MXPA99011128A - (imidazol-5-yl)methyl-2-quinolinone derivatives as inhibitors of smooth muscle cell proliferation - Google Patents

Abstract

La presente invención comprende el uso de compuestos de fórmula I (Ver Fórmula) en donde la línea punteada representa un enlace opcional, X es oxígeno o azufre;R1 es hidrógeno;alquilo de C1-12, Ar1, Ar2alquilo de C1-6, quinolinilalquilo de C1-6;piridilalquilo de C1-6, alquiloxi de C1-6-aqluilo de C1-6 mono- o diamino(alquilo de C1-6)-alquilo de C-6, aminoalquilo de C1-6, o un radical de fórmula -Alk1-C(=O)-R9, -Alk1-S(O)-R9 o -Alk1-S(O)2-R9;R2, R3 Y R16 son cada uno independientemente hidrógeno, hidroxi, halógeno, ciano, alquilo de C1-6, alquiloxi de C1-6, alquiloxi de C1-6, hidroxialquiloxi de C1-6, alquiloxi de C1-6-alquiloxi de C1-6, aminalquiloxi de C1-6, mono- o diamino(alquilo de C1-6)-alquiloxi de C1-6, Ar1, Ar2alquilo de C1-6,AR2oxi, Ar2alquiloxi de C1-6, hidroxicarbonilo, alquiloxicarbonilo de C1-6, trihalogenometilo, trihalogenometoxi, alquenilo de C2-6;R4 y R5 son cada uno independientemente hidrógeno, halógeno, Ar1, alquilo de C1-6, hidroxialquilo de C1-6, alquiloxi de C1-6-alquilo de C1-6, alquiloxi de C1-6, alquiltio de C1-6, amino, hidroxicarbonilo;alquiloxicarbonilo de C1-6, alquilo de C1-6S(O)alquilo de C1-6 o alquilo de C1-6S(O)2alquilo de C1-6;R6 y R7 son cada uno independientemente hidrógeno;halógeno, ciano, alquilo de C1-6;4,4-dimetil-oxazolilo, alquiloxi de C1-6 o AR2oxi, R8 es hidrógeno, alquilo de C1-6, ciano, hidroxicarbonilo, alquilcarbonilo de C1-6-alquilo de C1-6, cianoalquilo de C1-6, alquiloxicarbonilo de C1-6-alquilo de C1-6, carboxialquilo de C1-6, hidroxialquilo de C1-6, aminoalquilo de C1-6, mono- o diamino(alquilo de C1-6)-alquilo de C1-6, imidazolilo, halogenoalquilo de C1-6, alquiloxi de C1-6-alquilo de C1-6, aminocarbonilalquilo de C1-6 o un radical de fórmula -O-R10, -S-R10, -N-R-11O12;R17 es hidrógeno, halógeno, ciano, alquilo de C1-6, alquiloxicarbonilo de C1-6, Ar1;R18 es hidrógeno, alquilo de C1-6, alquiloxi de C1-6 o halógeno;R19 es hidrógeno o alquilo de C1-6;para la fabricación de un medicamento para inhibir la proliferación de células de músculo liso.

Description

DERIVATIVES OF (IMIDAZOL-5-IDMETIL-2-QU1NOLINONA AS INHIBITORS OF THE PROLIFERATION OF SMOOTH MUSCLE CELLS DESCRIPTIVE MEMORY The present invention relates to a method of using compounds of formula (I) for inhibiting the proliferation of smooth muscle cells. The proliferation of smooth muscle cells of the arterial wall in response to local injury is an important etiologic factor of vascular proliferative disorders such as atherosclerosis and restenosis following angioplasty. It has been reported that the incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA) is as high as 45% within three to six months after treatment with PTCA (Indolfi et al., Nature medicine, 1, 541-545 (1995)). ). Accordingly, compounds that inhibit the proliferation of smooth muscle cells can be very useful in preventing or treating vascular proliferative disorders such as atherosclerosis and restenosis. Heparin is a well-known compound that inhibits the proliferation of smooth muscle cells after coronary angioplasty (Buchwald et al., J. Cardiovasc Pharmacol., 28, 481-487 (1996)). In the co-pending application PCT / EP96 / 04515 of the authors, published on June 19, 1997 as document WO-97/21701, the compounds of formula (I), their preparation and compositions containing them as farnesyl transferase inhibitors are described. useful for the treatment of ras-dependent tumors. Unexpectedly, it has been found that the compounds of formula (I) can be used to inhibit the proliferation of smooth muscle cells. Accordingly, the present invention relates to a method of using the compounds of formula (I) for the treatment of vascular proliferative disorders in a warm-blooded animal. The present invention relates to a method of using the compounds of formula (I): the pharmaceutically acceptable acidic or basic addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; R1 is hydrogen, C1-12 alkyl, Ar1, Ai ^ C6-6 alkyl, quinolinylalkyl of C-? 6, pyridylalkyl of d-6, hydroxyalkyl of d-6, alkyloxy of C-? -6-alkyl of C? -6, mono- or diamino (C? -6 alkyl) -C-? -6 alkyl, d-b aminoalkyl, or a radical of formula -Alk1-C (= O) -R9, - Alk1-S (O) -R9 or -Alk1- S (O) 2-R9, wherein Alk1 is alkanediyl of d-6, R9 is hydroxy, C? -6 alkyl, C? -6 alkyloxy, amino, d-b alkylamino or C? -8 alkylamino replaced with d-β alkyloxycarbonyl; R2, R3 and R16 are each independently hydrogen, hydroxy, halogen, cyano, C? -6 alkyl, C? -6 alkyloxy, hydroxyalkyloxy C6-C6-C6-alkyloxy-C6-6alkyloxy, d-6 aminalkyloxy, mono- or diamino (C6-6alkyl) -alkyloxy of d-β, Ar1, Ai ^ alkyl C? -6, Ai ^ oxy, Ai ^ C -? - 6 alkyloxy. hydroxycarbonyl, alkyloxycarbonyl of d-6, trihalogenomethyl, trihalogenomethoxy, C2-6 alkenyl, 4,4-dimethoxyloxazolyl; or when in adjacent positions R2 and R3 taken together can 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-CH-CH2- (a-5) or CH = CH-CH = CH- (a-6); R4 and R5 are each independently hydrogen, halogen, Ar1, d-6 alkyl, C? -6 hydroxyalkyl, d-β-alkyloxy-C? -6-alkyl, d-6-alkyloxy, C? -6-alkyl, amino, hydroxycarbonyl, C1-6-alkyloxycarbonyl , alkyl of d-6S (O) C? -6 alkyl or C? -6S (O) 2alkyl of d-6; R6 and R7 are each independently hydrogen, halogen, cyano, C1-6 alkyl. alkyloxy of d-6, Ai ^ oxy, trihalogenomethyl, alkylthio of C? -6, diamino (alkyl of d-?), or when in adjacent positions R6 and R7 taken together can form a bivalent radical of formula -O-CH2-O- (c-1) or -CH = CH-CH = CH- (c-2); R8 is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C6-6alkyloxycarbonyl, C6-6alkylcarbonyl of d-6alkyl, cyanoalkyl of C6-6, alkyloxycarbonyl of d6alkylalkyl ? -6, carboxyalkyl of d-6, hydroxyalkyl of d-6, aminoalkyl of C? -6, mono- or diamino (C 1-6 alkyl) -C 1-6 alkyl, imidazolyl, haloalkyl of d-6, alkyloxy of d-β-alkyl of d-6, aminocarbonylalkyl of C? -6, or a radical of formula O-R10 (b-1), S-R10 (b-2), N-R11R12 (b-3), wherein R 10 is hydrogen, d-6 alkyl, C 1-6 alkylcarbonyl) Ar 1, Ai ^ alkyl of d-6, C 1-6 alkyloxycarbonyl-C 1-6 alkyl, or a radical of formula -Alk 2 -OR 13 or -Alk2-NR14R15; R 11 is hydrogen, d-2 alkyl, Ar 1 or Ar 2 alkyl of d-β; R 12 is hydrogen, d-6 alkyl, C-Mβ alkylcarbonyl, C?-6alkyloxycarbonyl, d-6alkylaminocarbonyl, Ar 1, Ar 2 d-6 alkyl, C?-6-alkylcarbonyl C?-6alkyl , a natural amino acid, Ar1 carbonyl, Ar2 d-6 alkylcarbonyl, aminocarbonylcarbonyl, d-β-alkylcarbonyl C1-6alkyloxy, hydroxy, d-6alkyloxy, aminocarbonyl, diamino (C6-6alkyl) -alkylcarbonyl of C? -6, amino, C 1-6 alkylamino, d-β alkylcarbonylamino. or a radical of formula -Alk2-OR13 or -Alk2- 5 NR14R15; wherein Alk2 is alkanediyl of C? -6; R13 is hydrogen, d-6 alkyl, C6-6 alkylcarbonyl, d-6 hydroxyalkyl, Ar1 or Ar2 alkyl of d-ßl R14 is hydrogen, d-β alkyl, Ar1 or Ar2 C-i-β alkyl; R15 is hydrogen, -β-alkyl, d-6-alkylcarbonyl, Ar1 or Ar2-C6-alkyl; R17 is hydrogen, halogen, cyano, C6-alkyl, alkyloxycarbonyl of d-6, Ar1; R18 is hydrogen, C? -6 alkyl, C? -6 alkyloxy or halogen; R19 is hydrogen or C1-6alkyl; Ar1 is phenyl or phenyl substituted with C6-6 alkyl) hydroxy, amino, d-6alkyloxy or halogen; and Ar 2 is phenyl or phenyl substituted with d-6 alkyl, hydroxy, amino, d-β alkyloxy or halogen; for the inhibition of the proliferation of smooth muscle cells. R4 or R5 may also be attached to one of the nitrogen atoms in the imidazole ring. In that case, the hydrogen in the nitrogen is replaced by R4 or R5, and the meaning of R4 and R5 when they are bound to the nitrogen, is limited to hydrogen, Ar1, d-6 alkyl, hydroxyalkyl of C? -6, nn || M g ^ C? -6 alkyloxy-C? -6 alkyl, alkyloxycarbonyl of d-6, alkyl of d- 6S (O) alkyl of d-6, alkyl of C-? - 6S (O) 2alkyl of C? -6. As used in the above definitions and below, halogen defines fluorine, chlorine, bromine and iodine; d-6 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like; C 1-8 alkyl embraces the straight and branched chain saturated hydrocarbon radicals as defined in d-6 alkyl, as well as the higher homologues thereof containing from 7 to 8 carbon atoms such as, for example, heptyl or octyl; d-? 2 alkyl embraces C? -8 alkyl and higher homologs thereof containing from 9 to 12 carbon atoms such as, for example, nonyl, decyl, undecyl or dodecyl; C? -? 6 alkyl embraces C? _2 alkyl and higher homologs thereof containing from 13 to 16 carbon atoms such as, For example, tridecyl, tetradecyl, pentadecyl and hexadecyl; C2-6 alkenyl defines straight and branched chain hydrocarbon radicals containing a 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; C1-6 alkanediyl defines hydrocarbon radicals Saturated bivalent straight and branched chain having 1 to 6 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, , 6-hexanediyl, and the branched isomers thereof. The term "C (= O)" refers to a carbonyl group, "S (O)" is ^^^ TM ^ refers to a sulfoxide and "S (O) 2" to a sulfone. The term "natural amino acid" refers to an amino acid that is linked by a covalent amide bond formed by loss of a water molecule between the carboxyl group of the amino acid and the amino group of the rest of the molecule: Examples of natural amino acids are glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine and histidine. As mentioned above, pharmaceutically acceptable acidic or basic addition salts comprise the therapeutically active non-toxic additive basic or acid salt forms which the compounds of formula (I) are capable of forming. The compounds of formula (I) having basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Suitable acids comprise, for example, inorganic acids such as hydrohalic acids, for example, hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and similar acids; or organic acids such as, for example; acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (ie butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic , pamoic, and similar acids. ^^ & The compounds of formula (I) having acidic properties can be converted to their pharmaceutically acceptable basic addition salts by treating said acid form with an appropriate organic or inorganic base. Suitable base salt forms comprise, for example, the ammonium salts, the alkali metal and the alkaline earth metal salts, for example, the lithium, sodium, potassium, magnesium, calcium salts, and the like; salts with organic bases, for example, benzathine salts, N-methyl-D-glucamine, hydrabamine, and salts with amino acids such as, for example, arginine, lysine, and the like. The term "acidic or basic addition salt" also comprises hydrates and solvent addition forms which the compounds of formula (I) are capable of forming. Examples of such forms are, for example, hydrates, alcoholates, and the like. The term stereochemically isomeric forms of the compounds of formula (I), as used above, defines all possible compounds formed from the same atoms linked by the same sequence of bonds, but having different three-dimensional structures that 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 that said compound may possess. Said mixture may contain all the diastereomers and / or enantiomers of the basic molecular structure of said compound. It is intended that all stereochemically isomeric forms of the compounds of formula (I), both in pure form and in admixture with some other compound, be embraced within the scope of the present invention. Some of the compounds of formula (I) may also exist in their tautomeric forms. It is intended that said forms, although not explicitly indicated in the above formula, be included within the scope of the present invention. Whenever the term "compounds of formula (I)" is used consecutively, it means that it also includes pharmaceutically acceptable acidic or basic addition salts and all stereoisomeric forms. Preferably, the substituent R18 is located in the 5 or 7 position of the quinolinone portion, and the R19 substituent is located in the 8 position when R18 is in the 7 position. The compounds of interest are the compounds of formula (I), where X is oxygen. Also interesting compounds are the compounds of formula (I), wherein the dotted line represents a bond, to form a double bond. Another group of compounds of interest are the compounds of formula (I), wherein R 1 is hydrogen, C 1-6 alkyl, C 1-6 alkyloxy C 1-6 alkyl, diamino (Cr 6 alkyl) -Cr 6 alkyl, or a radical of formula -Alk1-C (= O) -R9, wherein Alk1 is methylene, and R9 is alkylamino of d-8 substituted with alkyloxycarbonyl of d-6. 'tfff f g'5' ^^ A further group of compounds of interest are the compounds of formula (I), wherein R3 is hydrogen or halogen; and R2 is halogen, C6-6 alkyl, C2-6 alkenyl, Cr6alkyloxy, trihalogenomethoxy or C6-6 hydroxyalkyloxy. A further group of compounds of interest are the compounds of formula (I), wherein R2 and R3 are in adjacent positions and taken together form a bivalent radical of formula (a-1), (a-2) or (a-3). Still another group of compounds of interest are the compounds of formula (I), wherein R 5 is hydrogen and R 4 is hydrogen or C 1-6 alkyl. Still another group of compounds of interest are the compounds of formula (I), wherein R7 is hydrogen; and R6 is C6-6alkyl or halogen, preferably chlorine, especially 4-chloro. A particular group of compounds are the compounds of formula (I), wherein R8 is hydrogen, hydroxy, haloalkyl of d-6, hydroxyalkyl of C? -6, cyanoalkyl of d-β, alkyloxycarbonyl of C? -6-alkyl C1-6, imidazolyl, or a radical of formula -NR11R12, wherein R11 is hydrogen or C1-12 alkyl, and R12 is hydrogen, d6 alkyl, Cr6 alkyloxy, hydroxy, C6-6 alkylcarbonyl alkyloxy Cr6, or a radical of formula -Alk2-OR13 , wherein R13 is hydrogen or Cr6 alkyl. Preferred compounds are compounds wherein R1 is hydrogen, Cr6 alkyl, C6-6 alkyloxy of d-6alkyl, diamino (C6-6alkyl) -alkyl of C6-6, or a radical of formula -Alk1-C (= O) -R9, wherein Alk1 is methylene, and R9 is C? -8 alkylamino substituted with d-6 alkyloxycarbonyl; R2 is halogen, Cr6 alkyl, C2-6 alkenyl, C6-6 alkyloxy, trihalogenomethoxy, C1-6 hydroxyalkyloxy or Ar1; R3 is hydrogen; R 4 is methyl linked to the nitrogen at the 3-position of the imidazole; R5 is hydrogen; R6 is chlorine; R7 is hydrogen; R8 is hydrogen, hydroxy, haloalkyl of d-6, hydroxyalkyl of Cβ, cyanoalkyl of C1-6. alkyloxycarbonyl of d-6-C-6 alkyl, imidazolyl, or a radical of formula -NR11R12, wherein R11 is hydrogen or alkyl of d-? 2, and R12 is hydrogen, d6 alkyl, alkyloxy C? -6, C? -6-alkylcarbonyl alkyloxy of Cr6, or a radical of formula -Alk2-OR13, wherein R13 is d6 alkyl; R17 is hydrogen and R18 is hydrogen. The most preferred compounds are: 4- (3-chlorophenyl) -6 - [(4-chlorophenyl) hydroxyl (1-methyl-1 H-imidazol-5-yl) methyl] -1-methyl-2 (1 H) -quinolinone; 6- [amino (4-chlorophenyl) -1-methyl-1 H-imidazol-5-ylmethyl] -4- (3-chlorophenyl) -1-methyl-2 (1 H) -quinolinone; 6 - [(4-chlorophenyl) hydroxy (1-methyl-1 H-imidazol-5-yl) methyl] -4- (3-ethoxyphenyl) -1-methyl-2 (1 H) -quinolinone; monohydrate monohydrate of 6 - [(4-chlorophenyl) (1-methyl-1 H-imidazol-5-yl) methyl] -4- (3-ethoxyphenyl) -1-methyl-2 (1 H) -quinolinone; 6- [amino (4-chlorophenyl) (1-methyl-1 H-imidazol-5-yl) methyl] -4- (3-ethoxyphenyl) -1-methyl-2 (1 H) -quinolinone; 6-amino (4-chlorophenyl) (1-methyl-1 H-imidazol-5-yl) methyl] -1-methyl-4- (3-propylphenyl) -2 (1 H) -quinolinone; a stereoisomeric form thereof, or a pharmaceutically acceptable acid or base additive salt thereof; and (+) - 6- [amino (4-chlorophenyl) (1-methyl-1 H-imidazol-5-yl) methyl] -4- (3-chlorophenyl) -1-methyl-2 (1 H) -quinolinone; or a pharmaceutically acceptable acid addition salt thereof. The compounds of formula (I), wherein X is oxygen, said compounds being represented by formula (Ia), can be prepared by hydrolyzing an intermediate ether of formula (II), wherein R is d-6 alkyl, in accordance with methods known in the art, such as by stirring the intermediate of formula (II) in an aqueous acid solution. A suitable acid is, for example, hydrochloric acid. Subsequently, the resulting quinolinone, wherein R 1 is hydrogen, can be transformed into a quinolinone, wherein R 1 has a meaning as given above apart from hydrogen, by N-alkylation known in the art. (l l) (I -a) The compounds of formula (I), wherein R 8 is hydroxy, said compounds being referred to as compounds of formula (lb), can be prepared by reacting an intermediate ketone of formula (III) with an intermediate of formula (IV-a), wherein P is an optional protecting group such as, for example, a sulfonyl group, for example, 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 of an appropriate silane derivative such as, for example, triethylchlorosilane. During the preparation process, an intermediate silane derivative is hydrolysed. Other processes with protective groups analogous to the silane derivatives may also be applied. (l l l) (l - b) Compounds of formula (lb-1), being compounds of formula (lb), 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 (IV -a), as described above for the synthesis of compounds of formula (lb). The intermediary thus obtained from ggl? The formula (XXII) undergoes ring opening of the isoxazole portion by stirring with an acid such as, for example, TiCl3, in the presence of water. Subsequent treatment of an intermediate of formula (XXIII) with a suitable reagent such as, for example, R17CH2COCI or R17CH2COOC2H5, directly produces a compound of formula (lb-1), or an intermediate which can be converted to a compound of formula (lb-1) by treatment with a base such as, for example, potassium tert-butoxide.

(XXI) (XXII) (XXIII) (l-b-1) Intermediates of formula (XXI) can be conveniently prepared by treating an intermediate of formula (XVI), described below, under acidic conditions. The compounds of formula (I), wherein R8 is a radical of formula -N-R11R12, said compounds being represented by the formula (Ig), can be prepared by reacting an intermediate of formula (XIII), wherein W is a suitable leaving group such as, for example, halogen, with a reagent of formula (XIV). Said reaction can be carried out by stirring the reagents in an appropriate solvent such as, for example, tetrahydrofuran.

(X I M) (i - g) The compounds of formula (I) can also be prepared by converting the compounds of formula (I) to other compounds of formula (I). Compounds wherein the dotted line represents a bond, can be converted into compounds where the dotted line does not represent a bond, by hydrogenation methods known in the art. Also, compounds where the dotted line does not represent a bond, can be converted into compounds where the dotted line represents a bond, by oxidation reactions known in the art. The compounds of formula (I) wherein R8 is hydroxy, said compounds being represented by formula (lb), can be converted to compounds of formula (Ic), wherein R8a has the meaning of R10 except for hydrogen, by reactions O-alkylation or O-acylation known in the art such as, for example, by reacting the compound of formula (lb) with an alkylating reagent such as R8a-W under appropriate conditions such as, for example, a dipolar aprotic solvent , for example, DMF, in the presence of a base, for example, sodium hydride. W is a suitable leaving group such as, for example, halogen or a sulfonyl group.

(I b) (l - c) As an alternative to the above reaction procedure, the compounds of formula (I-c) can also be prepared by reacting an intermediate of formula (I-b) with a reagent of formula R8a-OH in an acidic medium. The compounds of formula (I-b) can also be converted into compounds of formula (I-g), wherein R11 is hydrogen and R12 is d-? 6 alkylcarbonyl, by reacting compounds of formula (I-b) in acid medium, such as sulfuric acid, with Cp.sub.S-CN alkyl in a Ritter reaction type. In addition, the compounds of formula (1b) can also be converted to compounds of formula (1-g), wherein R 11 and R 12 are hydrogen, reacting compounds (1-b) with ammonium acetate and subsequent treatment with aqueous NH 3. The compounds of formula (lb) can also be converted to compounds of formula (Id), wherein R 8 is hydrogen, subjecting the compounds of formula (lb) to appropriate reducing conditions, such as stirring in trifluoroacetic acid in the presence of an agent suitable reducing agent, such as sodium borohydride or, alternatively, stirring the compounds of formula (lb) in acetic acid in the presence of formamide. In addition, compounds of formula (1-d), wherein R 8 is hydrogen, can be converted to compounds of formula (I-e), wherein R 8b is alkyl of d. 6, by reacting the compounds of formula (I-d) with a reagent of formula (V) in an appropriate solvent such as, for example, diglyme, in the presence of a base such as, for example, potassium butoxide. a ^^ & ^^^^^. ^^^^ nm ^ d-d) (I-e) A compound of formula (I), defined as a compound of formula (I) wherein X is sulfur, can be prepared by reacting the corresponding compound of formula (Ia) with a reagent such as phosphorus pentasulfide or Lawesson's reagent in a solvent suitable such as, for example, pyridine.

(I-a) (l-f) The compounds of formula (I), wherein R1 is hydrogen and X is oxygen, said compounds being defined as compounds of formula (Ial), can be prepared by reacting a nitrone of formula (VI) with the anhydride of a carboxylic acid such as, for example, acetic anhydride, thereby forming the corresponding ester in position 2 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.

(V I) (l - a - l) Alternatively, compounds of formula (lal) can be prepared by reacting a nitrone of formula (VI) with an electrophile reagent containing sulfonyl such as, for example, p-toluenesulfonyl chloride in the presence of a base such as, example, aqueous potassium carbonate. The reaction initially involves the formation of a 2-hydroxyquinoline derivative which is subsequently tautomerized to the desired quinolinone derivative. The application of phase transfer catalysis conditions known in the art can increase the speed of the reaction. The compounds of formula (1-a-1) can also be prepared by an intramolecular photochemical rearrangement of compounds of formula (VI). Said rearrangement can be carried out by dissolving the reactants in a solvent inert to the reaction, and applying irradiation to a Z ¿i wavelength of 366 nm. It is advantageous to use degassed solutions and carry out the reaction under an inert atmosphere such as, for example, nitrogen gas or oxygen free argon, to minimize the inconvenient side reactions or the reduction of the quantum yield.

(V I) (l - a - l) The compounds of formula (I) can also be converted to some other compound by reactions known in the art or transformations of the functional group. A number of such transformations have already been described above. Other examples are hydrolysis of carboxylic esters to the corresponding alcohol or carboxylic acid; hydrolysis of amides to the corresponding amines or carboxylic acids; hydrolysis of nitriles to the corresponding amides; the amino groups in the imidazole or phenyl can be replaced by a hydrogen by diazotization reactions known in the art, and subsequent replacement of the diazo group by hydrogen; the alcohols can be converted into esters and ethers; the primary amines can be converted into secondary or tertiary amines; and the double bonds can be hydrogenated to the corresponding single bond. The intermediates of formula (III) can be prepared by reacting a quinolinone derivative of formula (VIII) with an intermediate of formula (XI) or a functional derivative of the mimo under appropriate conditions such as, for example, a strong acid, example polyphosphoric acid, in an appropriate solvent. The intermediate of formula (VIII) can be formed by cyclization of an intermediate of formula (VII) by stirring in the presence of a strong acid such as, for example, polyphosphoric acid. Optionally, said cyclization reaction can be followed by an oxidation step, which can be carried out by stirring the intermediate formed after cyclization, in a suitable solvent such as, for example, a halogenated aromatic solvent, for example bromobenzene, in presence of an oxidizing agent, for example bromine or iodine. In this step, it may also be appropriate to change the substituent R1 by functional group transformation reaction known in the art.

A? U * * ^ * ^: ^. . . t The intermediates of formula (III-al), being intermediates of formula (II), wherein the dotted line is a bond, R1 and R17 are hydrogen and X is oxygen, they 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 alcohol, for example, methanol. The intermediate of formula (XVI) obtained in this way undergoes hydrolysis of the ketal and ring opening of the isoxazole portion 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) ^ 7, .z ^^ M ^ k (XV) (lll-a-1) Intermediates of formula (III-a-1) can be easily converted into intermediates of formula (II Ia) , defined as intermediates of formula (III), wherein the dotted line represents a bond, X is oxygen, R17 is hydrogen and R1 is different from hydrogen, using N-alkylation procedures known in the art. (lll-a) An alternative way to prepare intermediates of formula (III-1), wherein X is oxygen and R1 is hydrogen, part of an intermediate of formula (XVI), which is conveniently converted into intermediates of formula (XIX) using conditions of catalytic hydrogenation, for example, using hydrogen gas and palladium on carbon in a reaction-inert solvent such as, for example, tetrahydrofuran. The intermediates of formula (XIX) are converted to intermediates of formula (XX) by subjecting the intermediates of formula (XIX) to an acetylation reaction, for example, by treatment with the anhydride of a carboxylic acid, for example, acetic anhydride, in a solvent inert to the reaction, for example, toluene, and by subsequent treatment with a base such as, for example, potassium tert-butoxide in a reaction-inert solvent, for example, 1,2-dimethoxyethane. Intermediates of formula (III-1) can be obtained by treating intermediates of formula (XX) under acidic conditions.

Intermediates of formula (II) can be prepared by reacting an intermediate of formula (X), wherein W is an appropriate leaving group such as, for example, halogen, with an intermediate ketone of formula (XI). This reaction is carried out by converting the intermediary from ^^^^ rtí ^ i ^ ftfMt ^^ '- ^^^^. The formula (X) is an organometallic compound, stirring with a strong base such as butyl lithium and subsequently adding the intermediate ketone of formula (XI). Although this reaction first gives a hydroxy derivative (ie, R8 is hydroxy), said hydroxy derivative can be converted into other intermediates, wherein R8 has another definition, by carrying out (functional group) transformations known in the art.

(X) (X I) (H) The intermediary mironas of formula (VI) can be prepared by N-oxidizing quinoline derivatives of formula (XII) with an appropriate oxidizing agent such as, for example, m-chloro-peroxybenzoic acid or H 2 O in a suitable solvent such as, for example , dichloromethane.

Said N-oxidation can also be carried out on a precursor of a quinoline of formula (XIII). It is assumed that the intermediates of formula (XII) are metabolized in vivo to compounds of formula (I) by intermediates of formula (VI). Accordingly, the intermediates of formula (XII) and (VI) can function 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 can be represented in a configuration of R or S. The compounds of formula (I) as prepared in the procedures described above, are generally racemic mixtures of enantiomers which can be separated from one another following resolution procedures known in the art. The compounds of formula (I) can be converted to 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 alternative way of separating the enantiomeric forms of the compounds of formula (I) requires liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms can also be derived from the corresponding stereochemically isomeric pure 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 preparation methods. These methods will advantageously use enantiomerically pure starting materials. This invention provides a method of using the compounds of formula (I) to inhibit the proliferation of smooth muscle cells, as illustrated by pharmacological example C.1. Accordingly, the compounds of formula (I) can be used for the manufacture of a medicament for the inhibition of the proliferation of smooth muscle cells and, therefore, the use for the manufacture of a medicament for the treatment of vascular proliferative disorders such as atherosclerosis and restenosis. It has been proposed in the literature that the mechanism underlying the proliferation of smooth muscle cells involves the loss of normal regulation of cell growth, a process in which ras proteins play an important role. Accordingly, it has been suggested that compounds having farnesyl transferase inhibition properties may be useful for preventing the proliferation of smooth muscle cells after vascular injury (Indolfi et al., Nature medicine, 1, 541-545 (1995)). and Irani et al., Biochemical and Biophysical Research Communications, 202, 1252-1258 (1994) .Atherosclerosis is a disorder characterized by the deposition of fatty substances in, and fibrosis of, the inner layer of the arteries.

Restenosis is the narrowing of the tubular ducts of a subject after the tubular walls have been traumatized. This may be caused by uncontrolled cell proliferation of neointimal tissue, which is often a complication due to the use of revascularization techniques such as, for example, graft for saphenous vein shunt, endoarterectomy, percutaneous transluminal coronary angioplasty (PTCA). , and similar. Restenosis refers to a worsening or recurrence of luminal stenosis in an artery, which is characterized by hyperplasia of the arterial wall cells. In this regard, restenosis differs markedly from arterial occlusion by arterial atherosclerotic plaque or thrombus occlusion. Restenosis is not restricted or limited to the coronary arteries. It can also occur, for example, in peripheral vascular systems. Angioplasty is a technique by which an artery plugged by an atherosclerotic plaque and / or thrombus is mechanically cleared. This blocked or blocked artery prevents adequate blood flow. Angioplasty procedures are much less invasive and much less traumatic than conventional alternatives such as coronary bypass surgery, and have achieved wide acceptance as a means to obtain dilation or clearance of arteries. In conventional angioplasty procedures, a small balloon tip catheter is inserted into an artery, often using a guidewire or a catheter tube in which a collapsed balloon can be located at one or more points of stenosis (narrowing) arterial. Once located within the obstruction, the balloon is inflated, stretching and / or fracturing the obstruction in this way, and increasing the lumen (opening) of the artery. After the balloon is deflated and removed from the artery, the inside diameter of the artery is usually larger, resulting in restoration of blood flow. These balloon and catheter assemblies are often referred to as balloon catheters for coronary dilatation. However, said angioplasty procedures involve risks of local and systemic thromboembolic effects, damage to an arterial wall and restenosis. The restenosis following angioplasty with balloon catheter is also referred to as "restenosis by percutaneous transluminal coronary angioplasty", and is characterized by the return of obstruction in the artery due to the neointimal formation of a layer of smooth muscle cells in the intima after balloon catheter injury. Accordingly, the present invention provides a method of treating vascular proliferative disorders in a warm-blooded animal, such as atherosclerosis and restenosis, which comprises administering to said warm-blooded animal a prophylactically or therapeutically effective amount of a compound of formula (I). ). The present invention further provides a method for inhibiting the proliferation of smooth muscle cells in a warm-blooded animal, which comprises administering to said warm-blood anWWW a prophylactically or therapeutically effective amount of a compound of formula (I). Balloon catheter angioplasty can be followed by a mechanical / surgical procedure known as intravascular stenting (stenting), a procedure in which an expandable metal cuff, i.e., a stent, is placed inside the artery after practice angioplasty. However, after the stent is inserted, a condition known as "coronary artery restenosis by stent" may occur, causing artery blockage to return due to neointimal formation of a layer of smooth muscle cells in the intima. . Therefore, it may be advantageous to cover or coat said stent with a coating material comprising a compound of formula (I) to inhibit the proliferation of smooth muscle cells. Therefore, in one aspect, this invention also provides stents coated or coated with a coating material comprising an amount of a compound of formula (I) effective to prevent, treat or reduce the proliferation of smooth muscle cells. Commercially available stents are, for example, expandable balloon stents such as, for example, Palmaz-Schatz ™ stents, Strecker ™ stents and Gianturco-Roubin ™ stents, and self-expanding stents such as, for example, Gianturco ™ expandable wire stents. and Wallstent ™. Other stents are Palmaz-Schatz Crown ™, Cross-Flex ™, ACS Multi-Link ™, Nir ™, Micro Stent II ™ and Wiktor ™.

In one embodiment, the invention also relates to catheters, or other transluminal devices coated or coated with a coating material comprising an amount of a compound of formula (I) effective to prevent, treat or reduce the proliferation of smooth muscle cells. . The metallic surface of a stent can be coated in several ways. The surface can be prepared by a two-step process that includes the covalent attachment of an organosilane having amine-reactive sites to the surface of the metal member, typically through a metal oxide thereof. An organosilane having a vinyl functionality pending from the surface can also be used. Then, a biocompatible coating material can be covalently bound to the organosilane coating. The coating layer comprising an amount of a compound of formula (I) can also be applied as a mixture of a polymeric precursor and a compound of formula (I) which is finely divided or dissolved in a vehicle or polymeric solvent which It is then cured in situ. The coating can be applied by dipping or spraying using relatively high vapor pressure evaporative solvent materials to produce the desired coating viscosity and thickness. The coating is also one which adheres adherently to the surface of the filaments of the open structure of the stent, - ^ * so that the open crystalline structure nature of the ribbon structure or other pattern is preserved in the coated device. The main constituent of the stent coating must have elastomeric properties. The coating of the stent is preferably a biostable hydrophobic elastomeric material and suitable in which it does not degrade and minimize rejection and inflammation of the tissue, and one which will undergo encapsulation by the tissue adjacent to the stent implant site. Polymers suitable for said coating include silicones (for example, polysiloxanes and substituted polysiloxanes), polyurethanes, thermoplastic elastomers in general, ethylene vinyl acetate copolymers, polyolefin elastomers and EPDM rubbers. The coating load of the stent with the compound of formula (I) may vary. The desired profile of release rate can be adapted by varying the thickness of the coating, the radial distribution, the mixing method, the amount of said compound of formula (I), and the interlacing density of the polymeric material. Methods for coating stents are described, for example, in WO-96/32907, US-5,607,475, US-5,356,433, US-5,213,898, US-5,049,403, US-4,807,784 and US-4,565,740. The stents are made of a biocompatible material such as, for example, stainless steel, tantalum, titanium, nitinol, gold, platinum, inconel, iridium, silver, tungsten or other biocompatible metal, or alloys of any of them. Stainless steel and tantalum are particularly preferred. Saying The stent can be coated by one or more layers of a biocompatible coating material such as, for example, carbon, carbon fiber, cellulose acetate, cellulose nitrate, silicone, parylene, derivatives of parylene, polyethylene terephthalate, polyurethane, polyamide, polyester, 5-polyorthoester, polyanhydride, polyether sulfone, polycarbonate, polypropylene, high molecular weight polyethylene, polytetrafluoroethylene, or other biocompatible material, or mixtures or copolymers thereof. Parylene is a generic name for a group of known polymers based on p-xylene, and made by vapor phase polymerization, and a name for the unsubstituted member of said polymers. Said one or more layers of biocompatible material comprise a compound of formula (I) of the present invention, and advantageously provide controlled release of said compound of formula (I) effective to prevent, treat or reduce the proliferation of smooth muscle cells. Said one or more layers of material Biocompatible can further comprise bioactive materials such as, for example, heparin and other inhibitors of thrombin, hirudin, hirulog, argatroban, D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone, or other antithrombogenic agent, or mixtures thereof; urokinase, streptokinase, a tissue plasminogen activator or other thrombolytic agent, or mixtures of the same; a fibrinolytic agent; an inhibitor of vasospasm; a calcium channel blocker, a nitrate, nitric oxide, a nitric oxide or other vasodilator promoter; an antimicrobial agent or antibiotic; aspirin, ticlopdine, an inhibitor of glycoprotein llb / llla or another inhibitor of receptors for surface glycoproteins, or other antiplatelet agent; colchicine or another antimitotic, or another microtubule inhibitor; a retinoid or other antisecretory agent; cytochalasin or another actin inhibitor; deoxyribonucleic acid; an antisense nucleotide or other agent for molecular genetic intervention; methotrexate or another antiproliferative agent or antimetabolites; an anti-cancer chemotherapeutic agent; dexamethasone, sodium dexamethasone phosphate, dexamethasone acetate or other dexamethasone derivative, or other anti-inflammatory steroid or non-steroidal anti-inflammatory agent; cyclosporin or another immunosuppressive agent; trapidal (a PDGF antagonist), angiopeptin (a growth hormone antagonist), an anti-growth factor antibody; or another growth factor antagonist; dopamine, bromocriptine mesylate, pergolide mesylate or other dopamine agonist; captopril, enalapril or other angiotensin-converting enzyme (ACE) inhibitor; ascorbic acid, alpha tocopherol, superoxide dismutase, deferoxamine, a 21-aminosteroid (lasaroid) or other free radical scavenger; or a mixture of any of these compounds. Accordingly, the present invention also provides a method for treating vascular proliferative disorders in a warm-blooded animal, such as restenosis by percutaneous transluminal coronary angioplasty or coronary artery restenosis by stenting, which comprises administering said warm-blooded animal. a prophylactically or therapeutically effective amount of a compound of formula (I).

M? &?? TU 8uák &'J' 'In particular, said warm-blooded animal is a mammal, or more specifically a human. As is known to those skilled in the art, a prophylactically or therapeutically effective amount varies with the type of therapeutic agent. It is known to those skilled in the art how to determine a prophylactically or therapeutically effective amount of a suitable therapeutic agent. In view of their useful pharmacological properties, the present compounds can 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 the form of an acidic or basic addition salt, as the active ingredient, is combined in intimate admixture with a pharmaceutically acceptable carrier, which vehicle can take a wide variety of forms, depending on the form of preparation desired for administration. These pharmaceutical compositions are conveniently in unit dosage form suitable, preferably, for oral, rectal, percutaneous or parenteral injection. For example, in the preparation of the compositions in oral dosage form, any of the usual pharmaceutical means such as, for example, water, glycols, oils, alcohols and the like, in the case of oral liquid preparations such as suspensions may be used. , 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. Due to its ease of administration, tablets and capsules represent the most advantageous form of oral dosage unit, in which case solid pharmaceutical carriers are obviously used. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, although other ingredients may be included to facilitate solubility. Injectable solutions can be prepared, for example, in which case the vehicle comprises a saline solution, glucose solution or a mixture of saline and glucose. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents, and the like may be used. In 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, whose additives do not cause a significant detrimental effect to the skin. Said additives may facilitate administration to the skin and / or may be useful for preparing the desired compositions. These compositions may be administered in various ways, for example, as a transdermal patch, as an applicable preparation, or as an ointment. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form to facilitate their administration and uniformity of dosage. The unit dosage form as used in the specification and in the claims herein, refers to physically defined units suitable as dosages ^ H | ^ g ^^ | m ik ?? amaÉ »* unitary, each unit containing A predetermined amount 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, teaspoons, spoons and the like, and segregated multiples thereof. Those skilled in the art could easily determine the effective amount from the test results presented below. In general, it is contemplated that an effective amount would be from 0.0001 mg / kg to 100 mg / kg of body weight, and in particular from 0.001 mg / kg to 10 mg / kg of 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 can be formulated as unit dosage forms, for example, containing from 0.01 to 500 mg, and in particular from 0.1 mg to 200 mg of active ingredient per unit dosage form.

EXPERIMENTAL PART In the sequential, "THF" means tetrahydrofuran, "DIPE" means diisopropyl ether, "DCM" means dichloromethane, "DMF" means N, N-dimethylformamide and "ACN" means acetonitrile. Of some compounds of formula (I), the absolute stereochemical configuration was not determined experimentally. In such cases, the stereochemically isomeric form which was isolated by first veiP e designates as "A", and the second as "B", without further reference to the actual stereochemical configuration.

A. Preparation of intermediaries EXAMPLE A.1 1a) N-Phenyl-3- (3-chlorophenyl) -2-propenamide (58.6 g) and polyphosphoric acid (580 g) were stirred at 100 ° C overnight. The product was used without further purification, yielding quantitatively (±) -4- (3-chloropheyl) -3,4-dihydro-2 (1 / - /) -quinolinone (intermediate 1-a). (1 b) The 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. The precipitate was washed with water, then with a dilute solution of NH OH and absorbed in DCM. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 99/1 / 0.1). The pure fractions were collected and evaporated, and recrystallized from CH2Cl2 / CH3OH / DIPE, yielding 2.2 g of (±) -6- (4-chlorobenzoyl) -4- (3-chlorophenyl) -3,4-dihydro -2 (1 H) -quinolinone (intermediate 1-b, p.of f 194.8X). 1c) Bromine (3.4 ml) in bromobenzene (80 ml) is added dropwise at room temperature to a solution of intermediate (1-b) (26 g) in bromobenzene (250 ml), and the mixture is stirred at 160 ° C. ° C during the night. The mixture is cooled to room temperature and basified with NH OH. The mixture is evaporated, the residue is absorbed in ACN and filtered. The precipitate is washed with water and dried in air, yielding 24 g (92.7%) of product. A sample was recrystallized from CH2Cl2 / CH3OH / DIPE, yielding 2.8 g of 6- (4-chlorobenzoyl) -4- (3-chlorophenyl) -2- (1H) -quinolinone; p. of f. 234.8 ° C (intermediate 1-c). 1d) Iodomethane (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 (10N) (200 ml), and The mixture was stirred at room temperature overnight. Ethyl acetate was added and the mixture was decanted. The organic layer was washed with water, dried, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 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) -1-methyl-2 (1 / - /) -quinolinone; p. of f. 154.7 ° C (intermediate 1-d). In a similar manner, but starting from the intermediate (1-b), (±) -6- (4-chlorobenzoyl) -4- (3-chlorophenol) -3,4-dihydro-1-methyl- was prepared 2 (2H) -quinolinone (intermediate 1-e). aat ^ fltteriae EXAMPLE A.2 It was added dropwise at -20 ° C under N2 butyllithium in hexane (1.6 M) (12.75 ml) 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-1 H-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. environment during one night. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 97/3 / 0.1). The pure fractions were collected and evaporated, yielding 2.5 g (total, 48%) of (±) -a- (1-butyl-1 / - / - imidazol-5-yl) -4- (3-chlorophenyl) -a - (4-chlorophenyl) -2-methoxy-6-quinoline-methanol (intermediate 2).

EXAMPLE A.3 3a) Butyllithium (30.1 ml) was added slowly at -78 ° C to a solution of? /,? / - dimethyl-1 H-imidazol-1-sulfonamide (8.4 g) in tetrahydrofuran (150 ml), and the mixture it was stirred at -78 ° C for 25 minutes. Chlorotriethylsilane (8.1 ml) was added, and the mixture was stirred until the temperature reached 20 ° C. The mixture was cooled to -78 ° C, butyllithium (30.1 ml) was added, the mixture was stirred at -78 ° C for 1 hour, and allowed to reach -15 ° C: fcfca ^ aSftt * - *, mixture was again cooled to -78 ° C, a solution of 6- (4-chlorobenzoyl) -1-methyl-4-phenyl-2 (1 H ufholinone (15 g) in tetrahydrofuran (30 ml), and the mixture was stirred until the temperature reached 20 ° C. The mixture was hydrolyzed and extracted with ethyl acetate.The organic layer was dried, filtered and evaporated to dryness. no further purification, yielding 26 g (100%) of (±) -4 - [(4-chlorophenyl) (1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl) hydroxymethyl] - ? /,? / - dimethyl-2- (triethylsilyl) -1 / - / - imidazolo-1-sulfonamide (3-a intermediate) A mixture of the intermediate (3-a) (26 g) in sulfuric acid (2.5 ml) ) and water (250 ml) was stirred and heated at 110 ° C for 2 hours, the mixture was poured into ice, basified with NH 4 OH and extracted with DCM The organic layer was dried, filtered and evaporated to dryness The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4OH 99/1 / 0.2). The pure fractions were collected and evaporated, yielding 2.4 g (11%) of (±) -4 - [(4-chlorophenyl) (1,2-dihydro-1-methyl- 2-oxo-4-phenyl-6-quinolinyl) hydroxymethyl] -? /,? / - dimethyl-1 / - / - midazole-1-sulfonamide (intermediate 3-b).

EXAMPLE A.4 Compound (3) (3 g) in thionyl chloride (25 ml) was added at room temperature. The mixture was stirred and refluxed at 40 ° C overnight. The solvent was evaporated to dryness. The product was used without further purification, yielding 3.49 g of (±) -4- (3-chlorophenyl) -1-methyl-6- [1- (4-methylphenyl) -1 - (4-methyl-4H- hydrochloride. pyrrol-3-yl) ethyl] 2 (1 H) -quinolinone (intermediate 4).

EXAMPLE A.5 a) Toluene (1900 ml) was stirred in a round bottom flask (5 I) using a water separator: It was added in portions (4-chlorophenyl) (4-nitrophenyl) methanone (250 g). P-Toluenesulfonic acid (54.5 g) was also added in portions. Ethylene glycol (237.5 g) was poured into the mixture. The mixture was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (5 L) and washed twice with a 10% solution of K2CO3. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was stirred in DIPE, filtered and dried (vacuum, 40 ° C, 24 hours), yielding 265 g (91%) of 2- (4-chlorophenyl) -2- (4-nitrophenyl) -1, 3 -dioxolane (intermediate 5-a). b) Sodium hydroxide (16.4 g) and (3-methoxyphenyl) acetonitrile (20.6 ml) were added at room temperature to a solution of intermediate (5-a) (25 g) in methanol (100 ml), and the mixture was stirred at room temperature overnight. Water was added, the precipitate was filtered, washed with cold methanol and dried. The product was used without further purification, yielding 30 g (90%) of 5- [2- (4-chlorophenyl) -1,3-dioxolan-2-yl] -3- (3-methoxyphenyl) -2,1- benzisoxazole (intermediate 5-b). c) Intermediate (5-b) (30 g) in THF (250 ml) was hydrogenated with palladium on charcoal (3 g) as a catalyst at room temperature for 12 hours under a pressure of 2.6-105 Pa in a Parr apparatus. After uptake of H 2 (1 equivalent), the catalyst was filtered through Celite and the filtrate was evaporated to dryness. The product was used without further purification, yielding 31.2 g (100%) of (3-methoxyphenyl) [2-amino-5- [2- (4-chloro-phenyl) -1, 3-dioxolan-2-yl] phenyl ] methanone (intermediate 5-c). d) Acetic anhydride (13.9 ml) was added to a solution of intermediate (5-c) (31.2 g) in toluene (300 ml), and the mixture was stirred and refluxed for 2 hours. The mixture was evaporated to dryness, and the product was used without further purification, yielding 36.4 g (100%) of? / - [2- (3-methoxybenzoyl) -4- [2- (4-chlorophenyl) -1, 3 -dioxolan-2-yl] phenyl] acetamide (intermediate 5-d). e) Potassium fer-butoxide (33 g) was added in portions to a solution of the intermediate (5-d) (36.4 g) in 1,2-dimethoxyethane (350 ml), and the mixture was stirred at room temperature during the night. The mixture was hydrolyzed and extracted with DCM. The organic layer was dried, filtered and evaporated to dryness. The product was used without further purification, yielding 43 g of 6- [2- (4-chlorophenyl) -1,3-dioxolan-2-yl] -4- (3-methoxyphenyl) -2 (1 / - /) - quinolinone (intermediate 5-e). f) A mixture of the intermediate (5-e) (43 g) in HCl (3N, 400 ml) and methanol (150 ml) was stirred and refluxed overnight. The mixture was cooled and filtered. The filtrate was washed with water and diethyl ether and dried. The product was used without further purification, yielding 27 g (94%) of 6- (4-chlorobenzoyl) -4- (3-methoxyphenyl) -2 (1 / -) -quinolinone (intermediate 5-f). g) Methyl iodide (1.58 ml) was added to a solution of the intermediate (5-f) (7.6 g) and benzyltriethylammonium 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, filtered and the solvent was evaporated. The residue was purified by flash column chromatography on 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) -1-methyl-2 (1 H) -quinolinone (intermediate 5). -g).

EXAMPLE A.6 a) 3- (3-Chlorophenyl) -5- [2- (4-chlorophenyl) -1,3-dioxolan-2-yl] -2,1-benzisoxazole (intermediate 6-a) was prepared analogously to the intermediate (5-b). b) A mixture of intermediate (6-a) (30 g) in 3N HCl (220 ml) and methanol (165 ml) was stirred at 100 ° C for 5 hours. The mixture was poured into ice and basified with aqueous NH3, the precipitate was filtered, washed with water and diethyl ether and dried, yielding 24.9 g (93%) of (4-chlorophenyl) [3- (3-chlorophenyl)). -2,1-benzisoxazol-5-yl] methanone (intermediate 6-b). The product was used without further purification. c) Butyl lithium in hexanes was added slowly (10 JQg 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 during 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 slowly added, and the mixture was stirred at -70 ° C. 1 hour, it was 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, filtered and the solvent was evaporated.The residue (8.2 g) was purified by gel column chromatography. silica (eluent: CH2Cl2 / CH3OH / NH4OH 96/4 / 0.2), and crystallized from 2-propanone / diethyl ether The precipitate was filtered and dried, yielding 1.5 g (25%) of (±) -3 - (3-chlorophenyl) -o - (4-chlorophenyl) -oc - (1-methyl-1 H-imidazol-5-yl) -2,1-benzisoxazole-5-methanol (intermediate 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 on ice, basified with K2CO3, filtered over Celite, washed with ethyl acetate and decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 97/3 / 0.1 and 95/5 / 0.1), yielding 18.7 g (49%) of (±) - [2-amino- 5- (4-chlorophenyl) hydroxy (1-methyl-1 / - / - imidazol-5-yl) methyl] phenyl] (3-chlorophenyl) methanone (intermediate 6-d).

B. Preparation of the final compounds EXAMPLE B.1 The 1-methylimidazole (4.69 ml) in tetrahydrofuran was stirred at -78 ° C. (100 ml). A solution of butyl lithium in hexanes (2.5 M) (36.7 ml) was added dropwise, and the mixture was stirred at -78 ° C for 15 minutes. Chlorotriethylsilane (9.87 ml) was added, and the mixture was brought to room temperature. The mixture was cooled to -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 to -15 ° C. C. The mixture was cooled to -78 ° C, a solution of the intermediate (1-d) (20 g) in THF (40 ml) was added, and the mixture was brought to room temperature. The mixture was hydrolyzed at 0 ° C and extracted with ethyl acetate. The organic layer was dried, filtered and evaporated to dryness, yielding 36 g of product. The product was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 97/3 / 0.1). The pure fractions were collected, evaporated and crystallized from 2-propanone, CH3OH and (C2H5) 2O. The precipitate was filtered, washed with (C2H5) 2O and dried, yielding 12.4 g (52%) of (±) -4- (3-chlorophenyl) -6 - [(4-chlorophenyl) hydroxy (1-methyl- 1 / - / - midazol-5-yl) methyl] -1-methylene-2 (1 - /) - quinolone; (compound 3, page of F. 233.6 ° C). In a similar manner, but using the intermediate (5-g) or the intermediate (1-e) instead of the intermediate (1-d), respectively (±) -6 - [(4-chlorophenyl) hydroxy (1 - methyl-1 - / - imidazol-5-it) | ^ íl] -4- (3-methoxyphenyl) -1-methyl-2 (1 / -) -quinolinone (compound 36) and (±) -4- (3-chlorophenyl) -6 - [(4-chlorophenyl) hydroxy (1-methyl-1 / - / - imidazol-5-yl) methyl] -3,4-dihydro-1-methyl-2 (1 H) - quinolinone (compound 127).

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, washed with water, then with diethyl ether and dried, yielding 2.7 g (100%) of (±) - 6 - [(1-butyl-1 H-imidazole-5- il) - (4-chlorophenyl) hydroxymethyl] -4- (3-chlorophenyl) -2 (1 / - /) - quinolinone (compound 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. Iodomethane (1.5 ml) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was hydrolyzed and extracted with diethyl ether and methanol. The organic layer was dried, filtered and evaporated to dryness, yielding 4.4 g of residue. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 95.5 / 4.5 / 0.2). The Pure fractions were collected and evaporated. The product was converted to the ethanedioic acid salt (1: 1) in 2-propanone, and filtered. The residue was crystallized from 2-propanone, diethyl ether and DIPE. The precipitate was filtered, washed with diethyl ether, dried and recrystallized from 2-propanone, methanol and DIPE. The precipitate was filtered, washed with diethyl ether and dried, yielding 0.95 g (25%) of ethanedioate dihydrate (1: 1) of (±) -4- (3-chlorophenyl) -6 - [(4-chlorophenyl) methoxy (1-methyl-1 / - / - imidazol-5-yl) methyl] -1-methyl-2 (1 / - /) -quinolinone (compound 4, p.of f 154.6 ° C).

EXAMPLE B.4 At room temperature, iodomethane (0.38 ml) was added dropwise to a solution of compound (8) (2.44 g) and N, N, N-triethylbenzene-ammonium 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, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 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, washed with diethyl ether and dried, yielding 1.4 g (56%) of (±) -4- (3-chlorophenyl) -6 - [(1-butyl-1 H-imidazole-5 -yl) (4-chlorophenyl) hydroxymethyl] -1-methyl-2 (1 H) -quinolinone (compound 9, p.of f 174.6 ° C). s Ü ^ EXAMPLE B.5 Iodomethane (1.4 ml) was added to a mixture of (±) -6 - [(4-chlorophenyl) -1 / - / - imidazol-4-ylmethyl] -1-methyl-4-phenyl-2 (1 - /) -quinolinone (7.5 g) and benzyltriethylammonium chloride (2 g) in THF (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, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 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) (1-methyl-1 H-imidazol-4-yl) methyl ] -1-methyl-4-phenyl-2 (1H) -quinol-none; p. of f. 149.9 ° C (compound 44). Fraction 2 was recrystallized from 2-propanone, methanol and diethyl ether, yielding 1.6 g (20%) of (±) -6 - [(4-chlorophenyl) (1-meth? L-1H-imidazole-5 il) methyl] -1-methyl-4-phenyl-2 (1 - /) - quinolinone (compound 2, p.of f 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 overnight. The mixture was poured into ice, basified with 3N NaOH, then with concentrated NaOH and aa ^ aaito ^ a ^ a extracted with ethyl acetate. The organic layer was dried, filtered and evaporated to dryness. The residue column on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 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 to the ethanedioic acid salt (1: 1) in 2-propanone and diethyl ether. The precipitate was filtered, washed with diethyl ether and dried, yielding 4.7 g (55%) of ethanedioate monohydrate (1: 1) of (±) -4- (3-chlorophenyl) -6 - [(4-chlorophenyl) (1-methyl-1 H-imidazol-5-yl) methyl] -1-methyl-2 (1 / - /) - quinolinone (compound 5, page 157.5 ° C).

EXAMPLE B.7 A solution of compound 90 (4.2 g) in 1,2-dimethoxyethane (70 ml) was stirred under N2 for 30 minutes. Iodomethane (0.83 ml) was added portionwise, followed by potassium tert-butoxide (2 g), 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, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane / 2-propanol / NH4OH 85/5 / 0.5 to 80/20/1), and was converted to the ethanedioic acid salt, crystallized from -propanone, and filtered, yielding 1.16 g (23.6%) of ethanedioate (1: 1) of (±) -4- (3-chlorophenyl) -6- [1- (4- j & ^^^^^^ chlorophenyl) -1 - (1-methyl-1 H -medazol-5-yl) ||| pi -methyl-2 (1 / -) -quindinone (compound 12, p of f.203.9 ° C). In a similar manner, but replacing the iodomethane with dichloromethane or dibromethane, ethanedioate (1: 1) of (±) -6- [2-chloro-1- (4-chlorophenyl) -1- (1-methyl-1) was prepared respectively H-imidazol-5-yl) ethyl] -4- (3-chlorophenyl) -1-methyl-2 (1H) -quinolinone (compound 69) and (±) -6- [2-bromo-1- (4- chlorophenyl) -1 - (1-methyl-1 H-imidazol-5-yl) ethyl] -4- (3-chlorophenyl) -1-methyl-2 (1 H) -quinolinone (compound 70).

EXAMPLE B.8 a) Compound (3) (3 g) was separated (in its enantiomers), and purified by high performance liquid chromatography over Chiralcel OD (20 μm, eluent: hexane / ethanol 50/50). The pure fractions (A) were collected, and the solvent was evaporated yielding 1.6 g ((A); LCI:> 99%). The pure fractions (B) were collected, and the solvent was evaporated, yielding 1.5 g ((B), LCI:> 99%). The residue (A) was dissolved in 2-propanol, and converted to the ethanedioic acid salt (1: 1). The precipitate was filtered and dried, yielding 0.6 g (17%) of ethanedioate (1: 1) of (+) - 4- (3-chlorophenyl) -6 - [(4-chlorophenyl) -hydroxy (1-methyl) 1 - / - imidazol-5-yl) methyl] -1-methyl-2 (1 / -) -quinolinone; [a] D20 = + 17. 96 ° (c = 1% in methanol) (compound 23). The residue (B) was dissolved in 2-propanol, and converted to the ethanedioic acid salt (1: 1). The precipitate was filtered and dried, yielding 0.6 g (17%) of ethanedioate (1: 1) of (-) - 4- (3-chlorophenyl) -6 - [(4-chlorophenyl) hydroxy (1-mejSpp-imidazole -5-yl) methyl] -1-methyl-2 (1 / - /) - quinolinone; [α] D 20 = + 18.87 ° (c = 1% (w / v) in methanol) (compound 24). b) Compound 14 (4 g) was separated (in its enantiomers), and purified by chiral column chromatography on Chiralcel OD (25 cm, eluent: 100% ethanol, flow: 0.5 ml / min, wavelength: 220 nm). The pure fractions (A) 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 and dried, yielding 1.3 g of (-) - 6- [amino (4-chlorophenyl) (1-methyl-1 H-imidazol-5-yl) methyl] -4- (3-chlorophenyl) -1-methyl-2 (1 H) -quinolinone ([a] D20 = -6.16 ° (c = 0.67% (w / v) in methanol) (compound 74). B) were collected and evaporated.The residue was crystallized from 2-propanol.The precipitate was filtered, yielding 1.3 g of (+) - 6- [amino (4-chloro-phenyl) (1-methyl-1 / - -imidazol-5-yl) methyl] -4- (3-chlorophenyl) -1-methyl-2 (1H) -quinolinone ([a] D20 = + 22.86 ° (c = 0.98% (w / v) in methanol ) (compound 75).

EXAMPLE B.9 Air was bubbled through a solution of compound (47) (3.6 g) in THF (40 ml) for 30 minutes. Potassium salt of 2-methyl-2-propanol (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, filtered and the solvent was evaporated, yielding 2.9 g of product. He "MMam- - ^^^^^" product was purified by column chromatography on silica g @ J (eluent: CH 2 Cl 2 / CH 3 OH / 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 and dried, yielding 1.3 g (35%) of (±) -4- (3-chlorophenyl) -6 - [(4-chlorophenyl) hydroxy (1-methyl-1 / - / - imidazole-4). -yl) methyl] -1-methyl-2 (1H) -quinolinone (compound 48).

EXAMPLE B.10 A mixture of (±) -4 - [(4-chlorophenyl) (1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl) hydroxymethyl] -? /,? / - dimethyl-1 / - / - imidazolo-1-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 aqueous NH3 and extracted with DCM. The organic layer was dried, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / 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 - [(4-chlorophenyl) hydroxy (1 H-imidazol-4-yl) methyl] -1-methyl-4-phenyl-2 (1 H) -quinolinone monohydrate (compound 43).

EXAMPLE 6.11 Compound (3) (4 g) was dissolved in DCM (10 ml) and acetic acid (5.6 ml) at 45 ° C. Zinc r / o (5.5 g) was added followed by cyanoacetic acid (3.5 g). 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 10% K2CO3, dried, filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / CH3OH / NH4OH 96/4 / 0.2), crystallized from 2-propanone / DIPE, filtered and dried, yielding 1.95 g (45%) ) of (±) -4- (3-chlorophenyl) -β- (4-chlorophenyl) -1,2-dihydro-1-methyl-β- (1-methyl-1 H-imidazol-5-yl) -2 -oxo-6-quinolinopropanenitrile (compound 25, p.of f 151.3 ° C).

EXAMPLE B. 12 Sulfuric acid (1 ml) was added dropwise to acetonitrile (30 ml) with stirring. Compound 3 (3 g) was added. The mixture was stirred at 80 ° C for 3 hours, and then cooled. K3CO3 was added at 10%, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried and filtered, and the solvent was evaporated to dryness. The residue (3.58 g) was dissolved in 2-propanone, and converted to the ethanedioic acid salt (1: 1). The precipitate was filtered, dried and crystallized from 2-propanone / CH3OH. The precipitate was filtered and dried, yielding 3.5 g (92%) of ethanedioate (1: 1) of (±) -N - [(4-) ^ ^ ^ ^ Chlorophenyl) [4- (3-chlorophenyl) -1,2-dihydro-1 -ra'-tyl-2-oxo-6-quinolinyl] (1-methyl-1H-imidazol-5-yl) methyl] acetamide (compound 56).

EXAMPLE B.13 Aqueous NH 3 (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, filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: toluene / 2-propanol / NH OH 80/20/1). The pure fractions were collected and the solvent was evaporated, yielding 4.4 g of (±) -6- [amino (4-chlorophenyl) (1-methyl-1 H-imidazol-5-yl) methyl] -4- (3- chlorophenyl) -1-methyl-2 (1 H) -quinolinone (compound 14).

EXAMPLE B. 14 A solution of compound 36 (6.2 g) in DCM (140 ml) was cooled and tribromomethane (32 ml) was added dropwise. The mixture was stirred at room temperature for 2 days. The mixture was poured into ice water, basified with aqueous NH 3 and extracted with CH 2 Cl 2 / CH 3 OH. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness, yielding 6 g (100%) of (± -) - 6 - [(4-chlorophenyl) -hydroxy- (1-methyl-1) H-imidazol-5-yl) methyl] -4- (3-hydroxyphenyl) -1-methyl-2 (1 H) -quinolinone (compound 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 ACN (50 ml) and DMF (50 ml) was stirred at 100 ° C. ° C during the night. The solvent was evaporated to dryness. The residue was taken up in CH 2 Cl 2 / water and decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue (2.7 g) was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 97/3 / 0.1 to 90/10 / 0.1). The pure fractions were collected and the solvent was evaporated. The residue was converted to the ethanedioic acid salt (1: 1) in 2-propanone. The precipitate was filtered, washed with 2-propanone / diethyl ether, and dried. The residue was converted to the free base. The precipitate was filtered and dried. The residue was crystallized from diethyl ether. The precipitate was filtered and dried, yielding 0.35 g (12%) of (±) -6 - [(4-chlorophenyl) hydroxy (1-methyl-1 H-imidazol-5-yl) methyl] -4- [3 - [2- (dimethylamino) ethoxy] -phenyl] -1-methyl-2 (1 H) -quinolinone (compound 62).

EXAMPLE B.16 P S? O (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, washed with water and absorbed in DCM. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness The residue was taken up by column chromatography on silica gel (eluent: Ctt2CI2 / CH3OH / NH4OH 97.5 / 2.5 / 0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone / ethyl ether. The precipitate was filtered and dried, yielding 1 g of (±) -4- (3-chlorophenyl) -6 - [(4-chlorophenyl) (1-methyl-1 H-imidazol-5-yl) methyl] -1 -methyl-2 (1H) -qu? nolinone (compound 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 the intermediate (6-d) (15 g) and pyridine (10.7 ml) in DCM (150 ml). ). The mixture was stirred at room temperature overnight. Water was added, and the mixture was decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue (21 g) was purified by column chromatography on silica gel (eluent: CH 2 Cl 2/2-propanol / NH 4 OH 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 (1-methyl-1 H -imidazol-5-yl) methyl] -1,2-dihydro-2-oxo-3-quinolinecarboxylate (compound 144). a) A mixture of benzoyl chloride (3.1 ml) in DCM (25 μL) was added dropwise at room temperature to a solution of the intermediate (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, filtered and the solvent was evaporated, yielding 8.8 g of (±) -N- [2- (3-chlorobenzoyl) -4 - [(4-chlorophenyl) -hydroxy (1-methyl-1 H -imidazol-5-yl) methyl] phenyl] benzeneacetamide (intermediate 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-chlorophenyl) hydroxy (1-methyl-1 H-imidazole-5 -yl) methyl] -3-phenyl-2 (1 H) quinolinone (compound 140).

EXAMPLE B.19 Aqueous NH3 (150 mL) was cooled to 5 ° C. A solution of (±) -4- (3-chlorophenyl) -1-methyl-6- [1- (4-methylphenyl) -1- (4-methyl-4H-pyrrol-3-yl) ethyl hydrochloride was added. ] -2 (1 H) -quinolinone (16.68 g) in THF (150 ml). The mixture was stirred at room temperature for 2 hours, decanted and extracted with ethyl acetate. The organic layer was dried, filtered and the solvent was evaporated to dryness. The reaction was carried out twice. The residues were combined and purified by column chromatography on silica gel (eluent: toluene / 2-propanol / NH OH 70-29-1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH2Cl2 / CH3OH / CH3CN. The precipitate was filtered, and the mother layer was evaporated to dryness and purified by column chromatography (eluent: CH3OH / NH4OAc (0.5% in H2O) 70/30). Two pure fractions were collected, and their solvents were evaporated to dryness. Fraction 2 was recrystallized from CH 2 Cl 2 / diethyl ether. The precipitate was filtered and dried, yielding 0.8 g of (±) -6- [amino (4-chlorophenyl) (1-methyl-1 H-imidazol-5-yl) methyl] -3-chloro-4- (3 chlorophenyl) -1-methyl-2- (1 H) -quinolinone (compound 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 cooled, poured into ice, basified with aqueous NH3, and filtered. The precipitate was absorbed in DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 96/4 / 0.3). The pure fractions were collected, and the solvent was evaporated. The residue was converted to the hydrochloric acid salt (1: 1), and crystallized from ACN. The precipitate was filtered and (3-chlorophenyl) -1,2-dihydro-1-methyl-2-oxd-quinolinyl] (1-methyl-1H-imidazol-5-yl) methyl] -2-methoxyacetamide (compound 89).

EXAMPLE B.21 A solution of intermediate (4) (3.3 g) in THF (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, absorbed in water and extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 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 and dried, yielding 0.89 g (28%) of (±) -4- (3-chlorophenyl) -6 - [(4-chlorophenyl) (methylamino) - (1-methyl-1 H-imidazole). 5-yl) methyl] -1-methyl-2 (1 H) -quinolinone monohydrate (compound 61). Tables 1 to 8 include the compounds that were prepared according to one of the above examples, and Table 9 gives a list of experimental elemental analysis values (column heading, "esp.") And theoretical (header) column, "theory.") for carbon, hydrogen and nitrogen of the compounds prepared in the previous experimental part.

A ^ t teáfeafeZt J * SBIK * _fc. S ^ i ^ CUAMT1 ^^^^^ d ^ g *: prepared by transformation of the functional group of compound 70. **: prepared by transformation of the functional group of compound 25.

TABLE 2 g »a? -ay» «~ UktBtm? * ^?» Í¡ * ¡í * 10 *: prepared by transformation of the functional group of compound 54. **: prepared by transformation of the functional group of compound 104. s 3zfe, ^^^ X ^^^^^ & z Zí ^ g & '.Zb zTÍ CUADRQ TABLE 4 TABLE 5 TABLE 6 TABLE 8 *: R6 and R7 taken together form a bivalent radical between positions 3 and 4 in the phenyl portion. TABLE 9 7 ^ ÜH ¡gjitgkg? ^^^^ J C. Pharmacological example C.1. Inhibition of Smooth Muscle Cell Proliferation The Effects of the Compounds of the Present Invention on Human Pulmonary Artery Smooth Muscle Cells (PASMC) were studied, human coronary artery smooth muscle cells (CASMC) and smooth muscle cells of rat artery A10 growing under standard tissue culture conditions. The cultures of CASMC and PASMC cells were purchased from Clonetics (San Diego, CA). A10 smooth muscle cells were purchased from the American Type Culture Collection (Bethesda, MD). The cells were inoculated at an ial cell density of 50,000 cells per well in six-well tissue culture plastic plates in 3.0 ml of complete growth medium. The test compounds were dissolved in dimethyl sulfoxide (DMSO), and added to a volume of 3 μl into each well to produce the desired concentrations of said test compound (final concentrations of 5, 10, 50, 100 and 500 nM ). The cells were incubated for six days. On day 4, fresh medium plus a fresh solution containing the test compound was added. On day 6, the growth medium was removed by aspiration. The cells were separated by trypsinization in 1.0 ml of trypsin-EDTA solution. Cell suspensions were transferred to 20 ml of a sotonic diluent, and the 0.5 ml count of the cell suspension diluted with a Coulter particle counter was counted. The cell counts of the cultures treated with the test compound were normalized to cell counts obtained from controls treated with DMSO, and expressed as percent inhibition. IC50 values (concentration of the test compound producing a 50% inhibition of cell proliferation) were derived from the inhibition data. These results are summarized in Table C.1.

TABLE C.1 Inhibition of smooth muscle cell proliferation yes? Jc-, *. • - -i. "-, ~»

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a compound of formula (I): a stereoisomeric form thereof, or a pharmaceutically acceptable acid or base addition salt thereof, wherein the dotted line 15 represents an optional link; X is oxygen or sulfur; R1 is hydrogen, C?-Α2 alkyl, Ar1, Ai ^C? -6 alkyl, quinolinylC de? 66 alkyl, C?-6 pyridylalkyl, C -? 66 hydroxyalkyl, C alquilo alquilo alkyloxy ? -6- C? -6 alkyl, mono- or diamino (C? -6 alkyl) -C? -6 alkyl, C-? -6 aminoalkyl) or a radical of formula -Alk1-C (= O) -R9, -Alk1-S (O) -R9 or -Alk1-S (O) 2 -R9, wherein Alk1 is C1-6 alkanediyl, R9 is hydroxy, C? -6 alkyl, C1-6 alkyloxy, amino, C? -8 alkylamino or C1-8 alkylamino substituted with C1-6 alkyloxycarbonyl; R2, R3 and R16 are each independently hydrogen, hydroxy, halogen, cyano, C-? 6 alkyl, C? -6 alkyloxy, C? -6 hydroxyalkyloxy, C? -6-alkyloxy of C? -6, ¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡! a-C 1-6 aminalkyloxy, mono- or diamino (C 1 -C 6 alkyl) C 1-6 alkyloxy, Ar 1, C 1 -C 6 alkyl, A 1 oxy, C 1 alkyloxy 6 > hydroxycarbonyl, C? -6 alkyloxycarbonyl, trihalogenomethyl, trihalogenomethoxy, C2-6 alkenyl, 4,4-dimethoxyloxazolyl; or when in adjacent positions R2 and R3 taken together can 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-CH-CH - (a-5) or -CH = CH-CH = CH- (a-6); R4 and R5 are each independently hydrogen, halogen, Ar1, C-? 6 alkyl, C1-6 hydroxyalkyl, d-β-alkyl-C? -6alkyloxy, C? -6alkyloxy, C12-alkylthio ? -6, amino, hydroxycarbonyl, C? -6 alkyloxycarbonyl, C? -6S (O) C? -6 alkyl or C? -6S (O) 2 alkyl of C-? -6; R6 and R7 are each independently hydrogen, halogen, cyano, C6-6 alkyl, C-? 6 alkyloxy, Ai ^ oxy, trihalogenomethyl, C? -6 alkylthio, diamino (C1-6 alkyl), or when in adjacent positions R6 and R7 taken together can form a bivalent radical of formula -O-CH2-O- (c-1) or -CH = CH-CH = CH- (c-2); R8 is hydrogen, C6-6alkyl, cyano, hydroxycarbonyl, C-? 6alkyloxycarbonyl, d-6-alkylcarbonyl of C-? 6, cyanoalkyl of Ci-β, alkyloxycarbonyl of C? -6- Ci-β alkyl, C?-6 carboxyalkyl, C-6 hydroxyalkyl, C?-6 aminoalkyl, mono- or diamino (C?-6 alkyl) -C de alkyl -6,7 imidazolyl, Ci-β haloalkyl, C?-6-alkyloxy-C alquilo-6-alkyl, aminocarbonylalkyl of C?-6, or a radical of formula O-R10 (b-1), S-R10 (b-2), N-R11R12 (b-3), wherein R10 is hydrogen, C-? -6-alkyl, C? -6-alkylcarbonyl, ArI, C6-C6-6 alkyloxycarbonyl, C? -6-C? -6 alkyl, or a formula -Alk2-OR13 or -Alk2-NR14R15; R11 is hydrogen, C-M2 alkyl, Ar1 or Ar2 C6-6 alkyl; R12 is hydrogen, C6-6 alkyl, C-M6 alkylcarbonyl, C-? 6 -alkyloxycarbonyl, Ci-βalkylaminocarbonyl, Ar1, Ar2C1-6alkyl, Ci-β-alkylcarbonyl-C-alkyl? -6, a natural amino acid, Ar1 carbonyl, Ar2 alkylcarbonyl of C6-6, aminocarbonylcarbonyl, C6-6 alkyloxy-C6-alkylcarbonyl, hydroxy, C6-6alkyloxy, aminocarbonyl, diamino C? -6) -alkylcarbon? C? -6, amino, Ci-β alkylamino, C?? 6 alkylcarbonylamino, or a radical of formula -Alk2-OR13 or -Alk2-NRuRi5. in jjQ? jg ik = is a | canoc | ¡¡0 < je c., _ 6; R13 is hydrogen, C-i alkyl. 6, C? _6 alkylcarbonyl, hydroxyalkyl of Ar1 or Ar2 alkyl of C-i-β; R 14 is hydrogen, C 6 alkyl, Ar 1 or Ar 2 C 6 alkyl; R15 is hydrogen, C-? -6 alkyl, C? -6 alkylcarbonyl, Ar1 or Ar2 C-i-β alkyl; R17 is hydrogen, halogen, cyano, C6-6 alkyl, C1-6 alkyloxycarbonyl, Ar1; R18 is hydrogen, C-t-β alkyl, C-α-6 alkyloxy or halogen; R19 is hydrogen or C? -6 alkyl; Ar1 is phenyl or phenyl substituted with C? _6 alkyl, hydroxy, amino, C? -6 alkyloxy or halogen; and Ar2 is phenyl or phenyl substituted with C6-6alkyl, hydroxy, amino, Ci-βalkyloxy or halogen; for the manufacture of a medicament for preventing or vascular proliferation in a warm-blooded animal.

2. The use according to claim 1 of a compound wherein X is oxygen, the dotted line represents a bond and R1 is hydrogen, C-? 6 alkyl, C? -6 alkyloxy-C-alkyl? -6, or mono- or diamino (C6-alkyl) -C1-6 alkyl.

3. The use according to any of claims 1 to 2 of a compound, wherein R3 is hydrogen and R2 is halogen, C-? 6 alkyl, C2-6 alkenyl, C-? 6 alkyloxy , trihalogenomethoxy or hydroxyalkyloxy of C -? - 6.

4. The use according to any of claims 1 to 3 of a compound, wherein R8 is hydrogen, hydroxy, haloalkyl of C -? - 6, hydroxyalkyl of C1-6, cyanoalkyl of C1-6, alkyloxycarbonyl of C ? -6-C-? -6-alkyl, imidazolyl, or a radical of formula -NR11R12, wherein R11 is hydrogen or C? -? 2 alkyl, and R12 is hydrogen, d-6 alkyl, alkyloxy C -? - 6, C-? -6-alkylcarbonyl-6-alkyloxy, hydroxy, or a radical of formula -AIK2-OR13, wherein R13 is hydrogen or Ci-β alkyl.

5. The use according to claim 1, wherein the compound is (+) - 6- [amino (4-chlorophenyl) (1-methyl-1 / -imidazol-5-yl) methyl] -4- (3-chlorophenyl) -1-methyl-2 (1 / - /) -quinolinone, or a pharmaceutically acceptable acid addition salt thereof. jA-fca-attBM ^^ .-- ^

6. - The use according to any of claims 1 to 5, wherein the vascular proliferative disorder is atherosclerosis.

7. The use according to any of claims 1 to 5, wherein the vascular proliferative disorder is restenosis.

8. Use according to any of the claims 1 to 5, wherein the vascular proliferative disorder is restenosis by percutaneous transluminal coronary angioplasty or coronary artery restenosis by stenting.

9. The use of a compound of formula (I) as defined in any of claims 1 to 5, for the manufacture of a medicament for inhibiting the proliferation of smooth muscle cells in a warm-blooded animal.

10. A stent covered with a coating material which comprises an amount of a compound as defined in any of claims 1 to 5, effective in preventing, treating or reducing the proliferation of smooth muscle cells. The present invention undertakes the use of compounds of formula I: where the dotted line represents an optional link; X is oxygen or sulfur; R is hydrogen, alkyl of C-?. 2, Ar 1, Ar ^ alkyl of d-β. quinolinyl-C1-6 alkyl, C6-6 pyridylalkyl, C1-6 hydroxyalkyl, C-? 6 -alkyl-C6-6alkyl, mono- or diamino (C6-alkyl) -alkyl C -? - 6, aminoalkyl of C? -6, or a radical of formula -Alk1-C (= O) -R9, -Alk1-S (O) -R9 or -Alk1-S (O) 2 -R9; R2, R3 and R16 are each independently hydrogen, hydroxy, halogen, cyano, d-6 alkyl. alkyloxy, de, hydroxyalkyloxy of C -? - 6, alkyloxy of d-6-alkyloxy of d-6, aminalkyloxy of C? _6, mono- or diamino (C? .6 alkyl) -alkyloxy of C- ? -6, Ar1, Ai ^ C? -6 alkyl, Ar? Oxy, Ar? C6-6 alkyloxy, hydroxycarbonyl, C-? -6-alkyloxycarbonyl. trihalogenomethyl, trihalogenomethoxy, C2-6 alkenyl; R 4 and R 5 are each independently hydrogen, halogen, Ar 1, d-6 alkyl, C 1-6 hydroxyalkyl. alkyloxy of d-6-C1-6alkyl, dyalkyloxy of d-6, alkylthio of Ci-β, amino, hydroxycarbonyl, alkyloxycarbonyl of d-6, alkyl of d-6S (O) alkyl of C-? -6 or alkyl of C? -6S (O) llB- of d-6; R6 and R7 are each independently hydrogen, halogen, cyano, d-6, 4,4-dimethyl-oxazolyl alkyl, Ci-β alkyloxy or AI? DXI; R8 is hydrogen, d-β alkyl. cyano, hydroxycarbonyl, d-β-alkyloxycarbonyl, C6-6-alkyl-C1-6alkyl, d-6-cyanoalkyl) alkyloxycarbonyl of d-6-C6-6alkyl, C1-6carboxyalkyl, hydroxyalkyl d-6, aminoalkyl of C-? -6, mono- or diamino (C? -6 alkyl) -C1-6 alkyl, imidazolyl, d-6 haloalkyl, d-6-C6 alkyl-alkyloxy? 6, aminocarbonylalkyl of d-6, or a radical of formula -O-R10, -S-R10, -N-R11O12; R17 is hydrogen, halogen, cyano, C6-alkyl, alkyloxycarbonyl of d-6, Ar1; R18 is hydrogen, C-? -6 alkyl, C1-6 alkyloxy or halogen; R19 is hydrogen or C-? -6 alkyl; for the manufacture of a medicament for inhibiting the proliferation of smooth muscle cells. MG / sll * ald * jtc * mmr * mvh * xal * sff. P99 / 1457F.