonyl, Ci-6alkylS(O)Cι-6alkyl or Cι^alkylS(O)2Cι-6alkyl; R 6 and R 7 each independently are hydrogen, halo, cyano, Ci-6alkyl, Ci-6alkyloxy, Ar 2 oxy, trihalomethyl, Ci-6alkylthio, di(Ci-6alkyl)amino, or when on adjacent positions R 6 and R 7 taken together may form a bivalent radical of formula -O-CH2-O- (c-1), or -CH=CH-CH=CH- (c-2); R 8 is hydrogen, Cι-6alkyl, cyano, hydroxycarbonyl, Cι-6alkyloxycarbonyl, Cι-6alkylcarbonylCι-6alkyl, cyanoCi-rsalkyl, Cι-6alkyloxycarbonylCι-6alkyl, carboxyCι-6alkyl, hydroxyCι-6alkyl, aminoCι-6alkyl, mono- or di(Ci-6alkyl)aminoCι-6alkyl, imidazolyl, haloCi-βalkyl, aminocarbonylCi-όalkyl, or a radical of formula -O-R 10 (b- 1 ), -S-RlO (b-2), -N-R π R 12 (b-3), wherein R 10 is hydrogen, Ci-6alkyl, C]-6alkylcarbonyl, Ar 1 , Ar 2 C]-6alkyl, Cι-6alkyloxycarbonylC]-6alkyl, or a radical or formula -Alk 2 -OR 13 or -Alk 2 -NR 14 R 15 ; R 11 is hydrogen, Cι-i2alkyl, Ar 1 or Ar 2 C]-6alkyl; R 12 is hydrogen, Ci-6alkyl, Cι-i6alkylcarbonyl, Ci-6alkyloxycarbonyl, Ci-βalkylaminocarbonyl, Ar 1 , Ar 2 C]-6alkyl, Ci-6alkylcarbonylCι- 6 alkyl, a natural amino acid, A^carbonyl, Ar 2 Ci-6alkylcarbonyl, aminocarbonylcarbonyl, Ci-όalkyloxyCi-όalkylcarbonyl, hydroxy, Ci-όalkyloxy, aminocarbonyl, di(Ci-6alkyl)aminoCi-6alkylcarbonyl, amino, C] ^alkylamino, Ci-6alkylcarbonylamino, or a radical or formula -Alk 2 -OR 13 or -Alk 2 -NR 14 R 15 ; wherein Alk 2 is Ci^alkanediyl; R 13 is hydrogen, Ci-βalkyl, Ci-βalkylcarbonyl, hydroxyC i^alkyl, Ar 1 or Ar 2 Ci-6alkyl; R 14 is hydrogen, Cι-6alkyl, Ar 1 or Ar 2 Cι-6alkyI; R 15 is hydrogen, C]-6alkyl, Cι-6alkylcarbonyl, Ar 1 or Ar 2 Ci-6alkyl; R 17 is hydrogen, halo, cyano, Chalky!, Cι-6alkyloχycarbonyl, Ar 1 ; R 18 is hydrogen, or halo; R 19 is hydrogen or ^alkyl; Ar 1 is phenyl or phenyl substituted with Cι-6alkyl, hydroxy, amino, Cι-6alkyloxy or halo; and Ar 2 is phenyl or phenyl substituted with C]-6alkyl, hydroxy, amino, Ci-6alkyloxy or halo. R 4 or R 5 may also be bound to one of the nitrogen atoms in the imidazole ring. In that case the hydrogen on the nitrogen is replaced by R 4 or R 5 and the meaning of R 4 and R 5 when bound to the nitrogen is limited to hydrogen, Ar 1 , Cι-6alkyl, hydroxyC i-6alkyl, Cι-6alkyloxyCι-6alkyl, Ci-6alkyloxycarbonyl, Cι-6alkylS(O)Cι-6alkyl, Ci- 6 alkylS(O) 2 C 1 - 6 alkyl. As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; defines straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like; Ci.galkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in Cι.6alkyl as well as the higher homologues thereof containing 7 or 8 carbon atoms such as, for example heptyl or octyl; again encompasses .salkyl and the higher homologues thereof containing 9 to 12 carbon atoms, such as, for example, nonyl, decyl, undecyl, dodecyl; Ci-^alkyl again encompasses C ^alkyl and the higher homologues thereof containing 13 to 16 carbon atoms, such as, for example, tridecyl, tetradecyl, pentedecyl and hexadecyl; C 2 - a l enyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like; Cι.6alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1 ,5-pentanediyl, 1 ,6-hexanediyl and the branched isomers thereof. The term "C(=O)" refers to a carbonyl group, "S(O)" refers to a sulfoxide and "S(O)2" to a sulfon. The term "natural amino acid" refers to a natural amino acid that is bound via a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of the amino acid and the amino group of the remainder of the molecule. Examples of natural amino acids are glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylanaline, tryptophan, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine. The pharmaceutically acceptable acid or base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and non-toxic base addition salt forms which the compounds of formula (I) are able to form. The compounds of formula (I) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, /7-aminosalicylic, pamoic and the like acids. The compounds of formula (I) which have acidic properties may be converted in their pharmaceutically acceptable base addition salts by treating said acid form with a suitable organic or inorganic base. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. The terms acid or base addition salt also comprise the hydrates and the solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like. The term stereochemically isomeric forms of compounds of formula (I), as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formula (I) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention. Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. Whenever used hereinafter, the term "compounds of formula (I)" is meant to include also the pharmaceutically acceptable acid or base addition salts and all stereoisomeric forms. Preferably the substituent R 18 is situated on the 5 or 7 position of the quinolinone moiety and substituent R 19 is situated on the 8 position when R 18 is on the 7-position. Interesting compounds are these compounds of formula (I) wherein X is oxygen. Also interesting compounds are these compounds of formula (I) wherein the dotted line represents a bond, so as to form a double bond. Another group of interesting compounds are those compounds of formula (I) wherein R 1 is hydrogen, Ci-6alkyl, di(Ci-6alkyl)aminoCi-6alkyl, or a radical of formula -Alk 1 -C(=O)-R 9 , wherein Alk 1 is methylene and R 9 is Ci-salkylamino substituted with Cι-6alkyloxy carbonyl. Still another group of interesting compounds are those compounds of formula (I) wherein R 3 is hydrogen or halo; and R 2 is halo, C2-6alkenyl, Ci-6alkyloxy, trihalomethoxy or hydroxyCi ^alkyloxy . A fuπher group of interesting compounds are those compounds of formula (I) wherein R 2 and R 3 are on adjacent positions and taken together to form a bivalent radical of formula (a-1), (a-2) or (a-3). A still fuπher group of interesting compounds are those compounds of formula (I) wherein R^ is hydrogen and R 4 is hydrogen or Cι-6alkyl. Yet another group of interesting compounds are those compounds of formula (I) wherein R 7 is hydrogen; and R 6 is Ci-6alkyl or halo, preferably chloro, especially 4-chloro. A particular group of compounds are those compounds of formula (I) wherein R 8 is hydrogen, hydroxy, haloCi^alkyl, hydroxyC] .ό lkyi, cyanoC]-6alkyl, Ci- δ alkyloxycarbonylCi-όalkyl, imidazolyl, or a radical of formula -NR R 12 wherein R 11 is hydrogen or hydroxy, Ci-6alkyloxyCi-6alkylcarbonyl, or a radical of formula -Alk 2 -OR 13 wherein R 13 is hydrogen or Ci^alkyl. Prefered compounds are those compounds wherein R 1 is hydrogen, C]_6alkyl, di(Ci-6alkyl)aminoCi-6alkyl, or a radical of formula -Alk 1 -C(=O)-R 9 , wherein Alk 1 is methylene and R 9 is Ci-salkylamino substituted with Cι-6alkyloxycarbonyl; R 2 is halo, C]-6alkyl, C2-6alkenyl, Ci-6alkyloxy, trihalomethoxy, hydroxyC i-^alkyloxy or Ar 1 ; R 3 is hydrogen; R 4 is methyl bound to the nitrogen in 3-position of the imidazole; R 5 is hydrogen; R 6 is chloro; R 7 is hydrogen; R 8 is hydrogen, hydroxy, haloCi-όalkyl, Ci-rsalkyloxycarbonylCi-galkyl, imidazolyl, or a radical of formula -NR π R 12 wherein R 11 is hydrogen or Ci-røalkyl and R 12 is hydrogen, Cj-jalkyl, Ci-βalkyloxy, Ci- r salkyloxyCi^alkylcarbonyl, or a radical of formula -Alk 2 -OR 13 wherein R 13 is Ci-galkyl; R 17 is hydrogen and R 18 is hydrogen. Most preferred compounds are 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(l-methyl-lH-imidazol-5-yl)methyl]-l- methyl-2( 1 H)-quinolinone, 6-[amino(4-chlorophenyl)-l-methyl-lH-imidazol-5-ylmethylJ-4-(3-chiorophenyl)- l-methyl-2(lH)-quinolinone; 6-[(4-chlorophenyl)hydroxy(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-l- methyl-2(lH)-quinolinone; 6-[(4-chlorophenyl)( 1 -methyl- l /-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)- l-methyl- 2(lH)-quinolinone onohydrochloride.monohydrate; 6-[amino(4-chlorophenyl)(l -methyl- lH-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-l- methyl-2(lH)-quinolinone, 6-amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-l-methyl-4-(3- propylphenyl)-2(l )-quinolinone; a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salt; and (B)-6-[amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-chlorophenyl)- l-methyl-2(lH)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof. The compounds of formula (I), wherein X is oxygen, said compounds being represented by formula (Ta), may be prepared by hydrolysing an intermediate ether of formula (II), wherein R is Cι-6alkyl, according to aπ-known methods, such as stirring the intermediate of formula (II) in an aqueous acid solution. An appropriate acid is for instance hydrochloric acid. Subsequently the resulting quinolinone wherein R 1 is hydrogen may be transformed into a quinolinone, wherein R 1 has a meaning as defined hereinabove apaπ from hydrogen, by aπ-known N-alkylation. (ID (I-a) The compounds of formula (I), wherein R 8 is hydroxy, said compounds being referred to as compounds of formula (I-b) may be prepared by reacting an intermediate ketone of formula (III) with a intermediate of formula (IV-a), wherein P is an optional protective group such as, for example, a sulfonyl group, e.g. a dimethylamino sulfonyl group, which can be removed after the addition reaction. Said reaction requires the presence of a suitable strong base, such as, for example, butyl lithium in an appropriate solvent, such as, for example, tetrahydrofuran and the presence an appropriate silanederivative, such as, for example, triethylchlorosilane. During the work-up procedure an intermediate silane derivative is hydrolyzed. Other procedures with protective groups analogous to silanederivatives can also be applied. Compounds of formula (I-b-1), being compounds of formula (I-b) wherein the dotted line is a bond and R 1 is hydrogen, can be prepared by reacting an intermediate of formula (XXI) with an intermediate of formula (TV-a), as described hereinabove for the synthesis of compounds of formula (I-b). The thus obtained intermediate of formula (XXII) undergoes ring opening of the isoxazole moiety by stirring it with an acid, such as, e.g. TiCl3, in the presence of water. Subsequent treatment of an intermediate of formula (XXIII) with a suitable reagent such as, e.g. R 17 CH2θOCl or R 17 CH2COOC2H5, yields either directly a compound of formula (I-b-1) or an intermediate which can be convened to a compound of formula (I-b-1) by treatment with a base such as, e.g. potassium tert-butoxide. Intermediates of formula (XXI) can conveniently be prepared by treating an intermediate of formula (XVI), described hereinafter, under acidic conditions. Compounds of formula (I) wherein R 8 is a radical of formula -N-R 1 ! R 12 , said compounds being represented by formula (I-g) may be prepared by reacting an intermediate of formula (XLII), wherein W is an appropriate leaving group such as, for example, halo, with a reagent of formula (XIV). Said reaction may be performed by stirring the reactants in an appropriate solvent such as, for example, tetrahydrofuran. The compounds of formula (I) may also be prepared by converting compounds of formula (I) into other compounds of formula (I). Compounds wherein the dotted line represents a bond can be convened into compounds wherein the dotted line does not represent a bond, by aπ-known hydrogenation methods. Vice versa, compounds wherein the dotted line does not represent a bond may be converted into compounds wherein the dotted line represents a bond by aπ-known oxidation reactions. Compounds of formula (I) wherein R 8 is hydroxy, said compounds being represented by formula (I-b) may be converted into compounds of formula (I-c), wherein R 8a has the meaning of R 10 except for hydrogen, by aπ-know 0-alkylation or O-acylation reactions; such as, for instance, reacting the compound of formula (I-b) with an alkylating reagent such as R 8a -W in appropriate conditions, such as, for example, a dipolar aprotic solvent, e.g. DMF, in the presence of a base, e.g. sodium hydride. W is a suitable leaving group, such as, for example, halo or a sulfonylgroup. As an alternative to the above reaction procedure, compounds of formula (I-c) may also be prepared by reacting an intermediate of formula (I-b) with a reagent of formula R 8a -OH in acidic medium. Compounds of formula (I-b) may also be converted into compounds of formula (I-g), wherein R 11 is hydrogen and R 12 is Cι-i6alkylcarbonyl, by reacting compounds of formula (I-b) in acidic medium, such as sulfuric acid, with Ci-i6alkyl-CN in a Ritter type reaction. Further, compounds of formula (I-b) may also be converted into compounds of formula (I-g), wherein R 1 1 and R 12 are hydrogen, by reacting compounds (I-b) with ammonium acetate and subsequent treatment with NH3 (aq.). Compounds of formula (I-b) may also be converted into compounds of formula (I-d), wherein R 8 is hydrogen, by submitting the compounds of formula (I-b) to appropriate reducing conditions, such as, stirring in trifluoroacetic acid in the presence of an appropriate reducing agent, such as sodium borohydride or alternatively stirring the compounds of formula (I-b) in acetic acid in the presence of formamide. Furthermore, compounds of formula (I-d) wherein R 8 is hydrogen may be converted into compounds of formula (I-e) wherein R 8D is Cι-6alkyl by reacting compounds of formula (I-d) with a reagent of formula (V) in an appropriate solvent, such as, for instance, diglyme in the presence of a base such as, for example, potassium butoxide. A compound of formula (I-f), defined as a compound of formula (I) wherein X is sulfur may be prepared by reacting the corresponding compound of formula (I-a), with a reagent like phόsphoms pentasulfide or Lawesson's reagent in a suitable solvent such as, for example, pyridine. Compounds of formula of formula (I), wherein R 1 is hydrogen and X is oxygen, said compounds being defined as compounds of formula (I-a-1) may be prepared by reacting a nitrone of formula (VI) with the anhydride of a carboxylic acid, such as, for example, acetic anhydride, thus forming the corresponding ester on the 2 position of the quinoline moiety. Said quinoline ester can be hydrolyzed in situ to the corresponding quinolinone using a base such as, for example, potassium carbonate. Alternatively, compounds of formula (I-a-1) can be prepared by reacting a nitrone of formula (VI) with a sulfonyl containing electrophilic reagent such as, for example, /?-toluenesulfonylchloride in the presence of a base such as, for example, aqueous potassium carbonate. The reaction initially involves the formation of a 2-hydroxy- quinoline derivative which is subsequently tautomerized to the desired quinolinone derivative. The application of art-known conditions of phase transfer catalysis may enhance the rate of the reaction. Compounds of formula (I-a-1) may also be prepared by an intramolecular photochemical rearrangement of compounds of formula (VI). Said rearrangement can be carried out by dissolving the reagents in a reaction-inert solvent and irradiating at a wavelength of 366 nm. It is advantageous to use degassed solutions and to conduct the reaction under an inert atmosphere such as, for example, oxygen free argon or nitrogen gas, in order to minimize undesired side reactions or reduction of quantum yield. The compounds of formula (I) may also be converted into each other via art-known reactions or functional group transformations. A number of such transformations are already described hereinabove. Other examples are hydrolysis of carboxylic esters to the corresponding carboxylic acid or alcohol; hydrolysis of amides to the corresponding carboxylic acids or amines; hydrolysis of nitriles to the corresponding amides; amino groups on imidazole or phenyl may be replaced by a hydrogen by art-known diazotation reactions and subsequent replacement of the diazo-group by hydrogen; alcohols may be converted into esters and ethers; primary amines may be converted into secondary or tertiary amines; double bonds may be hydrogenated to the corresponding single bond. Intermediates of formula (III) may be prepared by reacting a quinolinone derivative of formula (VIII) with an intermediate of formula (LX) or a functional derivative thereof under appropriate conditions, such as, for example, a strong acid, e.g. polyphosphoric acid in an appropriate solvent. The intermediate of formula (VIII) may be formed by cyclization of an intermediate of formula (VII) by stirring in the presence of a strong acid, e.g. polyphosphoric acid. Optionally said cyclization reaction may be followed by an oxidation step, which can be performed by stirring the intermediate formed after cyclization in an appropriate solvent, such as, for example, a halogenated aromatic solvent, e.g. bromobenzene, in the presence of a oxidizing agent, e.g. bromine or iodine. At this stage it may also be appropriate to change the R 1 substituent by art- known functional group transformation reaction. Intermediates of formula (ffi-a-1), being intermediates of formula (HI) wherein the dotted line is a bond, R 1 and R 17 are hydrogen and X is oxygen, can be prepared starting from an intermediate of formula (XVII), which is conveniently prepared by protecting the corresponding ketone. Said intermediate of formula (XVII) is stirred with an intermediate of formula (XVIII) in the presence of a base such as sodium hydroxide, in an appropriate solvent, such as an alcohol, e.g. methanol. The thus obtained intermediate of formula (XVI) undergoes hydrolysis of the ketal and ring opening of he isoxazole moiety by stirring the intermediate of formula (XVI) with an acid, such as for example, TiCl3, in the presence of water. Subsequently acetic anhydride is used to prepare an intermediate of formula (XV), which undergoes ring closure in the presence of a base such as, for example, potassium tert-butoxide. (XVII) (XVI) Intermediates of formula (III-a-1) can easily be converted to intermediates of formula (Ill-a), defined as intermediates of formula (HI) wherein the dotted line represents a bond, X is oxygen, R 17 is hydrogen and R 1 is other than hydrogen, using art-known N-alkylation procedures. (Ill-a) An altemative way to prepare intermediates of formula (III-a-1), wherein X is oxygen and R 1 is hydrogen, starts from an intermediate of formula (XVI), which is conveniently converted to intermediates of formula (XIX) using catalytic hydrogenation conditions, e.g. by using hydrogen gas and palladium on carbon in a reaction-inert solvent such as, e.g. tetrahydrofuran. Intermediates of formula (XIX) are converted to intermediates of formula (XX) by submitting intermediates (XIX) to an acetylation reaction, e.g. by treatment with the anhydride of a carboxylic acid, e.g. acetic anhydride in a reaction-inert solvent, e.g. toluene, and subsequent treatment with a base such as, e.g. potassium tβrt-butoxide in a reaction-inert solvent, e.g. 1,2-dimethoxyethane. Intermediates of formula (TII-a-1) can be obtained by treating intermediates of formula (XX) in acidic conditions. (XIX) (XX) Intermediates of formula (II) may be prepared by reacting an intermediate of formula (X), wherein W is an appropriate leaving group, such as, for example, halo, with an intermediate ketone of formula (XI). This reaction is performed by convening the intermediate of formula (X) into a organometallic compound, by stirring it with a strong base such as butyl lithium and subsequently adding the intermediate ketone of formula (XI). Although this reaction gives at first instance a hydroxy derivative (i.e. R 8 is hydroxy), said hydroxy derivative can be convened into other intermediates wherein R 8 has another definition by performing art-known (functional group) transformations. The intermediate nitrones of formula (VI) may be prepared by N-oxidizing quinoline derivatives of formula (XII) with an appropriate oxidizing agent such as, for example, m-chloro-peroxybenzoic acid or H2O2 in an appropriate solvent such as, for example, dichloromethane. Said N-oxidation may also be carried out on a precursor of a quinoline of formula (XII). The intermediates of formula (XII) are supposed to be metabolized in vivo into compounds of formula (I) via intermediates of formula (VI). Hence, intermediates of formula (XII) and (VI) may act as prodrugs of compounds of formula (I). The compounds of formula (I) and some of the intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration. The compounds of formula (I) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An altemative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of the invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g. loss of contact inhibition). This includes the abnormal growth of : (1) tumor cells (tumors) expressing an activated ras oncogene; (2) tumor cells in which the ras protein is activated as a result of oncogenic mutation of another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant ras activation occurs. Furthermore, it has been suggested in literature that ras oncogenes not only contribute to the growth of of tumors in vivo by a direct effect on tumor cell growth but also indirectly, i.e. by facilitating tumor-induced angiogenesis (Rak. J. et al, Cancer Research, 55, 4575-4580, 1995). Hence, pharmacologically targetting mutant ras oncogenes could conceivably suppress solid tumor growth in vivo, in pan, by inhibiting tumor-induced angiogenesis. This invention also provides a method for inhibiting tumor growth by administering an effective amount of a compound of the present invention, to a subject, e.g. a mammal (and more particularly a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumors expressing an activated ras oncogene by the administration of an effective amount of the compounds of the present invention. Examples of tumors which may be inhibited, but are not limited to, lung cancer (e.g. adenocarcinoma), pancreatic cancers (e.g. pancreatic carcinoma such as, for example exocrine pancreatic carcinoma), colon cancers (e.g. colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), hematopoietic tumors of lymphoid lineage (e.g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal origin (e.g. fibrosarcomas and rhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumor of the skin (e.g. keratoacanthomas), breast carcinoma, kidney carninoma, ovary carcinoma, bladder carcinoma and epidermal carcinoma. This invention may also provide a method for inhibiting proliferative diseases, both benign and malignant, wherein ras proteins are aberrantly activated as a result of oncogenic mutation in genes, i.e. the ras gene itself is not activated by mutation to an oncogenic mutation to an oncogenic form, with said inhibition being accomplished by the administration of an effective amount of the compounds described herein, to a subject in need of such a treatment. For example, the benign proliferative disorder neuro- fibromatosis, or tumors in which ras is activated due to mutation or overexpression of tyrosine kinase oncogenes may be inhibited by the compounds of this invention. Hence, the present invention discloses the compounds of formula (I) for use as a medicine as well as the use of these compounds of formula (I) for the manufacture of a medicament for treating one or more of the above mentioned conditions. Some of the intermediates of formual (XIII), wherein W is halo may also show famesyl protein transferase inhibiting activity. In view of their useful pharmacological properties, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions of this invention, an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier ay take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, to aid solubility for example, 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 liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof. Those skilled in the art could easily determine the effective amount from the test results presented hereinafter. In general it is contemplated that an effective amount would be from 0.0001 mg/kg to 100 mg kg body weight, and in particular from 0.001 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 0.01 to 500 mg, and in particular 0.1 mg to 200 mg of active ingredient per unit dosage form. Experimental part Hereinafter "THF" means tetrahydrofuran, "DIPE" means dusopropylether, "DCM" means dichloromethane, "DMF" means N,N-dirnethylformarnide and "ACΝ" means acetonitrile. Of some compounds of formula (I) the absolute stereochemical configuration was not experimentally determined. In those cases the stereochemically isomeric form which was first isolated is designated as "A" and the second as "B", without further reference to the actual stereochemical configuration. A. Preparation of the intermediates Example A.l la) N-Phenyl-3-(3-chlorophenyl)-2-proρenamide (58.6 g) and polyphosphoric acid (580 g) were stirred at 100°C ovemight. The product was used without further purification, yielding quant. (±)-4-(3-chlorophenyl)-3,4-dihydro-2(l )-quinolinone (interm. 1-a). lb) Intermediate (1-a) (58.6 g), 4-chlorobenzoic acid (71.2 g) and polyphosphoric acid (580 g) were stirred at 140°C for 48 hours. The mixture was poured into ice water and filtered off. The precipitate was washed with water, then with a diluted ΝH 4 OH solution and taken up in DCM. The organic layer was dried (MgSO 4 ), filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent : CH2CI2/CH3OH/NH 4 OH 99/1/0.1). The pure fractions were collected and evaporated, and recrystallized from CH2CI2/CH3OH DIPE, yielding 2.2g of (±)-6-(4- chlorobenzoyl)-4-(3-chlorophenyl)-3,4-dihydro-2(l /)-quinolinone (interm. 1-b, mp. 194.8°C ). Ic) Bromine (3.4 ml) in bromobenzene (80 ml) was added dropwise at room temperature to a solution of intermediate (1-b) (26 g) in bromobenzene (250 ml) and the mixture was stirred at 160°C overnight. The mixture was cooled to room temperature and basified with NH 4 OH. The mixture was evaporated, the residue was taken up in ACN and filtered off. The precipitate was washed with water and air dried, yielding 24 g (92.7%) of product. A sample was recrystallized from CH2CI2/ CH3OH/DIPE, yielding 2.8 g of 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-2(l /)-quinolinone; mp. 234.8°C (interm. 1-c). Id) lodomethane (6.2 ml) was added to a mixture of intermediate (1-c) (20 g) and benzyltriethylammonium chloride (5.7 g) in tetrahydrofuran (200 ml) and sodium hydroxide (ION) (200 ml) and the mixture was stiπed at room temperature ovemight. ethyl acetate was added and the mixture was decanted. The organic layer was washed with water, dried (MgSO 4 ), filtered off and evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent : CH2CI2/CH3OH/NH OH 99.75/0.25/0.1). The pure fractions were collected and evaporated, yielding 12.3 g (75%) of 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-l-methyl-2(lH)-quinolinone; mp. 154.7°C (interm. 1-d). In a similar way, but starting from intermediate (1-b), (±)-6-(4-chlorobenzoyl)-4-(3- chlorophenyl)-3,4-dihydro-l-methyl-2(lH)-quinolinone (interm 1-e) was prepared. Example A.2 Butyllithium in hexane (1.6 M) (12.75 ml) was added dropwise at -20°C under N2 to a solution of 6-bromo-4-(3-chlorophenyl)-2-methoxyquinoline (6.7 g) in THF (60 ml) and the mixture was stirred at -20°C for 30 minutes. A solution of (1 -butyl- 1H- imidazol-5-yl)(4-chlorophenyl)methanone (3.35 g) in tetrahydrofuran (30 ml) was added at -20°C under N2 and the mixture was stirred at room temperature for one night. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent : CΗ2CI2/CΗ3OΗ/NΗ4OΗ 97/3/0.1). The pure fractions were collected and evaporated, yielding 2.5 g (total 48%) of (±)-α-(l-butyl- lH-imidazol-5-yl)-4-(3-chlorophenyl)-α-(4-chlorophenyl)-2-methoxy-6-quinoline- methanol (interm. 2). Example A.3 3a) Butyllithium (30.1ml) was added slowly at -78°C to a solution of N,N-dimethyl- lH-imidazol-1 -sulfonamide (8,4 g) in tetrahydrofuran (150 ml) and the mixture was stirred at -78°C for 15 minutes. Chlorotiiethylsilane (8.1 ml) was added and the mixture was stirred till the temperature reached 20°C. The mixture was cooled till -78°C, butyllithium (30.1 ml) was added, the mixture was stirred at -78°C for 1 hour and allowed to reach -15°C. The mixture was cooled again till -78"C, a solution of 6-(4- chlorobenzoyl)-l-methyl-4-phenyl-2(lH)-quinolinone (15 g) in tetrahydrofuran (30 ml) was added and the mixture was stirred till the temperature reached 20°C. The mixture was hydrolized and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The product was used without further purification, yielding 26 g (100%) of (±)-4-f(4-chlorophenyl)(l,2-dihydro-l-methyl-2- oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N /-dimethyl-2-(triethylsilyl)-lH- imidazole- 1 -sulfonamide (interm. 3-a). A mixture of intermediate (3-a) (26 g) in sulfuric acid (2.5 ml) and water (250 ml) was stiπed and heated at 110°C for 2 hours. The mixture was poured into ice, basified with ΝH 4 OH and extracted with DCM. The organic layer was dried (MgSO_j), filtered off and evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent : CH 2 CI 2 /CH3OH/NH 4 OH 99/1/0.2). The pure fractions were collected and evaporated, yielding 2.4 g (11%) of (±)-4-[(4-chlorophenyl)(l,2-dihydro-l-methyl- 2-oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N,N-dimethyl-lH-imidazole-l- sulfonamide (interm. 3-b). Example A.4 Compound (3) (3 g) was added at room temperature to thionyl chloride (25 ml). The mixture was stirred and refluxed at 40°C overnight. The solvent was evaporated till dryness. The product was used without further purification, yielding 3.49 g of (±)-4- (3-chlorophenyl)-l-methyl-6-[ l-(4-methylphenyl)-l-(4-methyl-4H-pyrrol-3-yl)ethyl]- 2(lH)-quinolinone hydrochloride (interm. 4). Example A.5 a) Toluene (1900 ml) was stirred in a round-bottom flask (5 1) using a water separator. (4-Chlorophenyl)(4-nitrophenyl)methanone (250 g) was added portionwise. ^-Toluene¬ sulfonic acid (54.5 g) was added portionwise. Ethylene glycol (237.5 g) was poured out into the mixture. The mixture was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was dissolved into ethyl acetate (5 1) and washed twice with a K 2 CO3 10% solution. The organic layer was separated, dried (MgSO 4 ), filtered and the solvent was evaporated. The residue was stirred in DIPE, filtered off and dried (vacuum, 40°C, 24 hours), yielding 265 g (91%) of 2-(4-chloroρhenyl)-2-(4-nitrophenyl)- l,3- dioxolane (interm. 5-a). b) Sodium hydroxide (16.4 g) and (3-methoxyphenyl)acetonitrile (20.6 ml) were added at room temperature to a solution of interm. (5-a) (25 g) in methanol (100 ml) and the mixture was stirred at room temperature ovemight. Water was added, the precipitate was filtered off, washed with cold methanol and dried. The product was used without further purification, yielding 30 g (90%) of 5-[2-(4-chlorophenyl)-l,3-dioxolan-2-yl]-3-(3- methoxyphenyl)-2,l-benzisoxazoIe (interm. 5-b). c) Interm. (5-b) (30 g) in TΗF (250 ml) was hydrogenated with palladium on carbon (3 g) as a catalyst at room temperature for 12 hours under a 2.6 10 5 Pa pressure in a Parr apparatus. After uptake of H2 (1 equivalent), the catalyst was filtered through celite and the filtrate was evaporated till dryness. The product was used without fuπher purification, yielding 31.2g (100%) of (3-methoxyphenyl)[2-amino-5-[2-(4-chloro- pheny l)-l,3-dioxolan-2-yl]phenylJmethanone (interm. 5-c). d) Acetic anhydride (13.9 ml) was added to a solution of interm. (5-c) (31.2 g) in toluene (300 ml) and the mixture was stirred and refluxed for 2 hours. The mixture was evaporated till dryness and the product was used without further purification, yielding 36.4 g (100%) of N-[2-(3-methoxybenzoyl)-4-[2-(4-chlorophenyl)-l ,3-dioxolan-2- yl]phenyl]acetamide (interm. 5-d). e) Potassium tert-butoxide (33 g) was added portionwise at room temperature to a solution of interm. (5-d) (36.4 g) in 1,2-dimethoxyethane (350 ml) and the mixture was stirred at room temperature ovemight. The mixture was hydrolized and extracted with DCM. The organic layer was dried (MgSO 4 ), filtered off and evaporated till dryness. The product was used without further purification, yielding 43 g of 6-[2-(4-chloro- phenyl)- 1 ,3-dioxolan-2-yl]-4-(3-methoxyphenyl)-2( lH)-quinolinone (interm. 5-e). f) A mixture of interm. (5-e) (43 g) in HCl (3Ν, 400 ml) and methanol (150 ml) was stirred and refluxed ovemight. The mixture was cooled and filtered off. The precipitate was washed with water and diethyl ether and dried. The product was used without further purification, yielding 27g (94%) of 6-(4-chlorobenzoyl)-4-(3-methoxyphenyl)- 2(lH)-quinolinone (interm. 5-f). g) Methyl iodide (1.58 ml) was added to a solution of interm. (5-f) (7.6 g) and benzyl- triethylammonium chloride (BTEAC) (2.23 g) in THF (80 ml) and sodium hydroxide (40%, 80 ml). The mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent : DCM 100%). The desired fractions were collected and the solvent was evaporated, yielding 7.1 g (90%) of 6-(4-chlorobenzoyl)-4- (3-methoxyphenyl)-l-methyl-2(lH)-quinolinone (interm. 5-g). Example A.6 a) 3-(3-Chlorophenyl)-5-[2-(4-chlorophenyl)-l,3-dioxolan-2-ylJ-2,l-benzisoxazole (interm. 6-a) was prepared analogous as intermediate (5-b). b) A mixture of intermediate (6-a) (30 g) in HCl 3 N (220 ml) and methanol (165 ml) was stirred at 100°C for 5 hours. The mixture was poured into ice and basified with NH3 (aq.). The precipitate was filtered off, washed with water and diethyl ether and dried, yielding 24.9 g (93%) of (4-chlorophenyl)[3-(3-chlorophenyl)-2,l-benzisoxazol- 5-yl]methanone (interm. 6-b). The product was used without further purification. c) Butyllithium in hexanes (10 ml) was added slowly at -70°C under N2 flow to a solution of 1-methylimidazole (1.31 g) in THF (30 ml). The mixture was stirred at -70°C for 45 minutes. Chlorotriethylsilane (2.7 ml) was added. The mixture was allowed to warm to 15°C and cooled to -70° C. Butyllithium (10 ml) was added slowly. The mixture was stirred at -70°C for 1 hour, allowed to warm to -15°C and cooled to -70 * C. A solution of intermediate (6-b) (4.9 g) in THF (60 ml) was added. The mixture was stirred at -70°C for 30 minutes, then hydrolyzed with water, extracted with ethyl acetate and decanted. The organic layer was dried (MgSU4), filtered and the solvent was evaporated. The residue (8.2 g) was purified by column chromatography over silica gel (eluen : CH2Q2/CH3OH/NH4OH 96/4/0.2) and crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried, yielding 1.5 g (25%) of (±)-3-(3- chlorophenyl)-α-(4-chlorophenyl)-α-(l-methyl-lH-imidazol-5-yl)-2,l-benziso\azole-5- methanol (interm. 6-c). d) TiCl3/15% in H2O (200 ml) was added at room temperature to a solution of intermediate (6-c) (38 g) in THF (300 ml). The mixture was stirred at room temperature for 90 minutes. The mixture was poured out on ice, basified with K2CO3, filtered over celite, washed with ethyl acetate and decanted. The organic layer was dried (MgSO 4 ), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent : CH2CI2 CH3OH NH 4 OH 97/3/0.1 and 95/5/0.1), yielding 18.7 g (49%) of (±)-[2-amino-5-[(4-chlorophenyl)hydroxy(l- methyl- lH-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)methanone (interm. 6-d). B. Preparation of the final compounds Example B.l 1 -Methylimidazole (4.69 ml) in tetrahydrofuran (100 ml) was stirred at -78 Φ C. A solution of butyllithium in hexanes (2.5 M) (36.7 ml) was added dropwise and the mixture was stirred at -78°C for 15 minutes. Chlorothiethylsilane (9.87 ml) was added and the mixture was brought to room temperature. The mixture was cooled till -78°C, a solution of butyllithium in hexanes (2.5 M) (36.7 ml) was added dropwise, the mixture was stirred at -78"C for 1 hour and brought till -15°C. The mixture was cooled till -78°C, a solution of intermediate (1-d) (20 g) in THF (40 ml) was added and the mixture was brought to room temperature. The mixture was hydrolized at 0°C and extracted with ethyl acetate. The organic layer was dried (MgSU 4 ), filtered off and evaporated till dryness, yielding 36 g of product. The product was purified by column chromatography over silica gel (eluent : CH2CI2/CH3OH/NH4OH 97/3/0.1). The pure fractions were collected, evaporated, and crystallized from 2-propanone, CH3OH and (C2H5)2θ. The precipitate was filtered off, washed with (C^Hs^O and dried, yielding 12.4 g (52%) of (±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(l -methyl- lH-imidazol-5- yl)methyl]-l-methyl-2(lH)-quinolinone; (comp. 3, mp.233.6°C ). In a similar way, but using intermediate (5-g) or intermediate (1-e) instead of intermediate (1-d), respectively (±)-6-[(4-chlorophenyl)hydroxy(l -methyl- l//-imidazol- 5-yl)methylJ-4-(3-methoxyphenyl)-l-methyl-2(l/7)-quinolinone (comp. 36) and (±)-4- (3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(l -methyl- l//-imidazol-5-yl)methyl]-3,4- dihydro-l-methyl-2(lH)-quinolinone (comp. 127) were prepared. Example B.2 Hydrochloric acid (60 ml) was added to a solution of intermediate (2) (2.5 g) in THF (10 ml) and the mixture was stirred and heated at 100°C for 3 hours. The mixture was cooled, the precipitate was filtered off, washed with water, then with diethyl ether and dried, yielding 2.7 g (100%) of (±)-6-[(l-butyl-lH-imidazol-5-yl)-(4-chloro- phenyl)hydroxymethyl]-4-(3-chlorophenyl)-2(lH)-quinolinone (comp. 8). Example B.3 Sodium hydride (0.28 g) was added to a mixture of compound (3) (3 g) in DMF (50 ml) under N2 and the mixture was stirred for 15 minutes. lodomethane (1.5 ml) was added and the mixture was stirred at room temperature for lhour. The mixture was hydrolized and extracted with diethyl ether and methanol. The organic layer was dried (MgSO 4 ), filtered off and evaporated till dryness, yielding 4.4 g of residue. The residue was purified by column chromatography over silica gel (eluent : CΗ2CI2/CΗ3OΗ/NΗ4OΗ 95.5/4.5/0.2). The pure fractions were collected and evaporated. The product was converted into the ethanedioic acid salt (1 : 1 ) in 2-propanone and filtered off. The residue was crystallized from 2-propanone, diethyl ether and DIPE. The precipitate was filtered off, washed with diethyl ether, dried and recrystallized from 2-propanone, methanol and DIPE. The precipitate was filtered off, washed with diethyl ether and dried, yielding 0.95 g (25%) of (±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)methoxy(l -methyl- 1H- imidazol-5-yl)methyl]-l-methyl-2(lH)-quinolinone ethanedioate(l:l).dihydrate; (comp. 4, mp. 154.6°C). Example B.4 lodomethane (0.38 ml) was added dropwise at room temperature to a solution of compound (8) (2.44 g) and N,N,N-triethylbenzenemethanaminium chloride (0.54 g) in tetrahydrofuran (30 ml) and sodium hydroxide (40%) (30 ml) and the mixture was stirred at room temperature for 3 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO 4 ), filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent : CΗ2CI2/CΗ3OΗ ΝH 4 OH 96.5/3.5/0.1 ). The pure fractions were collected, evaporated and crystallized from 2-propanone and DIPE. The precipitate was filtered off, washed with diethyl ether and dried, yielding 1.4 g (56%) of (±)-4-(3-chlorophenyl)-6-[(l-butyl- lH-imidazol-5-yl)(4-chlorophenyl)hydroxymethyl]-l-methyl-2(lH)-quinolinone; (comp. 9, mp. 174.6'C). Example B.5 lodomethane (1.4 ml) was added to a mixture of (±)-6-[(4-chlorophenyl)-lH- imidazol-4-ylmethyl]-l-methyl-4-phenyl-2(lH)-quinolinone (7.5 g) and benzyltriethylammonium chloride (2 g) in TΗF (75 ml) and sodium hydroxide (75 ml) and the mixture was stirred at room temperature for 1 hour. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent : CΗ2CI 2 CΗ3OΗ/NΗ 4 OΗ 98.5/1.5/0.1). The pure fractions were collected and evaporated. Fraction 1 (3.5 g) was recrystallized from diethyl ether, yielding 3.3 g (42%) of (±)-6-[(4-chlorophenyl)(l-methyl-lH-imidazol-4-yl)methyl]-l- methyl-4-phenyl-2(lH)-quinolinone; mp. 149.9°C (comp. 44). Fraction 2 was recrystallized from 2-propanone, methanol and diethyl ether, yielding 1.6 g (20%) of (±)-6-[(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-l-methyl-4-phenyl-2(lH)- quinolinone (comp. 2, mp. 96.8°C). Example B.6 Sodium borohydride (5.6 g) was added portionwise at 0°C under N2 to compound (3) (7.2 g) dissolved in trifluoroacetic acid (150 ml) and the mixture was stirred at room temperature ovemight. The mixture was poured into ice, basified with NaOΗ 3N, then concentrated NaOΗ and extracted with ethyl acetate. The organic layer was dried (MgSO 4 ), filtered off and evaporated till dryness. The residue was purified by column chromatography over silica gel (eluen : CΗ2CI2/CΗ3OΗ 95/5). The pure fractions were collected and evaporated, yielding 4.3 g (62%) of fraction 1 ; 0.2 g (3%) of fraction 2 and 2 g (29%) of fraction 3. Fraction 1 was converted into the ethanedioic acid salt (1 : 1) in 2-propanone and diethyl ether. The precipitate was filtered off, washed with diethyl ether and dried, yielding 4.7 g (55%) of (±)-4-(3-chlorophenyl)-6-f(4-chlorophenyl)(l- methyl- lH-imidazol-5-yl)methyl]-l-methyl-2(lH)-quinolinone ethanedioate(l :l). mono¬ hydrate (comp. 5, mp. 157.4°C). Example B.7 A solution of compound 90 (4.2 g) in 1,2-dimethoxyethane (70 ml) was stiπed under N2 for 30 minutes. lodomethane (0.83 ml), followed by potassium tert-butoxide (2 g) were added portionwise and the mixture was stirred at room temperature for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO 4 ), filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent : cyclohexane/2-propanol/NΗ 4 θΗ 85/5/0.5 to 80/20/1) and converted into the ethanedioic acid salt, crystallized from 2-propanone and filtered off, yielding 1.16 g (23.6%) of (±)-4-(3-chlorophenyl)-6-[ l-(4-chloro-phenyl)- l-(l-methyl-lH-imidazol-5-yl)ethyl]-l-methyl-2(lH)-quinolinone.ethanedioate (1: 1); (comp. 12, mp. 203.9°C). In a similar way, but replacing iodomethane by dichloromethane or dibromomethane, respectively (±)-6-[2-chloro-l-(4-chlorophenyl)-l-(l-methyl-lH-imidazol-5-yl)ethyl]-4- (3-chlorophenyl)-l-methyl-2(lH)-quinolinone ethanedioate (1 :1) (comp. 69) and (±)-6- [2-bromo-l-(4-chlorophenyl)-l-(l -methyl- lH-imidazol-5-yl)ethyl]-4-(3-chlorophenyl)- l-methyl-2(lH)-quinolinone (comp. 70) were prepared. Example B.8 a) Compound (3) (3 g) was separated (into its enantiomers) and purified by high-performance liquid chromatography over Chiracel OD (20 μm; eluent : hexane/ethanol 50/50). The pure (A)-fractions were collected, and the solvent was evaporated, yielding 1.6 g ((A); LCI: > 99%). The pure (B)-fractions were collected, and the solvent was evaporated, yielding 1.5 g ((B); LCI: > 99%). The (A)-residue was dissolved in 2-propanol and converted into the ethanedioic acid salt (1:1). The precipitate was filtered off and dried, yielding 0.6 g (17%) of (A)-4-(3-chlorophenyl)-6-[(4-chloro- phenyl)-hydroxy ( 1 -methyl- 1 H-imidazol-5-yl)methyl] - 1 -methyl-2( 1 H)-quinolinone ethanedioate (1:1) ; [α]^ = + 17.96° (c = 1% in methanol) (comp. 23). The (B)-residue was dissolved in 2-propanol and converted into the ethanedioic acid salt (1 :1). The precipitate was filtered off and dried, yielding 0.6 g (17%) (B)-4-(3-chlorophenyl)-6-[(4- chlorophenyl)hydroxy(l -methyl- lH-imidazol-5-yl)methyl]-l-methyl-2(lH)-quinolinone ethanedioate(l:l); [α]^ 0 = - 18.87° (c = 1% in methanol) (comp. 24). b) Compound 14 (4 g) was separated (into its enantiomers) and purified by chiral column chromatography over Chiralcel OD (25 cm; eluent : 100% ethanol; flow: 0.5 ml/min; wavelength : 220 nm). The pure (A)-fractions were collected, and the solvent was evaporated. This residue was dissolved in DCM (100 ml), filtered, and the filtrate was evaporated. The residue was stirred in DIPE (100 ml), filtered off and dried, yielding 1.3 g (A)-6-[amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-chloro- phenyl)-l-methyl-2(lH)-quinolinone (comp. 74). The pure (B)-fractions were collected and evaporated. The residue was crystallized from 2-propanol. The precipitate was filtered off, yielding 1.3 g (B)-6-[amino(4-chloro- phenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-l-methyl-2(lH)- quinolinone ([α] 2 D 0 = + 22.86° (c = 49.22 mg/5 ml in methanol) (comp. 75). Example B.9 Air was bubbled through a solution of compound (47) (3.6 g) in TΗF (40 ml) for 30 minutes. 2-Methyl-2-propanol potassium salt (4.4 g) was added. The mixture was stirred at room temperature for 3 hours, hydrolyzed and then extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaparated, yielding 2.9 g of product. The product was purified by column chromatography over silica gel (eluent : CH2CI2/ CH3OH/NH 4 OH 97.5/2.5/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone / DIPE. The precipitate was filtered off and dried, yielding 1.3 g (35%) of (±)-4-(3-chlorophenyl)-6-f(4-chlorophenyl)hydroxy(l -methyl- lH-imidazol-4- yl)methyl]-l-methyl-2(lH)-quinolinone (comp. 48). Example B.10 A mixture of (±)-4-f(4-chlorophenyl)(l,2-dihydro-l-methyl-2-oxo-4-phenyl-6- quinolinyl)hydroxymethylJ-N,N-dimethyl-lH-imidazole-l-sulfonamide (2.4 g) in hydrochloric acid (10 ml), water (30 ml) and methanol (15 ml) was stirred and heated at 110°C for 14 hours. The mixture was cooled, basified with ΝΗ3 (aq.) and extracted with DCM. The organic layer was dried (MgSO 4 ), filtered off and evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent : CH2CI2 CH3OH/NH 4 OH 95/5/0.2). The pure fractions were collected and evaporated. The residue (1.25 g) was crystallized from 2-propanone/ DIPE, yielding 1 g (48.3%) of (±)-6-f(4-chlorophenyl)hydroxy(lH-imidazol-4-yl)methyl]-l-methyl-4-phenyl-2(lH)- quinolinone monohydrate (comp. 43). Example B. l l Compound (3) (4 g) was dissolved in DCM (10 ml) and acetic acid (5.6 ml) at 45°C. Zinc chloride (5.5 g), followed by cyanoacetic acid (3.5 g) were added. The mixture was stirred at 120°C for 3 hours and then at 160°C for 10 hours. Water was added and the mixture was extracted with DCM. The organic layer was washed with K2CO3 10%, dried (MgSO 4 ), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent : CΗ2CI2 CΗ3OΗ/NΗ 4 OΗ 96/4/0.2), crystallized from 2-propanone/ DIPE, filtered off and dried, yielding 1.95 g (45%) of (±)-4-(3-chlorophenyl)-β-(4-chlorophenyl)-l,2-dihydro-l-methyl-β-(l-methyl-lH- imidazol-5-yl)-2-oxo-6-quinolinepropanenitrile; (comp. 25, mp. 151.3°C). Example B.12 Sulfuric acid (1 ml) was added dropwise to acetonitrile (30 ml), while stirring. Compound 3 (3 g) was added. The mixture was stirred at 80°C for 3 hours and then cooled. K2CO3 10% was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried (MgSO 4 ), filtered and the solvent was evaporated till dryness. The residue (3.58 g) was dissolved in 2-propanone and converted into the ethanedioic acid salt (1 :1). The precipitate was filtered off, dried and crystallized from 2-propanone/CΗ3θΗ. The precipitate was filtered off and dried, yielding 3.5 g (92%) of (±)-N-[(4-chlorophenyl)[4-(3-chlorophenyl)-l,2-dihydro-l-methyl-2-oxo-6- quinolinyl]( 1 -methyl- lH-imidazol-5-yl)methyl]acetamide ethanedioate (1: 1) (comp. 56). Example B.13 ΝΗ3 (aq.) (40 ml) was added at room temperature to a mixture of intermediate 4 (7 g) in THF (40 ml). The mixture was stirred at 80°C for 1 hour, then hydrolyzed and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent : toluene/2-propanol/NH 4 OH 80/20/1). The pure fractions were collected and the solvent was evaporated, yielding 4.4 g(±)-6-[amino(4-chlorophenyl)(l -methyl- 1H- imidazol-5-yl)methyl]-4-(3-chlorophenyl)-l-methyl-2(lH)-quinolinone (comp. 14). Example B.M A solution of compound 36 (6.2 g) in DCM (140 ml) was cooled and tribromoborane (32 ml) was added dropwise. The mixture was stirred at room temperature for tho days. The mixture was poured out into ice water, basified with NΗ3 (aq.) and extracted with CH2CI2/CH3OH. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 6 g (100%) of (±-)-6-[(4-chlorophenyl)- hydroxy( 1 -methyl- lH-imidazol-5-yl)methyl]-4-(3-hydroxyphenyl)- 1 -methyl-2( 1H)- quinolinone (comp. 54). Example B.15 A mixture of compound 54 (2.5 g), 2-chloro-N,N-dimethyl-ethanamine (1.9 g) and potassium carbonate (2.2 g) in ACΝ (50 ml) and DMF (50 ml) was stirred at 100°C ovemight. The solvent was evaporated till dryness. The residue was taken up in CΗ2θ2/wa er and decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue (2.7 g) was purified by column chromatography over silica gel (eluent : CH2CI2/CH3OH/ΝH4OH 97/3/0.1 to 90/10/0.1). The pure fractions were collected and the solvent was evaporated. The residue was converted into the ethanedioic acid salt (1:1) in 2-propanone. The precipitate was filtered off, washed with 2-propanone / diethyl ether and dried. The residue was converted into the free base. The precipitate was filtered off and dried. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 0.35 g (12%) of (±)-6-f(4-chloro- phenyl)hydroxy(l-methyl-lH-imidazol-5-yl)methyl]-4-[3-[2-(dimethylamino)ethoxy]- phenyl] -l-methyl-2(lH)-quinolinone (comp. 62). Example B.16 P4S10 (12 g) was added to a mixture of compound 90 (6 g) in pyridine (72 ml). The mixture was stirred and refluxed for 6 hours. Ice water was added. The precipitate was filtered off, washed with water and taken up in DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent : CH2CI2/CH3OH/NH 4 OH 97.5/2.5/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried, yielding 1 g of (±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)(l -methyl- 1H- imidazol-5-yl)methyl]-l-methyl-2(lH)-quinolinethione (comp. 128). Example B.17 A mixture of ethyl malonyl chloride (6.4 ml) in DCM (50 ml) was added dropwise at room temperature to a solution of intermediate (6-d) (15 g) and pyridine (10.7 ml) in DCM (150 ml). The mixture was stirred at room temperature ovemight. Water was added and the mixture was decanted. The organic layer was dried (MgSO 4 ), filtered and the solvent was evaporated. The residue (21 g) was purified by column chromatography over silica gel (eluent : CΗ2Cl2/2-propanol/NΗ 4 θΗ 92/8/0.4). The desired fractions were collected and the solvent was evaporated, yielding 10.9 g (60%) of (±)-ethyl 4-(3- chlorophenyl)-6-[(4-chlorophenyl)hydroxy(l-methyl-lH-imidazol-5-yl)methyl]-l,2- dihydro-2-oxo-3-quinolinecarboxylate (comp. 144). Example B.18 a) A mixture of benzoyl chloride (3.1 ml) in DCM (25 ml) was added dropwise at room temperature to a solution of interm. (6-d) (7 g) and pyridine (5 ml) in DCM (70 ml). The mixture was stirred at room temperature for 45 minutes. Water was added and the mixture was decanted. The organic layer was dried (MgSO 4 ), filtered and the solvent was evaporated, yielding 8.8 g of (±)-N-[2-(3-chlorobenzoyl)-4-[(4-chlorophenyl)- hydroxy(l -methyl- lH-imidazol-5-yl)methyl]phenyl]benzeneacetamide (interm. 7). The product was used without further purification. b) Potassium tert-butoxide (8.7 g) was added to a mixture of intermediate 7 (8.8 g) in DME (70 ml). The mixture was stirred at 50°C for 3 hours. Water (5 ml) was added and the solvent was evaporated, yielding 8.5 g of (±)-4-(3-chlorophenyl)-6-[(4-chloro- phenyl)hydroxy(l -methyl- lH-imidazol-5-yl)methyl]-3-phenyl-2(lH)-quinolinone (comp. 140). Example B.19 NH3 (aq.) (150 ml) was cooled to 5°C. A solution of (+)-4-(3-chlorophenyl)-l-methyl- 6-[ 1 -(4-methylphenyl)- 1 -(4-methyl-4H-pyrrol-3-yl)ethyl] -2( 1 Η)-quinolinone hydrochloride (16.68 g) in THF (150 ml) was added. The mixture was stirred at room temperature for 2 hours, decanted and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and the solvent was evaporated till dryness. The reaction was carried out twice. The residues were combined and purified by column chromatography over silica gel (eluent : toluene/2-propanol/NH4OH 70-29-1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH2CI2/CH3OH/CH3CN. The precipitate was filtered off and the mother layer was evaporated till dryness, purified by column chromatography (eluent : CH3OH/NH 4 OAC (0.5% in H2O) 70/30). Two pure fractions were collected and their solvents were evaporated till dryness. Fraction 2 was recrystallized from CH2θ2/diethyl ether. The precipitate was filtered off and dried, yielding 0.8 g of (±)-6-[amino(4-chlorophenyl)(l- methyl- lH-imidazol-5-yl)methyl]-3-chloro-4-(3-chlorophenyl)-l-methyl-2(lH)- quinolinone (comp. 143). Example B.20 Sulfuric acid (1 ml) was added at room temperature to a solution of compound 3 (3.5 g) in methoxyacetonitrile (10 ml) and the mixture was stirred and heated at 80°C for 3 hours. The mixture was couled, poured into ice, basified with NΗ3 (aq.) and filtered off. The precipitate was taken up in DCM. The organic layer was separated, dried, (MgSO 4 ), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent : CH2CI2/CH3OH/NH4OH 96/4/0.3). The pure fractions were collected and the solvent was evaporated. The residue was converted into the hydrochloric acid salt (1:1) and crystallized from ACN. The precipitate was filtered off and dried, yielding 2.5 g (58%) of (±)-N-[(4-chlorophenyl)[4-(3-chlorophenyl)-l,2- dihydro-l-methyl-2-oxo-6-quinolinyl](l -methyl- lH-imidazol-5-yl)methyl]-2- methoxyacetamide monohydrochloride (comp. 89). Example B.21 A solution of intermediate (4) (3.3 g) in TΗF (10 ml) was added dropwise at room temperature to a solution of methanamine in water (40 ml). The mixture was stirred at 80°C for 45 minutes, taken up in water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent : CΗ 2 CI2/CΗ3OΗ/ΝΗ4OΗ 97/3/0.3 and 95/5/0.3). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 0.89 g (28%) of (±) 4-(3-chlorophenyl)-6-I(4-chloro- phenyl)(methylamino)(l-methyl-lH-imidazol-5-yl)methyl]-l-methyl-2(lH)-quinolinone monohydrate (comp. 61). Tables 1 to 8 list the compounds that were prepared according to one of the above Examples and table 9 lists both the experimental (column heading "exp.") and theoretical (column heading "theor.") elemental analysis values for carbon, hydrogen and nitrogen of the compounds as prepared in the experimental part hereinabove. Table 1 : * : prepared by functional- group transformation of compound 70 ** : prepared by functional- group transformation of compound 25 Table 2: * : prepared by functional-group transformation of compound 54 ** : prepared by functional-group transformation of compound 104 Table 3 : Co. Ex. Rl R8 Physical data No. No. 39 B.4 CH2CONHCH(COOCH3)(CH 2 CH(CH3) 2 ) H mp. 240°C (S) 40 B.4 CH2-2-quinolinyl H mp. 240°C; .2 HCl 41 B.4 CH 2 CONHCH(COOCH3)(CH 2 CH(CH3)2) OH p. > 260°C (S) Table 4 : Co. Ex. R2 R4 R 5a R6 R8 Physical data No. No. 42 B.6 H H H 4-Cl H mp. 170°C; .C 2 H 2 O 4 .l/2 H 2 O 43 B.10 H H H 4-Cl OH p. 180°C; .H 2 O 44 B.5 H H CH 3 4-Cl H mp. 152°C 45 B.6 3-C1 H H 4-Cl H p. 175°C; .C 2 H 2 O 4 46 B.5 3-C1 H CH2CH3 4-Cl H mp. 132°C; .C 2 H 2 O 4 47 B.5 3-C1 H CH 3 4-Cl H mp. 115°C; .3/2 C2H 2 O 4 48 B.9 3-C1 H CH 3 4-Cl OH mp. 230°C 118 B.4 3-C1 3-CH 3 CH3 4-Cl OH mp. 222°C Table 5 : Co. No. Ex. No. -R2-R3- R6 R8 119 B. l -O-CH 2 -O- 4-Cl OH 120 B.13 -O-CH2-O- 4-Cl NH 2 121 B. l -O-CH2-CH2-O- 4-Cl OH 122 B.13 -O-CH2-CH2-O- 4-Cl NH 2 123 B. l -O-CH=CH- 4-Cl OH Table 6 Co. Ex. X R2 R3 R 16 R8 Physical data No. No. 124 B. l O double 3-OCH3 4-OCH3 5-OCH3 OH mp. 230°C 125 B.13 O double 3-OCH3 4-OCH3 5-OCH3 NH 2 mp. 218°C .C2H2O4 126 B. l O single 3-Cl H H OH mp. 160°C 127 B. l O single 3-Cl H H OH 128 B.16 s double 3-Cl H H H Table 7 Co. Ex. Rl R17 Rl8 Rl9 R8 Physical data No. No. 139 B.4 CH 3 C 6 H 5 H H H .3/2(C 2 H 2 O 4 ) mp.180°C 140 B.18 H C6H5 H H OH - 141 B.4 CH 3 C 6 H 5 H H OH - 142 B.13 CH 3 C 6 H 5 H H NH 2 - 143 B.13 CH 3 Cl H H NH 2 - 144 B.17 H -COOCH2CH3 H H OH - 145 B.4 CH 3 -COOCH2CH3 H H OH - 146 B.l CH 3 H 8-CH3 H OH - 147 B.13 CH 3 H 8-CH3 H NH 2 .H 2 O 148 B.l CH 3 H 7-C1 H OH - 149 B.l CH H 7-CH3 H OH - 150 B.l CH H 5-CH3 H OH - 151 B.l CH 3 H 8-OCH3 H OH - 161 B.l CH 3 H 7-CH3 8-CH3 OH mp.255°C Table 8 Co. Ex. R2 R3 R6 R7 R8 Physical data No. No. 152 B.l 3-OCH2CH3 H 4-OCH2CH3 H OH .3/2(C 2 H 2 O 4 ) 153 B.l 3-Cl H H H OH - 154 B.l 3-Cl H 4-CH3 H OH - 155 B.l 3-Cl H 4-OCH3 H OH - 156 B.l 3-Cl H 4-CF3 H OH - 157 B.l 3-Cl H 2-C1 4-Cl OH - 158 B.l 3-Cl 5-C1 4-Cl H OH - * : R 6 and R 7 taken together to form a bivalent radical between positions 3 and 4 on the phenyl moiety Table 9 : Comp. Carbon Hydrogen Nitrogen No. Exp. Theor. Exp. Theor. Exp. Theor. 57 67.78 69.66 4.82 5.24 7.83 8.40 58 58.59 58.50 4.58 4.76 5.96 6.20 59 69.68 69.80 5.38 5.45 11.06 11.23 60 65.89 66.67 4.35 4.29 11.30 12.96 62 66.51 68.56 5.74 5.75 9.67 10.32 63 66.64 67.50 5.29 5.08 7.63 8.14 64 62.20 61.60 4.70 4.79 7.97 7.98 65 58.90 59.59 4.42 4.66 6.79 7.19 68 64.29 65.29 4.87 4.91 10.13 10.50 71 60.68 60.62 3.86 4.24 6.87 7.07 73 54.33 57.67 4.51 4.30 9.26 9.96 74 66.64 66.26 4.28 4.53 11.33 1 1.45 75 66.26 66.26 4.39 4.53 11.30 1 1.45 79 59.89 59.16 4.65 4.79 12.18 12.32 80 64.27 65.54 4.71 4.55 10.36 10.54 81 64.27 64.17 4.44 4.39 10.92 11.09 82 65.98 66.43 5.88 5.57 11.61 12.49 85 66.20 67.31 5.22 5.06 10.44 10.83 86 64.83 64.81 4.96 5.09 12.12 12.19 87 69.63 70.58 6.88 6.72 8.70 8.90 Comp. Carbon Hydrogen Nitrogen No. Exp. Theor. Exp. Theor. Exp. Theor. 88 65.21 65.42 5.10 5.11 13.22 13.15 97 71.38 71.97 5.60 5.41 8.17 8.68 98 71.38 72.1 1 5.58 5.63 11.31 1 1.60 100 71.92 72.50 5.65 5.88 10.92 11.27 103 70.72 71.71 5.42 5.37 11.80 11.95 104 60.56 60.63 3.99 3.96 7.84 7.86 105 60.33 60.75 3.72 4.15 10.28 10.49 106 62.37 62.29 3.71 3.92 7.71 7.78 108 74.22 74.50 4.94 4.93 7.83 7.90 109 74.17 74.64 5.23 5.12 10.60 10.55 110 68.17 68.43 4.28 4.47 8.75 8.87 115 65.98 66.13 4.08 4.32 8.53 8.57 116 66.49 66.67 4.38 4.60 8.47 8.33 117 67.97 69.93 4.60 4.40 11.14 1 1.65 120 67.35 67.40 4.62 4.65 1 1.14 1 1.23 121 67.32 67.77 4.72 4.71 7.78 8.18 122 67.88 67.90 4.72 4.91 10.88 10.92 123 69.75 70.23 4.77 4.47 8.06 8.47 128 65.88 66.12 4.24 4.32 8.37 8.57 132 65.20 65.25 3.77 3.91 10.42 10.87 136 66.77 66.67 4.64 4.60 8.34 8.33 142 69.26 70.09 4.42 4.63 9.59 9.91 145 64.36 64.06 4.19 4.48 7.49 7.47 148 61.88 61.79 3.65 3.84 7.88 8.01 150 66.56 66.67 4.64 4.60 8.08 8.33 151 64.76 64.62 4.86 4.45 7.80 8.07 153 70.99 71.13 5.17 4.86 9.25 9.22 154 71.67 71.56 5.08 5.15 9.14 8.94 158 61.72 61.79 3.76 3.84 7.96 8.01 159 69.28 69.50 5.21 5.29 10.01 10.13 160 62.71 64.19 3.91 4.04 7.36 8.02 C. Pharmacological example Example C l : in vitro Assay for Inhibition of Farnesyl Protein Transferase. Human famesyl protein transferase was prepared essentially as described (Y. Reiss et al, Methods: A Companion to Methods in Enzymology vol 1, 241-245, 1990). Kirsten virus transformed human osteosarcoma (KHOS) cells (American Type Culture Collection, Rockville, MD, USA) grown as solid tumors in nude mice or grown as monolayer cell cultures were used as a source of human enzyme. Briefly, cells or tumors were homogenized in buffer containing 50 mM Tris, 1 mM EDTA, 1 mM EGTA and 0.2 mM phenylmethylsulfonylfluoride (pH 7.5). The homogenates were centrifuged 28,000 x g for 60 min and the supematants collected. A 30-50% ammonium sulfate fraction was prepared, and the resulting precipitate was resuspended in a small (10 to 20 ml) volume of dialysis buffer containing 20 mM Tris, 1 mM dithiothreitol and 20 μM ZnCl 2 . The ammonium sulfate fraction was dialyzed ovemight against two changes of the same buffer. The dialyzed material was applied to a 10 x 1 cm Q Fast Flow Sepharose (Pharmacia LKB Biotechnology Inc., Piscataway, NJ, USA) which had been preequilibrated with 100 ml of dialysis buffer supplemented with 0.05 M NaCl. The column was washed with an additional 50 ml of dialysis buffer plus 0.05 M NaCl followed by a gradient from 0.05 M to 0.25 M NaCl prepared in dialysis buffer. The enzyme activity was eluted with a linear gradient of 0.25 to 1.0 M NaCl prepared in the dialysis buffer. Fractions containing 4 to 5 ml volumes of column eluate were collected and analyzed for famesyl protein transferase activity. Fractions with enzyme activity were pooled and supplemented with 100 μM ZnCl 2 . Enzyme samples were stored frozen at -70° C. The activity of famesyl protein transferase was measured using the Famesyl Transferase H] Scintillation Proximity Assay (Amersham International pic, England) under the conditions specified by the manufacturer. To assay for inhibitors of the enzyme, 0.20 μCi of the [ 3 H]-famesylpyrophosphate substrate and the biotinylated lamin B peptide substrate (biotin- YRASNRSCAIM) were mixed with test compounds in a reaction buffer consisting of 50 mM HEPES, 30 mM MgCl 2 , 20 mM KC1, 5 mM dithiothreitol, 0.01% Triton X-1 0. Test compounds were delivered in a 10 μl volume of dimethylsulfoxide (DMSO) to achieve concentrations of 1 and 10 μg ml in a final volume of 100 μl. The reaction mixture was warmed to 37° C. T e enzyme reaction was started by adding 20 μl of diluted human famesyl protein transferase. Sufficient enzyme preparation was added to produce between 4000 to 15000 cpm of reaction product during the 60 min of reaction incubation at 37°C. Reactions were terminated by the addition of STOP/scintillation proximity bead reagent (Amersham). The reaction product [ 3 H]- farnesyl-(Cys)-biotin lamin B peptide was captured on the streptavidin linked scintillation proximity bead. The amount of [ 3 H]-farnesyl-(Cys)-biotin lamin B peptide synthesized in the presence or absence of test compounds was quantified as cpm by counting on a Wallac Model 1480 Microbeta Liquid Scintillation Counter. The cpm of product was considered to be famesyl protein transferase activity. The protein famesyl transferase activity observed in the presence of test compound was normalized to famesyl transferase activity in the presence of 10% DMSO and expressed as per cent inhibition. In separate studies, some test compounds exhibiting 50% or greater inhibition of famesyl protein transferase activity were evaluated for concentration -dependent inhibition of enzyme activity. The effects of test compounds in these studies were calculated as IC50 (concentration of test compound producing 50% inhibition of enzyme activity) using the LGIC50 computer program written by the Science Information Division of R. W. Johnson Pharmaceutical Research Institute (Spring House, PA, USA) on a VAX computer. Table 10 : Co. No. ICso(nM) Co. No. IC50(nM) 1 6.0 58 2.8 2 8.0 59 0.14 3 1.7 60 0.62 4 24 61 1.1 5 25 63 1.0 7 1.6 64 11.6 12 4.2 66 4.0 15 18.4 67 5.9 24 2.7 69 3.4 25 2.2 71 26 29 57 74 100 34 1.6 75 0.86 35 0.39 95 57 36 2.8 96 0.11 37 10.1 97 2.9 39 0.59 98 6.4 42 910 99 1.7 45 1000 100 0.52 52 5.7 146 68 Example C.2 : "Ras-Transformed Cell Phenotype Reversion Assay". Insertion of activated oncogenes such as the mutant ras gene into mouse NIH 3T3 cells converts the cells to a transformed phenotype. The cells become tumorigenic, display anchorage independent growth in semi-solid medium and lose contact inhibition. Loss of contact inhibition produces cell cultures which no longer form uniform monolayers. Rather, the cells pile up into multicellular nodules and grow to very high saturation densities in plastic tissue culture dishes. Agents such as protein famesyl transferase inhibitors which revert the ras transformed phenotype restore the uniform monolayer growth pattern to cells in culture. This reversion is easily monitored by counting the number of cells in tissue culture plates. Transformed cells will achieve higher cell numbers than cells which have reverted to an untransformed phenotype. Compounds which revert the transformed phenotype should produce antitumor effects in tumors bearing ras gene mutations. Method: Compounds are screened in tissue culture in NIH 3T3 cells transformed by the T24 activated human H-ras gene. Cells are seeded at an initial density of 200,000 cells per well (9.6 cm 2 surface area) in six-well cluster tissue culture plates. Test compounds are immediately added to 3.0 ml cell growth medium in a 3.0 μl volume of DMSO, with a final concentration of DMSO in the cell growth medium of 0.1%. The test compounds are mn at concentrations of 5, 10, 50, 100, and 500 nM along with a DMSO treated vehicle control. (In case a high activity is observed at 5 nM, the test compound is tested at even lower concentrations.) The cells are allowed to proliferate for 72 hours. Then the cells are detached in 1.0 ml trypsin-EDTA cell dissociation medium and counted on a Coulter particle counter. Measurements: Cell numbers expressed as cells per well are measured using a Coulter Particle Counter. All cell counts were corrected for the initial cell input density by subtracting 200,000. Control cell counts = [cell counts from cells incubated with DMSO vehicle - 200,000] Test compound cell counts = [cell counts from cells incubated with test compound - 200,000]. ^ Tes .t compound Λ O %, ι-n Lhι-Lbι-tι ■on = r [i1 - test compound cell counts , , „ ΛΛ , con -trXol. — ce πll coun :ts J x^ 1^00 W %. IC50 (i.e. the test compound concentration required to inhibit enzyme activity by 50%) is calculated if sufficient data are available, summarized in table 11. Table 11 : Co. No. ICso(nM) Co. No. ICso(nM) 5 32 88 136 12 66 89 24 14 3.8 91 47 22 63 92 218 23 395 93 45 24 16 94 62 25 86 96 0.78 29 345 98 15 34 3.0 100 11 35 3.4 101 366 39 104 102 24 40 340 104 4.5 56 23 105 3.8 58 96 107 12 59 0.4 109 409 60 70 111 16 61 310 112 18 63 53 119 46 66 19 120 7 67 51 122 133 68 35 123 41 69 14 125 128 71 288 126 208 72 4.6 128 177 73 6.1 130 3.2 74 100 130 547 75 1.7 137 655 76 18 143 82 78 4.6 146 65 79 657 148 25 80 500 152 67 81 83 153 3.5 83 174 154 4.5 Co. No. IC50 (nM) Co. No. IC50 (nM) 84 231 155 69 86 91 156 25 87 251 160 40 Example C.3 : "Faraesyl Protein Transferase Inhibitor Secondary Tumor Model". The enzyme famesyl protein transferase catalyzes the covalent attachment of a famesyl moiety derived from famesyl pyrophosphate to the oncogene product p21 rαϊ . This directs p21 rαy to attach to plasma membranes. Once attached to plasma membranes, mutant or oncogenic forms of p21 rfl,ϊ will provide a signal for the transformation and uncontrolled growth of malignant tumor cells. Therefore, inhibitors of protein famesyltransferase will prevent the membrane attachment of p21 rαs and inhibit growth of / y-transformed tumors. Nude mice are inoculated with 1 x IO 6 of T24 activated human U-ras gene transformed NIH 3T3 fibroblast cells (T24 cells), subcutaneously in the inguinal region. After three days to allow tumors to become established, treatment with test compounds is begun via the oral route. The test compounds are dissolved in a 20% β-cyclodextrin in 0.1 N HCl solution and administered orally as 0.1 ml of compound solution per 10 g mouse body weight. Routinely used doses are 6.25, 12.5 and 25 mg/kg. Body weights and tumor sizes are monitored during the ensuing 15 days of treatment. At the end of treatment, animals are sacrificed and tumors are weighed. The "mean vehicle treated tumor weight" is defined as the mean tumor weight from 10 to 15 mice treated with the test compound. The "mean tumor weight" is defined as the mean tumor weight from 10 to 15 mice not treated with the test compound. n %r r R.edjucti-on . fi-nail tumor wei •g u π , 1 , „„„ b ht = [ l 1 J x 100%. Table 12 : Co. No. % reduction final tumor weight at a dose of 25 mg/kg bid, po 14 66 % 34 56 % Co. No. % reduction final tumor weight at a dose of 25 mg/kg bid, po 35 39 % 56 42 % 59 56 % 75 86 % D. Composition examples The following formulations exemplify typical pharmaceutical compositions in dosage unit form suitable for systemic or topical administration to warm-blooded animals in accordance with the present invention. "Active ingredient" (A.I.) as used throughout these examples relates to a compound of formula (I), a pharmaceutically acceptable acid or base addition salt or a stereochemically isomeric form thereof. Example D.l : Oral solutions 9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate are dissolved in 4 1 of boiling purified water. In 3 1 of this solution are dissolved first 10 g of 2,3-dihydroxybutanedioic acid and thereafter 20 g of the A.I. The latter solution is combined with the remaining part of the former solution and 12 1 of 1 ,2,3-propanetriol and 3 1 of sorbitol 70% solution are added thereto. 40 g of sodium saccharin are dissolved in 0.5 1 of water and 2 ml of raspberry and 2 ml of gooseberry essence are added. The latter solution is combined with the former, water is added q.s. to a volume of 20 1 providing an oral solution comprising 5 mg of the A.L per teaspoonful (5 ml). The resulting solution is filled in suitable containers. Example D.2 : Capsules 20 g of the A.L, 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose, 0.8 g colloidal silicon dioxide, and 1.2 g magnesium stearate are vigorously stirred together. The resulting mixture is subsequently filled into 1000 suitable hardened gelatin capsules, each comprising 20 mg of the A.L. Example D.3 : Film-coated tablets Preparation, pf ta.blet.cpre A mixture of 100 g of the A.L, 570 g lactose and 200 g starch is mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinyl¬ pyrrolidone in about 200 ml of water. The wet powder mixture is sieved, dried and sieved again. Then there are added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. The whole is mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient. .Coating To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanol there is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then there are added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol is molten and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then there are added 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concen-trated colour suspension and the whole is homogenated. The tablet cores are coated with the thus obtained mixture in a coating apparatus. Example D.4 : Injectable solution 1.8 g methyl 4-hydroxybenzoate and 0.2 g propyl 4-hydroxybenzoate were dissolved in about 0.5 1 of boiling water for injection. After cooling to about 50°C there were added while stirring 4 g lactic acid, 0.05 g propylene glycol and 4 g of the A.L The solution was cooled to room temperature and supplemented with water for injection q.s. ad 1 1 volume, giving a solution of 4 mg/ml of A.I. The solution was sterilized by filtration and filled in sterile containers. Example D.5 : Suppositories 3 Grams A.L was dissolved in a solution of 3 grams 2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400. 12 Grams surfactant and 300 grams triglycerides were molten together. The latter mixture was mixed well with the former solution. The thus obtained mixture was poured into moulds at a temperature of 37-38°C to form 100 suppositories each containing 30 mg/ml of the A.L

Claims: Claims 1. A compound of formula (I), a stereoisomeric form thereof, a pharmaceutically acceptable acid or base addition salt thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; R 1 is hydrogen, Cι-i2alkyl, Ar J , Ar 2 Ci-6alkyl, quinolinylCι-6alkyl, pyridylCι-6alkyl, hydroxyCι-6alkyl, Ci galley loxyCi-6alkyl, mono- or di(Cι -6alkyl)aminoC ι -6alkyl, aminoCi -6alkyl, or a radical of formula -Alk ! -C(=O)-R 9 , -Alk ! -S(O)-R 9 or -Alk 1 -S(O) 2 -R 9 , wherein Alk is Ci-6alkanediyl, R 9 is hydroxy, Cι-6alkyl, Cι-6alkyloxy, amino, Cι-8alkylamino or Ci-salkylamino substituted with Cι-6alkyloxycarbonyl; R 2 , R 3 and R* 6 each independently are hydrogen, hydroxy, halo, cyano, Cι-6alkyl, Cι-6alkyloxy, hydroxyC ι-6alkyloxy, Cι-6alkyloxyCι-6alkyloxy, aminoCi-6alkyloxy, mono- or di(Cι-6alkyl)aminoCι-6alkyloxy, Ar ] , Ar 2 Cι-6alkyl, Ar 2 oxy, Ar 2 Cι-6alkyloxy, hydroxycarbonyl, Ci-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, 4,4-dimethyloxazolyl; or when on adjacent positions R and R 3 taken together may form a bivalent radical of formula -O-CH2-O- (a- 1), -O-CH2-CH2-O- (a-2), -O-CH=CH- (a-3), -O-CH2-CH2- (a-4), -O-CH2-CH2-CH2- (a-5), or -CH=CH-CH=CH- (a-6); R 4 and R 5 each independently are hydrogen, halo, Ar 1 , Ci-^alkyl, hydroxyC] -6alkyl, Cι-6alkyloxyCι-6alkyl , Cι-6alkyloxy, Cι-6alkylthio, amino, hydroxycarbonyl, Cι-6alkyloxycarbonyl, Cι-6alkylS(O)C]-6alkyl or Cι- 6 alkylS(O)2C 1 - 6 alkyl; R 6 and R 7 each independently are hydrogen, halo, cyano, Ci-6alkyl, Ci-6alkyloxy, Ar 2 oxy, trihalomethyl, Ci-βalkylthio, di(Cι j5alkyl)amino, or when on adjacent positions R 6 and R 7 taken together may form a bivalent radical of formula -O-CH2-O- (c- 1), or -CH=CH-CH=CH- (c-2); R 8 is hydrogen, Cι-6alkyl, cyano, hydroxycarbonyl, Ci-6alkyloxycarbonyl, Cι-6alkylcarbonylCi-6alkyl, cyanoCι-6aIkyl, Ci-6alkyloxycarbonylCι-6alkyl, carboxyCι-6alkyl, hydroxyCι-6alkyl, aminoC,~6alkyl, mono- or di(Cι-6alkyl)aminoCι-6alkyl, imidazolyl, haloCi-6alkyl, Ci-όalkyloxyCi-βalkyl, aminocarbonylCi-όalkyl, or a radical of formula -O-RlO (b-1), -S-R10 (b-2), -N-R11R12 (b-3), wherein RlO is hydrogen, Cι-6alkyl, Cι-6alkylcarbonyl, Arl, Ar Cι-6alkyl, Cι-6alkyloxycarbonylCι-6alkyl, a radical or formula -Alk 2 -OR 13 or -Alk 2 -NRl4Rl5 ; Rl ! is hydrogen, Cι-i2alkyl, Ar 1 or Ar 2 Cι-6alkyl; Rl2 is hydrogen, Cι-6alkyl, Ci-i6alkylcarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkyIaminocarbonyl, Arl, Ar 2 Ci-6alkyl, Cι-6alkylcarbonylCi-6alkyl, a natural amino acid, Arlcarbonyl, Ar 2 Ci-6alkylcarbonyl, aminocarbonylcarbonyl, Cι_6alkyloxyCi-6alkylcarbonyl, hydroxy, Ci-6alkyloxy, aminocarbonyl, di(Ci-6alkyl)aminoCi-6alkylcarbonyl, amino, Cι_6alkylamino, Ci-όalkylcarbonylamino, or a radical of formula -Alk 2 -OR 13 or -Alk 2 -NRl 4 Rl 5 ; wherein Alk 2 is Ci-6alkanediyl; R 13 is hydrogen, Cι-6alkyl, Cι-6alkylcarbonyI, hydroxyCi-όalkyl, Ar ] or Ar 2 Cι-6alkyl; R ]4 is hydrogen, Ci-6alkyl, Arl or Ar 2 Cι-6alkyl; R' 5 is hydrogen, Cι-6alkyl, Cι-6alkylcarbonyl, Ar 1 or Ar 2 Cι-6alkyl; R 17 is hydrogen, halo, cyano, Ci-6alkyl, Ci-6alkyloxycarbonyl, Arl; R 18 is hydrogen, Ci-6alkyl, Ci^alkyloxy or halo; R 19 is hydrogen or Ci-6alkyl; Ar' is phenyl or phenyl substituted with Cι-6alkyl, hydroxy, amino, Cι-6alkyloxy or halo; and Ar 2 is phenyl or phenyl substituted with Cι-6alkyl, hydroxy, amino, Cj-fialkyloxy or halo. 2. A compound as claimed in claim 1 wherein X is oxygen. 3. A compound as claimed in claims 1 or 2 wherein the dotted line represents a bond. 4. A compound as claimed in claims 1, 2 or 3 wherein R is hydrogen, Ci-6alkyl, Cι.6alkyloxyCι.6alkyl or mono- or dHCi-όalky aminoCi.fialkyl. 5. A compound as claimed in any of claims 1 to 4 wherein R 3 is hydrogen and R 2 is halo, Ci-6alkyl, C2-6alkenyl, Ci-^alkyloxy, trihalomethoxy or hydroxyCi-όalkyloxy. 6. A compound as claimed in any of claims 1 to 5 wherein R 8 is hydrogen, hydroxy, haloC] -όalkyl, hydroxyC i^alkyl, cyanoCι_6alkyl, Ci. alkyloxycarbonylCi.όalkyl, imidazolyl, or a radical of formula -NRl 'R 12 wherein R l is hydrogen or and Rl2 is hydrogen, Ci^alkyl, Ci^alkyloxy, Ci^alkyloxyCi-όalkylcarbonyl, hydroxy, or a radical of formula -Alk 2 -ORl 3 wherein R 13 is hydrogen or Ci-βalkyl. 7. A compound as claimed in claim 1 wherein the compound is 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(l -methyl- lH-imidazol-5- yl)methyl]- 1 -methyl-2( lH)-quinolinone, 6-[amino(4-chlorophenyl)-l-methyl-lH-imidazol-5-ylmethyl]-4-(3-chlorophenyl)- 1 -methyl-2( 1 H)-quinolinone; 6-[(4-chlorophenyl)hydroxy(l -methyl- 1 H-imidazol-5-yl)methyl]-4-(3-ethoxy- phenyl)-l-methyl-2(lH)-quinolinone; 6-[(4-chlorophenyl)(l -methyl- lH-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-l- methyl-2( 1 H)-quinolinone monohydrochloride.monohydrate; 6-[amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)- l-mefhyl-2(lH)-quinolinone, and 6-amino(4-chlorophenyl)( 1 -methyl- lH-imidazol-5-yl)methyl]-l -methyl-4-(3- propylphenyl)-2(lH)-quinolinone; a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salts thereof. 8. A compound as claimed in claim 7 wherein the compound is (B)-6-[amino(4-chlorophenyl)(l-methyl-lH-imidazol-5-yl)methyl]-4-(3-chloro- phenyl)-l-methyl-2(lH)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof. 9. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claims 1 to 8. 10. A process of preparing a pharmaceutical composition as claimed in claim 9 characterized in that a therapeutically effective amount of a compound as claimed in any one of claims 1 to 8 is intimately mixed with a pharmaceutically acceptable carrier. 1 1. A compound as claimed in any of claims 1 to 8 for use as a medicine. 12. A compound of formula (XII) wherein the radicals R 2 , R 3 , R 4 , R5, R6, 7 8 > R 16 ; 17 ? R 18 arjj 19 gj-g ^ defined in claim 1; a stereoisomeric form or a pharmaceutically acceptable acid or base addition salt form thereof. (XII) 13. A compound of formula (VI) wherein the radicals R 2 , R 3 , R4, R5, 6 ^ R7 > 8 5 R 16 , R l7 , R 18 and R i9 are as defined in claim 1; a stereoisomeric form or a pharmaceutically acceptable acid or base addition salt form thereof. 14. A process for preparing a compound as claimed in claim 1, characterized by a) hydrolysing an intermediate ether of formula (II), wherein R is Ci-6alkyl in an aqueous acid solution, preferably an aqueous solution hydrochloric acid, yielding a compound of formula (I-a) wherein R l is hydrogen; and optionally transforming the compound of formula (I-a) wherein R 1 is hydrogen into a compound of formula (I-a); b) reacting an intermediate ketone of formula (III) with a intermediate of formula (IV-a), wherein P is an optional protective group which is removed after the addition reaction, in the presence of a suitable strong base in an appropriate solvent, yielding a compound of formula (I-b); c) reacting an intermediate of formula (XXI) with an intermediate of formula (IV-a), as described in the synthesis of compounds of formula (I-b), subsequent treatment with an acid such as, e.g. TiCl3 in the presence of water, and reacting the thus formed intermediate (XXIII) with a suitable reagent such as, e.g. Rl 7 CH 2 COCl or R l7 CH2COOC2H5, optionally followed by treatment with a base such as, e.g. potassium tert-butoxide, yielding a compound of formula (I-b-1), (XXI) (XXII) d) reacting an intermediate of formula (XTII), wherein W is an appropriate leaving group with a reagent of formula (XIV) in an appropriate solvent, yielding a compound of formula (I-g); wherein the substituents R 1 to R J6 are as defined in claim 1; or, converting compounds of formula (I) into each other, or if desired; a compound of formula (I) into a pharmaceutically acceptable acid addition salt, or conversely, converting an acid addition salt into a free base form with alkali; and/or preparing stereochemically isomeric forms thereof.

Inventors: ANGIBAUD PATRICK RENE, MULLER PHILIPPE, SANZ GERARD CHARLES, VENET MARC GASTON, ANGIBAUD, PATRICK, RENE, MULLER, PHILIPPE, SANZ, GERARD, CHARLES, VENET, MARC, GASTON
Applicants: ANGIBAUD PATRICK RENE, JANSSEN PHARMACEUTICA NV, MULLER PHILIPPE, SANZ GERARD CHARLES, VENET MARC GASTON, ANGIBAUD, PATRICK, RENE, JANSSEN PHARMACEUTICA N.V., MULLER, PHILIPPE, SANZ, GERARD, CHARLES, VENET, MARC, GASTON
Application year: 1996
Main classification: C07D401
IPC codes: A61K31, A61P35, A61P43, C07D215, C07D401, C07D405, C07D407, C07D413, C07D521