MXPA97010034A - Bencimida compounds - Google Patents

Abstract

This invention provides a compound of the following formula (I), and the pharmaceutically acceptable salts thereof, wherein Ar is phenyl, C3-8 cycloalkyl, C48 cycloalkenyl, or heteroaryl, X2 and X3 are independently C1-4 alkyl, halo C1-4alkyl is unsubstituted, hydroxy, C1-4alkoxy, mercapto, (C1-4alkyl) thio, (C1-4alkyl) sulfinyl, (C1-4alkyl) sulfonyl or similar groups, X1 is H, halo, alkyl C1-4, hydroxy, cyano, nitro, (C 1-4 alkyl) thio, (C 1-4 alkyl) sulfinyl, (C 1-4 alkyl) sulfonyl or similar groups, and is -CR 1 = CR 2 - or -C = C- wherein R1 and R2 are independently H, methyl, ethyl or halo; 1 is 0, 1, 2, 3, 4, and m and n are independently 0, 1, 2 or 3, with the proviso that when Ar is phenyl, and 1, m and n are zero, then Y is not -CH = CH-, and when Ar is phenyl, 1 and m are zero, n is 1, and Y is -CH = CH-, then X3 is not C1-4 alkoxy attached to position 2 of Ar or amino, (C 1-4 alkyl) amino or (C 1-4 dialkyl) amino attached to the 4-position of Ar, and a composition f useful for the treatment of a medical disorder in which prostaglandins are implicated as pathogens

Description

BENCIMIDAZOL TECHNICAL FIELD COMPOUNDS This invention relates to new inhibitors of bencirnidazole cyclooxygenase. The compounds of this invention inhibit prostaglandin biosynthesis by intervening the action of the cyclooxygenase enzyme on arachidonic acid and, therefore, are useful in the treatment or alleviation of inflammation in mammals. This invention also relates to pharmaceutical compositions comprising said compounds.

BACKGROUND Anti-inflammatory + non-steroidal opposition drugs (NSflID) are widely used in the treatment of pain and the signs and symptoms of arthritis due to their analgesic and anti-inflammatory activity. It is recognized that common NSflIDs act by blocking the activity of cyclooxygenase (COX), also known as prostaglandin G / H synthase (PGHS), the enzyme that converts arachidonic acid into prostanoids. Prostaglandms, especially prostaglandin E2 (PGE2), which is the predominant eicosanoid detected in inflammatory conditions, are mediators of pain, fever and other symptoms associated with inflammation. Inhibition of prostaglandin synthesis has been a therapeutic goal in the discovery of anti-inflammatory drugs. However, the use of conventional NSflID is limited due to adverse side effects, especially gastrointestinal and renal toxicity. Recently, we have identified doe forms of COX, a constitutive isoform (COX-1) and an inducible isoform (COX-2) whose expression is upregulated at sites of inflammation (Vane 3.R., Mitchell 3.R., Appleton I., Tomlinson fl, Bishop-Bailey D. Croxtoll 3. and lilloughby d.fl., Proc. Natil, Acad. Sci. USfi, 1994, 91, 2.046). It is believed that COX-1 plays a physiological role and is responsible for gastrointestinal and renal protection. On the other hand, it seems that COX-2 plays a pathological role and is the predominant isoform present in inflammatory conditions. Prostaglandins have been linked to a pathological role in a number of human diseases, including rheumatic diseases and osteoarthritis, pyrexia, asthma, bone resorption, cardiovascular diseases, nephrotoxicity, atherosclerosis, hypotension, shock, pain, cancer and fllzheirner's disease. The NSAIDs currently present in the market inhibit the two isoforms of COX with little variation in selectivity, which explains their beneficial effects (inhibition of COX-2) and detrimental effects (inhibition of COX-1). It is possible that a selective COX-2 inhibitor can eliminate the COX-2 and harmful side effects (inhibition of COX-1). It is possible that a selective inhibitor of COX-2 can eliminate the side effects associated with the inhibition of COX-1, while providing anti-inflammatory effects. A variety of benzimidazole compounds are known and described in various patent specifications. Specifically, Japanese Patent Publication Kokai (open to public information) number S49-81369 discloses 1-benzylbenzene diazo compound as antiflamatory agents. Publications of the Japanese Kokai patents (open to public information) numbers S59-75257 and H06-194780 describe a variety of benzimidazole compounds as electrophotographic materials.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a compound of the following formula: and the pharmaceutically acceptable salts thereof, wherein Ar is femlo, C3-β cycloalkyl, cycloalkenyl d-β or heteroaryl q is connected to Y by a carbon atom, the hetero-chain being selected from pyridyl, pyridazinyl, pyrinidinyl, pyrazinyl, pyrrolyl, fryl, thienyl, oxazolyl, thiazolyl, isozazolyl, isothiazolyl, lidozolyl, pyrazolyl, oxadiazolyl, tpazolyl and tetrazolyl; i is H, halo, C 1-4 alkyl, hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkyl (preferably C 1-4 alkyl substituted with 1 to 5 halogen atoms), C 1-4 hydroxy-substituted alkyl, (C 1-4 -alkoxy), (C 2-4 -alkyl), -no, (C 1-4 dialkylamino, ammo (C 1-4 alkyl), (C 1-4 alkyl) amine (C1-4alkyl), (C1-4alkyl) ammo (C1-4alkyl), (C1-laminoalkanoyl, (dialkanoyl C1-lamino, (C1-4alkyl), (C1-4alkanoyl) am? no, (C1- alkyl) sulfonamino, Ci-4 alkanoyl, carboxyl, (C1-4 alkoxycarbonyl, aminocarbomlo, (C1-4alkylaminocarbonyl, (C1-4 dialkylcarbonyl, cyano, nitro, rnercapto, ( C 1 -4) alkyl, (C 1-4 alkyl) -sulfamyl, (C 1-4 alkyl), sulfonyl, to mosulfonyl, (C 1-4 alkyl) aminosulfonyl or (C 1-4 alkyl) arn? nosulfon? lo; X 2 and β 3 are independently C 1-4 alkyl, halo, halo-substituted C 1-4 alkyl, hydroxy, C 1-4 alkoxy, mercapto, (C 1-4 alkyl) t, or (C 1-4 alkyl) sulfur, (C 1-4 alkyl) ) sulfonyl, C1-4alkonyl, carboxyl, (C1-4alkoxy) carbonyl, ammocarbonyl, (alkylCal) ammoncarbonyl, (C4-4alkyl) -ammocarbonyl, cyano, nitro, ammonium (C1-4alkylamino, (C1-4alkyl) arnyl or (C1-4alkyl) sulphomlamino; Y is -CE1 = CR2- or -CsC-, wherein R1 and R2 are independently H, methyl, ethyl or halo; O, 1, 2, 3 or 4 (preferably 0, 1 or 2) and rn and n are independently 0, 1 2 or 3 (preferably 0, 1 or 2), with the proviso that when Ar is phenyl and 1, rn and n are 0, then Y is not -CH = CH-, then X3 is not C 4 alkoxy linked to position 2 of Ar, nor amino, (C 1-4 alkyl) am? no od? (alkyl? C -? - 4) ammo attached to position 4 of Ar. The benzimidazole compounds of the present invention exhibit inhibition of COX activity. Preferably, the compounds of this invention exhibit inhibitory activity against COX-2, the compounds more preferably having selectivity for COX-2. Accordingly, the present invention also provides a pharmaceutical composition, useful for the treatment of a medical disorder in which the pathogenic prostaglandins are involved, comprising a compound of formula (I), wherein Ar, Y, i, X2 ,? 3 tt rn and n are as defined above, and pharmaceutically salts thereof. Also, the present invention provides a method for the treatment of a medical disorder in which prostaglandins are implicated as pathogens in a mammalian patient, comprising administering to said patient a therapeutically effective amount of said composition.

Medical conditions in which prostaglandins are implicated as pathogens include pain relief, fever and inflammation of a variety of disorders, including rheumatic fever, symptoms associated with influenza and other viral infections, common cold, cervical and lumbar pain , dysrnenorrhea, headache, toothache, sprains and strains, iositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint disease (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, and secondary injuries due to surgical and dental interventions. The compounds and the pharmaceutical composition of this invention can inhibit cellular neoplastic transformations and the metastatic development of tumors and, therefore, can be used in the treatment of cancer. The compounds and the pharmaceutical composition of this invention are used in the treatment and / or prevention of proliferative disorders mediated by cyclooxygenase, such as those that occur in diabetic retinopathy and in tumor angiogenesis. The compounds and the pharmaceutical composition of this invention can be used in the treatment of dysmenorrhea, premature delivery, asthma and disorders related to eosinophils, in the treatment of Alzheiner's disease and in the treatment of bone loss (treatment of Osterthritis) for its ability to inhibit smooth muscle contraction induced by prostanoids avoiding the synthesis of contractile prostanoids. In addition, said compounds and pharmaceutical compositions that show more specificity for COX-2 than for COX-1, will be useful as an alternative to conventional NSAIDs, particularly when said NSAIDs may be contraindicated, as in patients with peptic ulcer, gastritis, regional enterotis. , ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions, gastrointestinal hemorrhage, coagulation disorders, including anemia, such as hypothrombinaemia, hemophilia or other hemorrhagic problems; kidney disease; before anticoagulant surgery.

DETAILED DESCRIPTION OF THE INVENTION As used herein, "halo" is fluoro, chloro, bromo or iodo. Preferred compounds of this invention are those of formula (I) wherein Ar is phenyl, C3-8 cycloalkyl, C4-8 cycloalkyl, or heteroaryl, selected from pyridyl, pyrrolyl and oxazolyl; X2 and X3 are independently C1- alkyl, halo, halo-substituted C1-4 alkyl, hydroxy, C1- alkoxy, (C1-4 alkyl), (C1-4 alkyl) sulphonyl or (C1-alkyl) sul fonilo;? i is H, halo, C 1-4 alkyl, hydroxy, C 1-7 alkoxy, halo-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, amino, (C? -4 alkyl) amine, cyano or nitro 1 is 0 or 1, and rn and n are independently 0 or 1. The most preferred compounds of this invention are those of formula (I) in which flr is phenol or C3-8 cycloalkyl, X2 and X3 are independently halo, (C1-4 alkyl Rio, (alkyl) C1-) sulfinyl or (C 1-4 alkyl) sulfonyl; X is H, halo, amino, cyano or nitro, which is attached to the 5 or 6 position of the benzyl idazo ring system; and Y is -CE1 = CR2-, wherein R1 and R2 are independently H or methyl. The still more preferred compounds of this invention are those of formula (I) wherein flr is phenyl, cyclopentyl or cyclohexyl; X2 and X3 are independently fluoro, methylthio, methyleufinyl or ethylsul onyl; X * is H, fluoro, chloro, bromo, amino, cyano or nitro, which is attached to the 5-position of the benzylidazole ring system; and Y is -CH = CH-. The preferred individual compounds of this invention are: (E) -2- (4-fluorostyryl) -1-femyl-lH-benzamidazole, hydrochloride of (E) -2- (2-fluorosterol? -feml- lH-benz? rn? dazol, (E) -5-n? tro-l-phen? l-2-estinl-lH-benz? rn? dazol, dihydrochloride (E) -5-arn? No-l-feml-2-est? R? L-lH-benzrnidazole, (E) -5-brorno-l-phenyl-2-est? Pl-lH- benz? rn? dazol, (E) -5-c? ano-l-phen? l-2-est? r? l-lH-benz? rn dazol, (E) -2- (2? c clohex? lv ml) -l-phen? l-lH-benz? dazole, hydrochloride of (E) -2- (2-c? clopent-? lv n? l) -1-phen? l-lH-benz? rn ? dazol and (E) -l-phen? l-2-C2- (2? ?? pd? l) vn? l] -lH-benz? rn? dazol.

Particularly preferred individual compounds are: (E) -5-nitro-l-phenyl-2-styryl-lH-benzylnidazole, (E) -5-cyano-l-phenyl-2-styryl-lH-benzimidazole and hydrochloride of (E) -2- (2-cyclopentylvinyl) -1-phenyl-1H-benzimidazole. Preferred pharmaceutical compositions of this invention comprise compounds of formula (I) wherein Ar is phenyl, C3-8 cycloalkyl, C4-8 cycloalkenyl, or heteroaryl selected from pyridyl, pyrrolyl or xazolyl; X 2 and 3 3 are independently C 1-4 alkyl, halo, halo-substituted C 1-4 alkyl, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 1-4 alkyl, sulfinyl or (C 1-4 alkyl) sulfonyl; is H, halo, Cl-4 alkyl, hydroxy, Cl-4 alkoxy, halo-substituted C 1-4 alkyl, C 1-4 alkyl hydroxy-substituted, (C 1-4 alkyl) amino, cyano or nitro; 1 is 0 or 1; are independently 0 or 1. The most preferred pharmaceutical compositions of this invention comprise compounds of formula (I) wherein Ar is phenyl or C3-β cycloalkyl; X2 and X3 are independently halo, (C1-4 alkyl Rio, (Ci alkyl) -4) sulfinyl or (C1- alkylsulfonyl); X * is H, halo, amino, cyano or nitro, which is attached to the 5 or 6 position of the benzylnidazole ring system, and Y is -CRi = CR2- / wherein R and R2 are independently H or methyl The still more preferred pharmaceutical compositions of this invention comprise compounds of formula (I) wherein flr is phenyl, cyclopentyl or cyclohexyl; X2 and X3 are independent fluoro, methylthio, rnetylsulinyl or rnetileulfinyl; X * is H, fluoro, bromo, amino, cyano or nitro, which is attached to the 5-position of the benzylidazole ring system; and Y is ~ CH = CH ~. The preferred individual compounds to be contained in the pharmaceutical compositions of this invention are: (E) ll-phen-l-2-est? Nl-lH-benz? Rn? Dazole, (E) -2- (4-fluoroest? pl) -l-feml-lH-benz? m? dazole, hydrochloride (E) -2- (2-fluoroest? R? L) -l-feml-lH-benz? Rn? Dazol, (E) -5- n? Tro-l-feml-2-est? R? L- lH-benz? rn? dazol, di (E) -5-am? no-l-phen? l-2-est? pl-lH-benz? dazole dihydrochloride, (E) -5-bromo-l- feml-2-est? r? l-lH-benz? dazol, (E) -5-c? ano-l-phen? l-2-est? r? l-lH-benz? rn? dazol, (E) -2- (2-c? Clohex? Lv? N? L) -l-phen? L-lH-benz? M? Dazole, hydrochloride of (E) -2- (2-c? Clopent? Lv (n) l) -l-feml-lH-benzrn? dazol The preferred individual compounds to be contained in the pharmaceutical compositions of this invention are: (E) ll-phen-l-2-est? nl-lH -benz? rn? dazol, (E) -2- (4-fluoroest? pl) -l-phen? l-lH-benz? rn? dazol, hydrochloride of (E) -2- (2-fluorostyril) -1 - feni 1-lH-benz? rn? dazol, (E) -5- n? tro-l-phen? l-2-est? nl-lH-benc? m? dazol, di hydrochloride of (E) -5 -am? no-l-phen? l-2-es +? pl-lH-benc rn? dazol, (E) -5-brorno-l-fen? l-2-est? pl-lH-benc? rn? dazol, (E) -5-c? ano-l-feml-2-est? r? l-lH-benz? rn? dazol, (E) -2- (2-c? clohex? lv? n? ) -l-phen? l-lH-benz? rn? dazol, hydrochloride of (E) -2- (2-c? clopen +? lv? n? l) -l-phen? l-lH-benc? rn? dazol and (E) -l-phen? l- 2-C2- (2p? Pd? L) v? N? L] -lH-benz? Rn? Dazol. Particularly preferred individual compounds to be contained in the pharmaceutical compositions of this invention are: (Es) -l-phen? L-2-est? R? L-lH-benz? Rn? Dazol, (E) -5-n? Tro-l-phen? L-2-est? R? L-lH-benz? Rn? Dazol, (E) -5-c? Ano-l-phen? L-2 -βε-lH-benzrinodazole and (E) -2- (2-c? clopent? lv? n? l) -l-fem-lH-benz? rn? ldazole hydrochloride. The compounds of formula (I) of this invention can be administered to mammals orally, parenterally or topically. In general, of the most desirable form these compounds are administered to humans in doses ranging from 0.01 g to 100 mg per kg of body weight per day, although variations may necessarily occur depending on the weight, sex and disorder of the patient to be treated, of the disease to be treated and the specific route of administration chosen. However, for the treatment of the aforementioned diseases, a dose level which is in the range of 0.1 mg to 10 mg per kg of body weight per day, in a single dose or in divided doses, is most desirably employed. The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or diluents, by any of the routes indicated above, and said administration can be carried out in a single dose, or in divided doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, that is, they can be combined with various inert, pharmaceutically acceptable carriers, to form tablets, capsules, lozenges, tablets to dissolve in mouth, hard candy, powders, sprays, creams, ointments, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and similar compositions. Such vehicles include solid diluents or fillers, aqueous or sterile media, various non-toxic organic solvents, etc. In addition, oral pharmaceutical compositions can be conveniently flavored and / or flavored. In general, the therapeutically effective compounds of this invention are present in said dosage forms at concentration levels ranging from 5% to 70% by weight, preferably from 10% to 50% by weight. for oral administration, tablets may be used which contain various excipients, such as icrocris + aline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine, together with various disintegrants, such as starch (preferably corn starch, potato or tapioca). ), alginic acid and certain complex silicates, together with ligand + is granulation, such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, for the formation of the tablets, lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc, are often very useful. In gelatin capsules, solid compositions of a similar type can also be used as charge.; Preferred materials in this regard also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, with emulsifying and / or suspending agents, together with diluents such as water. , ethanol, propylene glycol, glycerol and various similar combinations thereof. For parenteral administration, solutions of a compound of the present invention in sesame or peanut oil or in aqueous propylene glycol can be employed. If necessary, the aqueous solutions should be conveniently pumped (usually at? H > 8) and first the liquid diluent should be made isotonic. These aqueous solutions are suitable for intravenous injections. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injections. The preparation of these solutions under sterile conditions is easily accomplished by standard pharmaceutical techniques - well known to those skilled in the art. In addition, it is also possible to administer the compounds of the present invention topically to treat inflammatory disorders of the skin and this can be done preferably by means of creams, jellies, gels, pastes, ointments and similar compositions, in accordance with pharmaceutical practice. conventional.

GENERAL SYNTHESIS A compound of formula (I) can be prepared by any synthetic process applicable to compounds of related structure, well known to those skilled in the art. The following representative examples, described in schemes I-VII, are illustrative of the invention, in which flr, X1, X2,? 3 and Y are as defined above, unless otherwise indicated. For the synthesis of compounds of structure related to that of the compounds of the present invention, see "Benzirnidazoles and Congenepc-Tricyclic Compounds" in Heterocyclic Cornpounds, vol. 40, preson, P. N. Ed., Dohn Uliley & Sons, NY, 1981.

SCHEME I For example, the compound of formula (I) can be prepared according to the reaction depicted in Scheme I. In the present example, a phenylenendiary of formula I is reacted with a compound of formula 2, wherein the group 0 is a moiety of carboxylic acid, carboxylic acid ester, carboxarnide, carboxylic acid anhydride, carboxylic acid chloride, orthoester, rninoester, carbalde or similar. The reaction can be carried out in the presence or in the absence of a solvent inert to the reaction. Preferred reaction inert solvents include benzene, toluene, xylene, pyridine 1,2-d-chloroethane, o-dichlorobenzene, itrobenzene or dichloro-methane. Preferably, it is carried out in the presence of a promoter, such as hydrochloric acid, polyphosphobic acid, phosphorus pentoxide, phosphorous oxychloride, ethyl ether of a polyphosphoric acid, tprnet-silsilic ether of a poly-osoric acid, p-toluenesulfonic acid, z? nc (II) or similar. When the compound of formula 2 is a carboxaldehyde, the reaction can be carried out in the presence of an oxidant, such as cupric acetate, chloranil or the like. The temperatures of the reaction are preferably in the range of -40 ° C to 250 ° C, usually in the range of 20 ° C to 200 ° C, although, if necessary, lower or higher temperatures may be employed. The reaction time may vary, in general, from 5 minutes to 6 days, preferably from 20 minutes to 1 day. Alternatively, the reaction can be carried out in a sealed tube or in an autoclave, at a pressure of medium (1-10 kg / cm2) to high (20-200 kg / cm2) to accelerate it, preferably in the range from 2 to 150 kg / crn2.

SCHEME II Alternatively, the compounds of formula (I) can be prepared by a two-step process from femlendiarnines of formula 1 through the (N-acylamino) phenylalanms of formula 4, as indicated in Scheme II . in the first step, a phenylenediamine of formula 1 is reacted with a compound of formula 3, wherein Z is selected from halo, OH, -OR (R is C1-4 alkyl), -NH2 and -0C (0) Y-Ar- (X3) n, by conventional procedures well known to those skilled in the art, to form amides of formula 4. For example, when the compound of formula 3 is a carboxylic acid (ie, Z is OH) , the reaction is preferably carried out in the presence of a coupling reagent, such as l- (d? met? lam? no? ro? l) -3-et? lcarbod? m? da (USE, N, N'- dicyclohexylcarbodiirnidazole (DCC), carbomldiirnidazoi, diethyl ester of cyanophosphonic acid or the like Preferred reaction inert solvents include acetone, acetonitrile, dichloromethane, N, Nd? met? lformamide, N, N-dimethylacetarnide, dimethylsulfoxide (DMSO) , d-oxano, tetrahydrofuran (THF () and pyridine.) In the next step, the compounds of formula (I) are provided by cyclization of the compounds of formula 4. The reaction ion can be carried out in the presence or in the presence of a solvent inert to the reaction. Preferred reaction inert solvents include benzene, toluene, xylene, pyridine, 1-2-d-chloro-methane, o-dichlorobenzene, nitrobenzene, dichloromethane and ethanol. Preferably, the reaction is carried out in the presence of a promoter, such as hydrochloric acid, polyphosphoric acid, phosphorus pentoxide, phosphorous oxychloride, ethyl ether of a polyphosphoric acid, trimethylsilyl ether of a polyphosphoric acid, thionyl chloride, p-acid. Tol? ensulfonic or similar promoters. Alternatively, the cyclization reaction can be carried out under the conditions of a riitsunobu reaction, for example, in the presence of tpferul fos ina and diethyl azodicarboxylate. The reaction temperatures are preferably in the range of -40 ° C to 250 ° C, usually in the range of 20 ° C to 200 ° C, although, if necessary, lower or higher temperatures can be used. The reaction time may vary, in general, from 5 minutes to 6 days, preferably from 20 minutes to 1 days.

SCHEME III In another embodiment, the compounds of formula (I) wherein Y is C (H) = C (H) can be prepared as indicated in Scheme III. Thus, 2-rnet-l-benzylnidazoles of formula 5 are reacted with aldehydes of formula 6 in the presence or absence of a base. When said reaction is carried out in the absence of a base, the reaction is preferably carried out in a sealed tube or in an autoclave, at a pressure of medium (1-10 kg / cm2) at high (20-200 kg / cm2) , preferably in the range of 2 to 150 kg / n2. The reaction can be carried out in the presence or in the absence of a solvent inert to the reaction. Preferred reaction inert solvents include benzene, toluene, xylene, chlorobenzene, nitrobenzene, acetic acid, acetic anhydride and the like. The temperatures of the reaction are generally in the range of -100 ° C to 250 ° C, preferably in the range of 20 ° C to 200 ° C, although, if necessary, lower or higher temperatures may be employed. The reaction time may vary, in general, from 5 minutes to a day, preferably from 20 minutes to 5 hours, although, if necessary, lower or higher reaction times may be used. When said reaction is carried out in the presence of a base, the temperatures of the reaction are generally in the range of -100 ° C to 250 ° C, preferably in the range -B0 ° C to 20 ° C, although, if necessary, lower or higher temperatures can be used. Preferred reaction inert solvents include tetrahydrofuran, benzene, toluene and xylenes. the reaction time may vary, in general, from 5 minutes to a day, preferably from 20 minutes to 5 hours; however, if necessary, longer or longer reaction times may be used. Preferred lae baees include, for example, a hydroxide, alkoxide, carbonate or hydride of an alkali or alkaline earth metal, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride; an amine, such as triethylamine, diisopropylamine, diisopropylethiiarnine, piperidine or dimethylaminopyridine; and an alkyl lithium, such as n-butyl lithium, sec-butyl lithium, tert-butylthio, lithium rnethyl lithium or diisopropylamide.

SCHEME IV In another embodiment, the compounds of formula (I) wherein Y is C (H) = C (H) can be prepared by partial hydrogenation of a compound of formula (I) wherein Y is -Cs- as represented in scheme IV. Preferred catalysts include, for example, nickel-based catalysts, such as nickel P-2 and nickel boron (Choi 3. and Yoon NM, Tetrahedron Lett., 1996, 37, 1057), and palladium-based catalysts. , as catalyst Lindlar and Pd / U. Preferred reaction inert solvents include, for example, water, ethanol, ethanol, acetone, acetonitrile, ethyl acetate, dichloromethane, dioxane, tetrahydrofuran, diethyl ether and diieopropyl ether. The temperatures of the reaction are preferably in the range of -40 ° C to 200 ° C, usually in the range of 20 ° C to the reflux temperature of the solvent, although, if necessary, lower or higher temperatures may be employed. . The reaction time is, in general, from 5 minutes to 6 days, preferably from 100 minutes to 5 days.

SCHEME V The compounds of formula (I) can also be prepared by reacting a compound of formula? with a compound of formula 9, according to the procedure represented in Scheme V. In Scheme V, the compound of formula 8 can be synthesized by any of the methods described in the above-mentioned Schemes I to IV. The group L of the compound of formula 9 is selected from suitable displaceable groups., for example, halo, (such as fluoro, chloro, bromo or iodo) and eulfonyloxy (co or trifluoromentanesul onyloxy, r-methanesulfonyloxy or p-tol-ene-s-lfonyloxy), all easily accessible by conventional procedures known to those skilled in the art. matter. Preferably, the present reaction is carried out in the presence of a suitable base, for example a hydroxide, alkoxide, carbonate or hydride of an alkali metal or alkaline metal, such as sodium hydroxide, hyroxy or potassium oxide, sodium, sodium oxides, potassium, potassium, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or the presence of a organic substance, an amine such as pelarin, dusopropylethylamine, dusopropylamine or dirnetiiaininopí r-? d? na Preferred reaction inert solvents include acetone, acetone, dichloroethane, N, N-dirnethylforrnarnide, N, N-imet i lacet amide, dimethyl sulfoxide, dioxane, tetrahydrofuran and pin dina. The reaction temperatures are [preferably in the range of -40 ° C to 200 ° C, usually in the range of 20 ° C to the reflux temperature of the solvent, although, if necessary, lower temperatures can be employed. or higher. In general, the reaction time is 5 minutes to b days, preferably from 0 minutes to 5 days. Conveniently, the reaction can be carried out in the presence of a suitable catalyst, for example, tet rak? S (tpfeni l fosfina) palad? O (O), b? S chloride (tp fen? Lfo f? Na) palad? or (ll), copper (O), cuprous chloride, cuprous oxide, iodide c? proso, cuprous bromide or cup bear chloride.

SCHEME VI SCHEME VII Alternatively, the compounds of formula (T) wherein Y is C (H) -0 (H) can be prepared by reacting a suitable aldehyde with a suitable phosphorus (Maryanoff BE and Reitz fl.B., Chern Rev., 1989, 89, 063) or with a dialkyl phosphonate salt (Seguí nea? And Villieras, Tetr-ahedron Lett., 1980, 29, 477), as indicated in schemes VI and VII, on which P is a suitable dialkyl phosphonate or phosphonate salt. For suitable bibliographic references, see DE1939BÜ9A. The starting material of formulas i, 2, 1, 4, b, b, 9, 11, 11, 12 and L3 can be obtained by conventional procedures known to those skilled in the art. The preparation of such starting materials is described in the non-limiting examples herein that are provided only with Illustrative Tines. Alternatively, the required starting materials can be obtained by analogous procedures, or by modifications of the same as described herein. more ahead. The products appearing in the above-mentioned general synthetic procedures and illustrated in the experimental examples of this specification can be isolated by conventional methods and their purification can be achieved by conventional means known to those skilled in the art, such as distillation techniques. , recp sta 1 í aci on y c r-ornag rag y "I oo revention compounds that contain one or more double bonds and / or asymmetric centers can exist in vain stereoisomeric forms. All of these individual forms, and mixtures thereof, are included within the scope of the invention. The various isomers can be obtained by conventional methods. For example, cis / trans mixtures can be separated into the individual stereoisomers by stereoselective synthesis or by separation of the mixtures by fractional crystallization or chromatography techniques. One of the compounds of the present invention can form addition salts with inorganic and organic acids. Pharmaceutically acceptable salts by addition of acids are those which form non-toxic salts by the addition of acids (but not limited thereto) such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or acetate, fumarate, tartrate, succinate, rnaleate, gluconate salts , saccharate, benzoate, rnetanosul fonate, benzenesul fonate, p-toluens? l fonate and pato cesto is 1, l-rnet? len-b? s (2-hydrox? -3-naphthoate)]. The compounds of the invention which also have acidic groups can form basic salts with various pharmaceutically acceptable cations. Examples of such salts include the alkali and alkaline earth metal salts and, particularly, the sodium and potassium salts. All these salts are prepared by conventional techniques. For example, these salts can be prepared easily by treating the aforementioned compounds with an aqueous solution containing the desired pharmaceutically acceptable cation and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing with a lower alkoxide and then evaporating to dryness, in the same way, the resulting solution. In any case, stoichiometric amounts of reagents are preferably employed in order to ensure that the reaction is complete and to the maximum yield yield of the desired final product. Also included within the scope of the invention are bioprecursors (also prodrugs) of the compounds of formula (I), a bioprecipher of a compound of formula (I) is a chemical derivative thereof which easily converts again to the Main compound of formula (I) in biological systems. In particular, a β-bioprecursor composed of formula (I) is converted again into the parent compound of formula (I) after the bioprecipsor has been administered to and absorbed by a mammalian patient, for example , a human patient. For example, it is possible to make a bioprecipsor of the compound of formula (I); wherein X * is a hydroxy group, forming an ester of the hydroxy group. Typical esters are esters of simple alkanoates, such as acetate, propionate and butyrate. Furthermore, when X is a hydroxy group, bioprecursors can be made by converting the hydroxy group to an acyloxirnethionic derivative (e.g., a pivaloyloxyrnethyl derivative) by reaction with an acyloxirneyl halide (e.g., pivaloyloxirnethyl chloride). When the compounds of formula (I) of this invention can form solvates, such as hydrate, said solvates are included within the scope of this invention.

BIOLOGICAL EVALUATION The activity of the compounds of formula (I) of the present invention is demonstrated by the following tests. Monnaga Bioscience Lab., Yoharna, Japan, acquired human umbilical vein endothelial cells (HUVEC), which were characterized by positive staining with Von Uillibrand factor and an absorption of acetylated lipproteins from ba to density. The HUVEC were maintained at E-Gil UV 8 from Kurashikibouseki Co., Neyagaua, Japan) in a? Re / C02 95% / 5% at 37 ° C. PGE2, TXB2 and 6-keto-PGF? A were from Cayman Chemical Co. (flnn Arbor, United States). The human recombinant interleukin-1 was from RSD Systems (Minneapolis, United States). The radioimmunoassay (RIA) kits of PGE2, TXB2 and 6-keto-PGFi were from Amersham (Tokyo, Japan). The invention and other reagents were from Sigma Chemical Co. (St. Louis, United States). Dexamethasone (DecadronE was from Becton Dickinson (Bedford, United States), Male Sprag? E-Dawley rats were purchased from Charles River (Hmo, Japan).

TEST E COX-l BASED ON HUMAN CELLS the COX-1 assay based on human cells was performed essentially in accordance with a procedure described above (Grossman et al., Inflarn, Res., 44, 1995, 253). Human peripheral blood was obtained from healthy volunteers using Vacutainer containing 1/10 volumes of 3.8% sodium citrate solution. After centrifugation, the platelet-rich plasma was washed with 0.14 rn sodium chloride containing 12 mil Tris-HCl (pH 7.4) and 1.2 mM ethylenediaminetetraacetic acid (EDTA). The resulting platelets were washed with 20 mM Caps free Hepes-Hanks buffer, containing 0.2% bovine serum albumin (BSA). washed human platelets (UHP) were sued at the concentration of 2.85x107 cells / ml in the aforementioned buffer, and stored at room temperature until the time of use. Immediately before the assay, 10 μl of CaCl 2 was added. 12.6 mM to 70 μl of UHP suspension (2.0x107 cells / rnl in a 96 well U-bottom plate). The platelets were incubated with a test compound dissolved in DMSO (final concentration lower than 0.01%) and A23187 (final 10 μM) at 37 ° C for 15 minutes. The reaction was stopped by the addition of EDTA (7.7 mM final). The TXB2 in the supernatant liquid was quantified by RIfl.

COX-2 ESSAY BASED ON HUMAN CELLS the enema of COX-2 based on human cells was performed essentially according to a procedure described previously (More et al., Inflam, Res., 45, 1996, 54). Confluent HUVECs were washed in a 96-well plate with 100 μl of RPM11640 containing 2% FCS and stimulated with hIL-Iβ (300 U / ml final) at 37 ° C for 24 hours, Ls HUVEC pretreated with hIL-lβ were washed with Hepes-Hanke buffer 20 rnM containing 0.2% BSA. The incubation was started in 100 μl of the aforementioned buffer, A23187 (final 30 μM) and a test compound dissolved in DMSO (final concentration less than 0.01%) at 37 ° C for 15 minutes. The 6-keto-PGFl2 was quantified in the supernatant liquid by RIA.

EDEMA INDUCED BY CARREGENANO IN RAT PATAS It was injected intradermally / \ - carregenano (0.1 ml of a 1% p / v sperionion in saline solution) to male Sprague-Dawley rats (5 sernanae), not fed overnight, on the right hind paw , as previously published (Uinter et al., Proc. Soc. Exp. Biol. Med., 111, 1962, 544; and Lornbardino et al., Arzneirn. Forsch., 25, 1975, 1629). The paw volume was measured by displacement of water using a pletiernórnetro (Unicom Co., Yachiyo, Japan) antee and 3 hours after the injection of carrageenan. The test compounds were suspended in 0.1% w / v hyprornelose and orally administered in a volume of 2.5 ml per 100 g of body weight 1 hour before the carrageenan injection.

MEASUREMENT OF PGEa IN THE INFLAMMATORY SITE AND IN RAT STOMACH The determination of PGE2 synthesized in the inflammatory site was performed essentially according to a procedure described previously (Opas et al., Biochem. Pharmacol., 36, 1987 547). Edema was induced in the legs of male Sprague-Da ley rats (5 weeks old) by subplantar injection of 0.1 ml of a 1% w / v suspension of / 1-carregenano. The animals were sacrificed by cervical dielocation 3 hours deep from the carrageenan injection. The leg was amputated, frozen in liquid nitrogen and stored at -80 ° C until the moment of analysis. The stomach of this animal was excised, frozen in liquid nitrogen and stored at -80 ° C until the time of analysis. The frozen leg was triturated, mixed with 7 rnl of ethanol containing 10 μg / ml indornetacin, sprayed in a Uar-ing mixer and clarified by centrifuging at 3,000 rprn for 10 minutes at 4 ° C. The frozen stomach was mixed with 7 rnl of ethanol containing 10 μg / rnl of indonetacin, it was baked in a Polytrone and clarified by centrifuging at 3,000 rprn for 10 minutes at 4 ° C.

PGE2 was extracted in a Sep-Pak * Cie cartridge (from Uaters, Mil ord, United States) and dried under vacuum. The samples were diluted to a final volume of 0.5 nmol with assay buffer (PBS containing 0.1% w / v gelatin) and the PGE2 level was quantified by RIA according to the Amersham protocol. The test compounds were suspended in methylcellulose 0.1% and were administered 1 hour before the carrageenan injection. Dexamethasone was dissolved in saline and administered subcutaneously 3 hours before the carrageenan injection.

G STRICT ULCERATION IN RATS The gastric ulcerogenicity of the test compounds was tested using a standard procedure described above (Ezer et al., J. Pharrn. Pharrnacol., 28, 1976, 655). In this test, male Sprag? e.Da law rats were used (from weeks), not fed overnight. The compounds were suspended in rnetiicellulose at 0.1% w / v and orally administered in a volume of 1.0 rnl per 100 g of body weight. Six hours after the administration of the compound, the animals were sacrificed by cervical dislocation. The stomach was removed and inflated with 10 nmol of 1% forrnalm solution. The stomach was opened by cutting along the greater curvature and the incidence of ulcer, including ecchymosis, was evaluated by an all-or-nothing procedure. During the experiments, the rats were deprived of water. The value of the semiulcerogémca dose (DU50) was calculated, that is, the dose required to induce at least one gastric lesion or a hemorrhagic erosion in 50% of the animals tested, by non-linear equation: 100% Control = 1 + CDosisH / DUso DATA ANALYSIS A SY? TAT statistical program for Macintosh was used (from Systat Inc). The differences between the group treated with compounds and the control group were tested using ANOVA. The IC50 values of the ED50 were calculated from the logarithm equation of the linear regression line of concentration (dose) as a function of the percentage of inhibition. By these methods, most of the compounds prepared in the working examples described herein were assayed, and showed CI values of 0.01 μM to 1.0 μM with respect to the inhibition of COX-2. The selectivity of COX-2 can be determined by the ratio, referred to the IC 50 value, of COX-1 inhibition to COX-2 inhibition. In general, it can be said that a compound that shows an inhibition ratio of C0X-2 / C0X-1 greater than 2 has a good selectivity towards COX-2. The compounds prepared in Examples 1, 14, 17 and 21 described herein showed an inhibition ratio of C0X-2 / C0X-1 above 10. The following examples contain detailed descriptions of the methods of preparing compounds of formula ( I). These detailed descriptions fall within the scope of the general synthesis procedures described above which are part of the invention, and serve to exemplify them. These detailed descriptions are presented for illustrative purposes only and not as a limitation on the scope of the invention. All parts are by weight and temperatures are in degrees centigrade, unless otherwise indicated.

EXAMPLES AND PREPARATIONS The present invention is illustrated by the following examples and preparations. However, it should be understood that the invention is not limited to the specific details of these examples and preparations. The melting points (p.f.) were taken with a Buchi melting point apparatus and were not corbeled. The infrared (IR) absorption spectra were measured with a Shirnazu infrared spectrometer (IR-470). Nuclear magnetic resonance (NMR) spectra of * H and 13c were measured in CDCI3 with a JEOL NMR spectrometer (JNM-GX270 MHz), unless otherwise indicated, and the positions of the peaks are expressed in parts per million (ppm) field below tetrarnethylsilane. the shapes of the peaks are defined as: s, smglete; d, doublet; t, complete; m, multiple; br, wide.

EXAMPLE 1 (E)) -l-phenyl-2-styryl-lh-benzimidazole To a stirred solution of N-phenyl-o-pheni lendiamian (1.0 g, 5.4 milliols) in toluene (30 rnl) was added cmamoyl chloride (0.90 g, 5.4 milliols) in small portions and the mixture was heated to reflux overnight. The reaction mixture was cooled and poured into saturated aqueous sodium bicarbonate solution (50 ml) and extracted with ethyl acetate. (100 mi) The organic extract was washed consecutively with water (50 ml) and brine (50 ml), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 150 g, n-hexane / ethyl acetate 4/1) to give pink solids. Recpetalization in d-neopropyl ether gave 1.35 g (84%) of the title compound in the form of white solids. This compound was used in a pharmaceutical composition. Molecular weight: 296.37. P.f. 133, 8-134, 5 ° C. NMR-lH (CDC13) d: 7.97 UH, d, J = 15.8 Hz), 7.84 (1H, d, J = 8, l Hz), 7.67-7.56 (3H, rn ), 7, 50-7.42 (4H, rn), 7.38-7.16 (6H, rn), 6.85 UH, d, J = 15.8 Hz).

EXAMPLE 2 (E) -2- (4-Fluorostyryl) -l-phenyl-lH-benzimidazole The title compound was prepared from N-phenol-o-phenollendronan and p-fluorocmamoyl chloride (Gepg J.T. and McLeod R.S., J. Chern. , 53, 1975, 513) according to the preparation of (E) -l-phen-l-2-est-pl-lH-benzamidazole (Example 1). Molecular peptide: 314.37. P.f. 108, 7-109, 5 ° C. NMR-lH (CDC13) d: 7.93 UH, d, J = 16, l Hz), 7.83 UH, d, J = 8, l Hz), 7.68-7.56 (3H, rn) , 7.49-7.40 (4H, m), 7.33HU, ddd, J = 7.7, 7.7, 1.8 Hz), 7.27-7.16 (2H, m), 7.07-6.98 (2H, m), 6.76 UH, d, J = 16, 1 Hz).

EXAMPLE 3 (E) -2- (3-Fluorostyril) -l-phenyl-lH-benzimidazole hydrochloride (E) -2- (3-fluoroest? R? L) -l-phen? L-lH-benzimidazole was prepared from N-phenyl-o-phenethiamine and m-fluoro-cynarnoyl chloride (Gepg JT and McLeod RS, Can. J. Chem., 53, 1975, 513) in accordance with the preparation of (E) ~ l-phenol-2-eetinyl-lH-benzimidazole (Example 1). The free base was dissolved in methanol, treated with a 10% hydrogen chloride solution and concentrated to dryness. The residue was recrystallized from dusopropyl ether to give the title compound in the form of white needles. Molecular weight: 350.83. P.f. 236, 0-243, 0 ° C. NMR-lH (DMSO-dβ) d: 8.27 UH, d, J = 16.8 Hz), 7.90 UH, d, J = 8, 1 Hz), 7.82-7-70 (5H, rn), 7.63-7.44 (5H, rn), 7.38-7.25 (2H, rn), 7.02HU, d), J = 16.8 Hz).

EXAMPLE 4 (E) -2- (fluorostyril) -l-phenyl-lH-benzimidazole hydrochloride The title compound was prepared from N-phenyl-o-phenylenediarnine and o-fluorocarninoyl chloride (Gerig J.T. and McLeod R.S., Can. J. Chem., 53, 1975, 513) according to the preparation of (E) -2- (3-fluorostyryl) -1-phenyl-1H-benzimidazole hydrochloride (Example 3). Molecular weight: 350.83. P.f. 225, 0-228, 0 ° C. NMR-1H (DMSO-dβ) or: 8.27 UH, d, J = 16.5 Hz), 7.91 UH, d, J = 8, 1 Hz), 7.82-7.69 (6H, rn), 7.63-7.46 (3H, rn), 7.39-7.25 (3H, m), 7.00 (1H, d, J = 16.6 Hz).

EXAMPLE 5 (E) -2- (4-Methylthiostyril) -l-phenyl-1H-benzimidazole The title compound was prepared from N-phenyl-o-phenylenediarnine and p-rnetthio cyano-cinyl chloride (Miller R.D. and Reiser-O.J., Heterocycl. Chern., 30, 1993, 755) according to < In the pre? ation of (E) - 1 -feru 1 -? - est i p 1 - 1 H-b ncunidaz? l (Example 1). Molecular weight: 342.47. P. f. 175, 7-179- p ° C. NMR-lH (CDC13) ñ: 7.91 UH, d, J- ~ 16, l H), 7.82 UH, d, J = 7.7 Hz), 7.67-7.55 (3H, rn ), 7.48-7.15 (9H, rn), 6.79 (1H, d, J = lb, l Hz), 2.47 (3H, s).

EXAMPLE 6 (E) -2- (4-Methylsulfinylstyryl) -l-phenyl-1H-benzimidazole hydrochloride a stirred solution of (E) -2-methylti sterile) -1-phenol-lH-benzrn-dazole (0.31 g, 0.92 inylirnols) in a mixture of methanol (10 ml) ) and water (10 rnl), cooled to 0 ° C, sodium periodate (0.21 g, 1.0 mmol) was added. The ice bath was removed and the reaction mixture was stirred at room temperature overnight, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (50 ml) and extracted with ethyl acetate. ethyl (100 ml). The organic extract was washed consecutively with water (bür l) and brine (50 ml), dried (sodium sulfate) and concentrated in vacuo. The residual solids were purified by column chromatography (silica gel, 100%).; ethyl acetate) giving brown solid solids. The solids were treated with a 10% hydrogen chloride solution (5 mL) and the volatiles were removed in vacuo. Replanting the ethanol redox gave 0.18 g (50%) of the title compound as yellow-colored solids. Molecular weight: 394.93. P.f. 192, 9-193, 8 ° C. NMR-lH (CDC13) d: 7.98 (1H, d, J = 16, l Hz), 7.84 UH, d, H = 8, l Hz), 7.69-7.59 (7H, rn ), 7.48-7.42 (2H, rn), 7.38-7.17 (3H, rn), 6.93 UH, d, J = 16, l Hz), 2.71 (3H, s) ).

EXAMPLE 7 (E) -2- (4-Methylsulfonylstyryl) -l-phenyl-lH-benzimidazole a stirred solution of (E) -2- (4-methylthioester D-1-phenyl-1H-benzylnidazole (0.60 g, 1.75 mmol) in a mixture of ethanol (5 ml), tetrahydrofuran (5 ml) and Water (5 mL) was added slowly OXONET (R) (1.63 g, 2.65 mmol) and the reaction mixture was stirred at room temperature overnight.The reaction mixture was poured into saturated aqueous solution of the reaction mixture. sodium bicarbonate (30 mL) and the aqueous mixture was extracted with ethyl acetate (100 mL) The organic extract was washed consecutively with water (50 mL) and brine (50 mL), dried (sodium sulfate) and concentrated to the The residual solids were purified by column chromatography (silica gel, 100 g, n-hexane / ethyl acetate 1/1) to give brown solids.Recrystallization from ethyl acetate gave 0.24 g (36%). ) of the title compound in the form of light yellow solids Molecular weight: 374.47, Mp 168, 6-169, 5 ° C. NMR-lH (CDC13) d: 8.03 (1H, d, J = 15.8 HZ), 7.93-7 , 82 (3H, m), 7.68-7.59 (5H, rn), 7.49-7.44 (2H, rn), 7.40-7.19 (3H, m), 6.97 UH, d, J = 15.8 Hz), 3.05 OH, s).

EXAMPLE 8 (E) -2- (β-Methylstyryl) -l-phenyl-1H-benzimidazole hydrochloride To a stirred solution of N-phenyl-o-phenylenediamma in toluene (50 ml) was added at room temperature and in 15 minutes a solution of 2-methyl? -phenolhaloyl chloride (1.81 g; rmlirnoles; Uatanabe T., Hayashi K., Yoshirnatsu S. and Sakai, KJ, J. Med. Chem., 23, 1980, 50) in toluene (20 ml). The resulting mixture was stirred at room temperature for 10 minutes and then heated to reflux for 12 hours by removing the water azeotropically using a Dean-Stark apparatus. After cooling, the volatiles were removed by evaporation and the residue was dissolved in xylenes (75 rnl). To the solution was added p-toluene sulonic acid hydrochloride (0.40 g, 2.1 mmol) and the mixture was heated to reflux by removing azeotropic water. After 9 hours, the reaction mixture was concentrated and the residue was dissolved in a mixture of ethyl acetate (100 i) and saturated aqueous sodium bicarbonate solution (100 rnl). The organic layer was separated and washed with brine (100 ml), dried (magnesium sulfate) and dryness was concentrated. The residue was dissolved in hot toluene and the solution was treated with active carbon. After filtering, the filtrate was concentrated to dryness. The residue was triturated with n-hexane to give 1.61 g (52%) of (E) -2- (f? -rnet? Iest? R? L) -l-phen? L-lH-benz? Dazole in the form of pink solids. The free base was dissolved in methanol (15 mL), treated with 10% methanolic hydrogen chloride solution (15 mL) and concentrated to dryness. The recrystallization from 2-propanol gave 1.52 g of the title compound as off-white solid. Molecular weight: 346.86. P.f. 222, 0-225, 0 ° C. NMR-lH (DMSO-dβ) d: 7.98-7.93 (1H, m), 7.79-7.51 (7H,), 7.48-7.29 (6H, rn), 7, 18 UH, br.s), 2.13 (3H, d, J = 1, 5 Hz).

EXAMPLE 9 (E) -6-Chloro-1-phenyl-2-styryl-1H-benzimidazole The title compound was prepared from 4-chloro-2-aml? Noan? Lna (Ernst O., Chern., Ber., 23, 1890, 3423) and cynarnoyl chloride, according to the preparation of (E) -l-phen? L-2-est? R? L-lH-benz? Dazole (Example 1). Molecular weight: 330.82 P.f. 163, 1-164, 2"C.

NMR-1H (CDCl 3) d: 7.95 UH, d, J = 16, 1 Hz), 7.73 (1H, d, J = 8.8 Hz), 7.67-7.58 (3H, rn ), 7.49-7.41 (4H, rn), 7.38-7.25 (4H, m), 7.17 UH, d, J = 1, 8 Hz), 6.81 UH, d, J = 16, l Hz).

EXAMPLE 10 (E) -5-Chloro-1-phenyl-2-styryl-1H-benzimidazole The title compound was prepared from 5-chloro-2-anilinoaniline (Ullmann F. Justus, Liebigs flnn.Chem., 332, 1904, 82) and cinnabarium chloride according to the preparation of (E) -l- phenyl-2-styryl-lH-benzimidazole (Example 1) . Molecular weight 330.82. P.f. 169, 5-170, 5 ° C. NMR-1H (CDCl 3) d: 7.96 UH, d, J = 16, 1 Hz), 7.80 (1H, d, J = 1, 8 Hz), 7.68-7.57 (3H, rn ), 7.49-7.40 (4H, rn), 7.38-7-29 (3H, m), 7.19 UH, dd, J = 8.8, 1.8 Hz), 7.09 UH, d, J = 8.8 Hz), 6.81 UH, d, J = 16, l Hz).

EXAMPLE 11 (E) -l- (4-flurophenyl) -l-styryl-lH-benzimidazole hydrochloride The title compound was prepared from N-4-fluorophenyl-o-phenylenediarnine (Elguero J., Estopa C. and Ilavsky D., J. Chern. Res. Miniprint, 12, 1981, 4.237) and cinnamoyl chloride, according to the preparation of the hydrochloride of (E) -2 - ((3-rnet? lest? r? l) -l-phen? l-lH-benz? rn? dazol (Example 8) Molecular weight: 350, 83. Mp 257.5-259-0 ° C. RMN-1H (DMS0-d6) d: 8.16 (1H, d, J = 16, 1 Hz), 7.90-7.75 (3H, m ), 7.69-7.42 (9H, rn), 7.33 UH, d, J = 7.7 Hz), 6.93 UH, d, J = 16, 1 Hz).

EXAMPLE 12 (E) -1- (4-Fluorophenyl) -2- (4-methylthio-styryl-1H-benzimidazole The title compound was prepared from N-4-fluorofen? Lo-phen? Lend? Am? A and p-rnetyl thiocyanoyl chloride, according to the preparation of (E) -l-phenyl-2-est? -lH-benzinidazole (Example 1). Molecular weight: 360.46. P.f. 187, 7-188, 5 ° C. NMR-lH (CDC13) d: 7.91 (1H, d, J = 16, l Hz), 7.82 UH, d, J = 7.7 Hz), 7.46-7.11 (11H, rn ), 6.73 UH, d, J = 16, l Hz), 2.48 (3H, s).

EXAMPLE 13 (E) -2- (-Fluoroest? Il) -1- (-methylthiophenyl) -lH-benzimidazole 1) N-4-Methyl-o-phenyl-o-phenylenediamine A mixture of 2-n-trochlorobenzene (10.0 g, 63.5 mmol) and 4-nitrate italoamine (8.84 g, 63.5 mmol) was added potassium fluoride (3.70 g). 63.7 quinoline) and the reaction mixture was heated at 170 ° C for 30 hours with vigorous stirring. The mixture was cooled and subjected directly to flash chromatography on silica gel (100 g) eluting with n-hexane / ethyl acetate (20/1) to give 12.5 g of a brown oil. The oil was dissolved in ethanol (250 ml), 5% palladium on carbon (1.5 g) was added and the mixture was hydrogenatured at medium pressure of hydrogen (2.5 kp / cm2) for 2 hours. The catalyst was removed by filtration through a short pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by chromatography on colunrna (silica gel), 500 g; n -hexane / ethyl acetate 4/1), giving 0.51 g (4%) of N-4-met? lt? ofen? l-o-phen? lend? am? na as black solids. NMR-1H (CDC13) d: 7.22 (2H, d, J = 8.4 Hz), 7.10 UH, dd, J = 7.7, 1.5 Hz), 7.02 UH, ddd, J = 7.7, 7.7, 1.5 Hz), 6.80 UH, dd, J = 7.7, 1.5 Hz), 6.76 UH, ddd, J = 7.7, 7, 7, 1.5 Hz), 6.69 (2H, d, J = 8.4 Hz), 5.16 (2H, br.s), 3.76 UH, br.s), 2.43 (3H , s). 2) (E) -2- (4-Fluorostyrene) -l- (4-methylthiophenyl) -lH-benzimidazole The title compound was prepared from N-4-methylthiophen-1-phenylenediamine and p-fluoro-cyanocinium chloride, according to the preparation of (E) -l-fem-2-est? r? IH-benzyne dazol (Example 1).

Molecular Peeo: 360.46. P.f. 106, 9-107, 9 ° C. NMR-lH (CDC13) d: 7.93, UH, d, J = 16.1 Hz), 7.82 UH, d, J = 7.7 Hz), 7.49-7-41 (4H, rn ), 7.38-7.14 (5H, rn), 7.08-6.98 (2H, rn), 6.74 UH, d, J = 16, l Hz), 2.60 (3H, e ).

EXAMPLE 14 (E) -5-Nitro-l-phenyl-2-styryl-lH-bepcimidazole The title component was prepared from 5-nitro-2-anilinoaniline (Brand K. and Uild E., Chem. Ber., 56, 1923, 105) and cinanoyl chloride, according to the preparation of (E) -l-phenyl-2-eethyryl-lH-benzimidazole (Example 1). Molecular peptide: 341.37 P.f. 173, 8-174, 7 ° C. NMR-1H (CDCl 3) d: 8.72 (1H, d, J = 2.2, Hz), 8.16 UH, dd, J = 8.8, 2.2 Hz), 8.04 UH, d , J = 16, l Hz), 7.72-7.62 (3h, rn), 7,52-7,42 (4H, rn), 7,38-7,31 (3H, m), 7, 22 UH, d, J = 8.8 Hz), 6.81 UH, d, J = 16, l Hz).

EXAMPLE 15 (E) -5-Amino-l-phenyl-2-styryl-lH-benzimidazole dihydrochloride A solution of (E) -5-nitro-l-phenyl-2-stipyl-1H-benzimidazole (0.21 g, 0.62 ylnol) in ethanol (4 ml) and water (2 ml) was added. iron (0.17 g, 3.1 rnilirnoles) and ammonium chloride (18 rng, 0.33 mmol). The reaction mixture was refluxed for 30 minutes and, while hot, was filtered through a short pad of Celite and the filtrate was evaporated under reduced pressure. The residue obtained was partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate solution (50 ml) and the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organic extracts were washed with brine (50 rnl), dried (sodium sulfate) and concentrated in vacuo to give 0.20 g of yellow-colored solids. The solids were treated with methanol solution of 10% hydrogen chloride (5 ml) and the volatiles were removed. Recrystallization of the residue from ethanol gave 0.14 g (59%) of the title compound as yellow solids. Weight to learn, 384.31. P.f. 20, 0-203-0 ° C. RMNiH (CDCl 3) d: 7.90 (1H, d, J = 16.1 H), 7.67.7.24 U0H, rn), 7.11 UH, d, J = 1.8 Hz), 6 , 99 UH, d, J-8.4 Hz), ñ, 8l UH, d, J = 16, l Hz), 6.66 UH, dd, JB, 4, 1.8 H), 3.71 ( 2H, br.s).

EXAMPLE 16 (E) -5-Bromo-l-phenyl-2-sty l-lH-benzimidazole H a stirred solution of (E) -5-arn? no-1-f eni 1-z -eetipl-lH-benzylnidazole (0.31 g, 1.0 rnilinol) in hydrochloric acid of 47% (5 rnl) and water (2 rnl) was added an aqueous solution (1 rnl) of sodium nitrite (84 mg, 1.2 rnilirnols) at -5 ° C and the reaction mixture was stirred for 10 minutes at the same temperature. The resulting diazomer salt was added to a solution of copper (I) bromide (0.30 g, 2.0 mmol) in 47% briquehydric acid (5 mL) cooled to -5 ° C and the mixture of the The reaction was stirred for 30 minutes at 0 ° C and for 30 minutes at room temperature, the reaction mixture was consecutively added N, N, N ', N'-tetramethylethylenediarnine (5 nl) and a 4N aqueous solution of potassium hydroxide. (30 rnl). The mixture was extracted with ethyl acetate (100 nmol) and the ethyl acetate extract was washed consecutively with water (50 ml) and brine (50 ml), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 50 g, n-hexane / ethyl acetate 4/1) giving white solids. Re-emplacement in dusopropyl ether gave 61 mg (16%) of the title compound as white solids. Molecular weight: 375.27. P.f. 164, 3-165, 5 ° C. NMR-1H (CDC13) d: 7.95 (1H, d ,, J = 16, 1 Hz), 7.95 (1H, d, J = 1, 8 Hz), 7.67-7.56 (3H , rn), 7.49-7.39 (4H, rn), 7.38-7.28 (4H, rn), 7.04 UH, d, J = 8.8 Hz), 6.81 (1H , d, JU6.1 Hz).

EXAMPLE 17 (E) -5-Cyano-l-phenyl-2-styryl-lH-benzimidazole A mixture of (E) -5-broth-1-phenyl-2-styryl-1H-benzylnidazole (1.54 g, 4.1 mmol) and copper (I) cyanide was refluxed for 2 hours. 82 g, 8.2 rnilirnoles) in 1-methyl-2-prirrolidone (10 rnl). Then, N, N, N ', N'-tetramethylethylenediamine (50 nl) was added and the mixture was partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate solution (200 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (200 nmol). The combined organic phase was washed with brine (300 rnl), dried (sodium sulfate) and concentrated. The residue was purified by column chromatography (silica gel, 150 g, n-hexane / ethyl acetate 3/1) and solids (1.05 g, 80%) were obtained which were recrystallized from ethyl acetate / diisopropyl ether giving the title compound in the form of a white-bone solid. Molecular weight: 321.38. P.f. 191.3 ~ 192-4 ° C. NMR-1H (CDC13) d: 8.12 UH, d, J = 1, 8 Hz), 8.01 (1H, d, J = 16, 1 Hz), 7.7-7.61 (3H, rn ), 7.50-7.42 (5h, rn), 7.38-7.11 (3H, m), 7.23 UH, d, J = 8.4 Hz), 6.80 (1H, d) , J = 16, l Hz).

EXAMPLE 18 (E)) -l-Phenyl-2-styryl-lH-benzyl idazole-5-carboxamide a solution of (E) -5-cyano-1-phenyl-2-styryl-1H-benzylnidazole (0.30 g, 0.93 millimol) in 2-rnethyl-2-propanol (10 ml) was added potassium hydroxide powder (0.19 g, 2.8 mmol). After stirring for 2 hours at 80 ° C, the volatiles were removed in vacuo and the residue was partitioned between ethyl acetate (50 rnl) and water (50 rnl). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (50 ml). The combined extracts were washed consecutively with water (50 ml) and brine (50 ml), dried (sodium sulfate) and concentrated in vacuo. The residue was recrystallized from ethyl acetate to give 0.16 g (52%) of the title compound as a white solid. Molecular weight 339.40. P.f. > 220 ° C. NMR-lH (CDC13) d: 8.24 UH, d, J = l, 8 Hz), 7.98 (1H, d, J = 16, l Hz), 7.81 UH, dd, J = 8, 4, 1.8 Hz), 7.69-7.58 (3H, rn), 7.51-7.41 (4H, rn), 7.39-7.29 (3H, rn), 7.23 UH, d, J = 8.4 Hz), 6.83 UH, d, J = 16, l Hz), 6.01 (2H, br.s).

EXAMPLE 19 (E) -l-phenyl-2-C2- (3-pyridyl) vinyl] -lH-benzimidazole dihydrochloride The title compound was prepared from N-phenyl-o-phenylenediarnine and 3- (3-? Iridyl) acryloyl chloride, according to the preparation of (E) -2- (3-fluoroetheryl) -l hydrochloride. phenyl-lH-benzimidazole (Example 3). The 3- (3-pyridyl) acryloyl chloride was obtained in the following manner: A mixture of 3- (3-pyridyl) acrylic acid and thionyl chloride was heated under reflux under a dry atmosphere for 140 minutes. The volatiles were removed by evaporating under reduced pressure and the 3- (3-pyridyl-) acryloyl chloride obtained was used without purification. Molecular weight: 370.28. P.f. 270.0-273-0 ° C. NMR-lH (DMSO-dβ) d: 9.10 (1H, d, J = 1, 5 Hz), 7.78 (1H, dd, 6.1, 1.5 Hz), 8.61-8, 45 UH, rn), 8.24 UH, br.d, J = 16, l Hz), 7.90-7.77 (7H, rn), 7.52 UH, ddd, J = 8.4, 7.7, 1.5 Hz), 7.44 UH, ddd, J = 8, 4, 7.7, 1.5 Hz), 7.32 UH, dd, J = 7.7, 1.5 Hz), 7.26 UH, d, J = 16, l Hz).

EXAMPLE 20 (E) -2- (2-Cyclohexylvinyl) -l-phenyl-lH-benzimidazole The title compound was prepared from N-phenol-fen? Lend? Am? Na and 3-c? Clohex? Lac? Loyl chlorur-o (Y terminus, Kawada K., Toi K., Kumashiro I. and Fukushirna K., Chem. Pharm. Bull., 11, 1988, 4.426), in accordance with the preparation of (E) -l-feml-2-est? R? L-lH-benz? (Example 1) . Molecular weight 302.42. P.f. 100, 0-101, 0 ° C. NMR-1H (CDC13 d: 7.78 (1H, br.d, J = 8, 1 Hz), 7.64-7.48 (3H, rn), 7.42-7.36 (2H, rn) , 7.31-7.13 (3H, rn), 7.07 UH, dd, J = 15.8, 7.3, Hz), 6.16 UH, dd, J = 15.8, 0.5 Hz) , 2.20-2.06 UH, m), 1.80-1.49 (5H, rn), 1.33-1.08 (5H, rn).

EXAMPLE 21 (•) -2- (2-Cyclopentylvinyl) -l-phenyl-1H-benzimidazole hydrochloride a stirred solution of (E) -3-c? clo? ent? -acrylic acid (0.40 g; 2.85 mmol; Roth R. and Erlenrneyer H., Helv. Chirn. fleta, 38, 1955; 1276) in dichloroethane (20 rnl), at 0 ° C and under a nitrogen atmosphere, oxalyl chloride (1.46 g, 11.5 mmol) was added. The mixture was stirred at 0 ° C for 40 minutes and then at room temperature for 100 minutes. Evaporation of the volatiles under reduced pressure gave 3-c? 11-acplo-clop in the form of a colorless liquid, which was used without purifying it. A stirred solution of N-phenyl-o-phenylenediarnine (0.38 g, 3.0 mmol) in xylenes (35 mmol) was added dropwise over 10 minutes to a solution of 3-cyclopentyl-chloro chloride (2.85 g). rnilirnoles) in xylenes (20 ml). The resulting mixture was stirred at room temperature for 80 minutes and then refluxed for about 13 hours to remove the water using a Dean-Stark apparatus. To the mixture was added p-toluene sulphonic acid rnonohydrate (0.10 g) and the reaction was continued for 10 hours. After cooling, the volatiles were removed by evaporation and the residue was dissolved in a mixture of ethyl acetate ( 100 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The organic layer was dried (magnesium sulfate) and concentrated to dryness. Column chromatography on silica gel [silica gel, 100 g; n-hexane / ethyl acetate (4 / la 7/3)] gave 0.15 g (18%) of (E) -2- (2-c? clopentUv? n? l) -1-phen? l-lH-benzimidazole in the form of an amber oil. The oil was dissolved in ethyl ether and hydrogen chloride was passed through the stirred solution. The volatiles were removed by evaporation and the residue triturated with dusopropyl ether. The precipitates were collected by suction, washed with d-neopropyl ether and dried in vacuo to give the title compound as white solids. Molecular weight: 324.86. P.f. 136, 0-137.0 ° C. NMR-lH (DMSO-dβ) d: 7.86-7.60 (6H, m), 7.57-7.38 (2H, m), 7.32-7.11 (2H, rn), 6 , 23 UH, d, J = 15.8 Hz), 2.78-2.66 UH, n), 1.82-1.75 (2H, rn), 1.73-1.50 (4H, rn ), 1.45-1.29 (2H, m).

EXAMPLE 22 2-Phenylethynyl-1-phenyl-1H-benzimidazole The title compound was prepared from N-phenyl-ofenylenediarnine and phenylpropinoyl chloride (Berg ann F. and Haskelberg L., ftrn Chem. Soc., 63, 1941, 2243), according to the preparation of (E ) -l-phenyl-2-styryl-lH-benzimidazole (Example 1). Molecular weight: 294.36. P.f. 118, 0-119, 0 ° C. 1 H-NMR (CDCl 3) d: 7.87-7.82 UH, m), 7.64-7.49 (5H, rn), 7.43-7.27 (8H, m).

EXAMPLE 23 (Z) -l-Phenyl-2-styryl-lH-benzimidazole a solution of 2. phenylethynyl-1-phenyl-1H-benzimidazole (0.98 g, 3.0 mmol) in toluene (30 mmol) was added quinoline (10 drops) and palladium on calcium carbonate (0.20 g) and the reaction mixture was stirred vigorously for 1 hour under an atmosphere of hydrogen. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. Purification by column chromatography (silica gel, 250 g, n-hexane / ethyl acetate 5/1) gave 0.53 g (54%) of the title compound (Rf-0.2) as an oil colorless. Molecular poso-. 296.37. P.f. OIL RMN-1H (CDCl 3): 7.83 (1H, dd, ~ 8.4, 1.8 Hz), 7.48-7.38 (5H, m), 7.34-7.16 (8H, rn) 6.78 UH, d, JU, 8 Hz), 6.39 UH, d, J = 12.8 Hz).

EXAMPLE 24 (E) -l-Phenyl-2- [2-pyridyl) inyl] -lH-bepcimidazole 1) N (2-Anilino enyl) -3- (2-pyridyl) acrylamide Pl a stirred solution of acid (E) -3- (2-pindi l) acr? L? Eo (0.44 g; 3.0 rniliols; Ried U. and Keller H., Chern. Ber-., 89, 195b, 2,578), N-phenol-phen-lend? A? N? Na (0.61 g, 3.3 rnilirnoles) and chlorhydrate of 1 - (-dirnetiiami nopropyl) - -et 1 lcarbodiirní da (0.69 g, 3.6 inilunoles) in dirnetiiforrnamida (5 rnl), at ~ 20 ° 0 and under a nitrogen atmosphere, was added tpeti lamina (0.7 ml). The resulting mixture was stirred at a temperature of -10 ° C to -8 ° C for 40 minutes and then at room temperature for 8 hours. The mixture was diluted with water (50 ml). The organic extract was washed consecutively with water (50 ml) and brine (50 ml), dried (magnesium sulfate) and concentrated to dryness. column chromatography (silica gel, 85 g; n-hexane / otyl acetate 1/1) gave 0.40 g (42%) of N- (α-ammophenyl) -3- (2-? ? pd? l) acplam? It gives in the form of a liquid liquid-orange. 1H NMR (CDCl3) d: 8.63-8.59 UH, rn), 8.23-8.16 UH, rn), 8.03 UH, br.s), 7.75-7.68 UH , rn), 7.69 UH, d, J = 15.0 Hz), 7.40-7.36 UH, rn), 7.30-7.12 (6H, m), 7.08 UH, d, J = 15.0 Hz), 6.91-6.85 UH, rn), 6.82-6.75 B2H, rn), 5.55 UH, br.s). 2) (E) -l-Phenyl-2-C2- (2-pyridyl) inyl) -lH-benzimidazole A stirred mixture of N- (2-an? Lofenol) -3- (2-p? R? D? L) acr? Lamma, p-toluenesulfonic acid rnonohydrate (0, was heated at reflux for 4 hours. 48 g, 2.5 millimoles) and xylenes (80 ml) to remove the water using a Dean-Stark apparatus. After cooling, the mixture was concentrated to dryness and the residue was stirred with ethyl acetate (nOO) and saturated aqueous sodium bicarbonate solution (50 ml). The aqueous layer was separated and extracted with ethyl acetate (2x100 ml). The combined organic layers were dried (magnesium sulfate) and concentrated to dryness. The crude product was purified by column chromatography (silica gel, 85 g, n-hexane / ethyl acetate 1/2) to give 0.29 g of product in the form of reddish solids. Recrystallization from diisopropyl ether / ethyl acetate 5/1 gave 0.17 g (45%) of the title compound as white solids. Molecular weight: 297, 36. P.f. 144, 0-145, 0 ° C. NMR-1H (CDCl 3) d: 8.58-8.53 (1H, rn), 7.99 (1H, d, J = 15.6 Hz), 7.88-7.83 (1H, rn), 7.71-7.57 (4H, rn), 7.52 (1H, d, J = 15.6 Hz), 7.49-7.44 (2H, rn), 7.38-7.14 (5H, m).

EXAMPLE 25 (E) -l-Phenyl-2- [2- pyridyl) vinyl-t-lH-benzimidazole The title compound was prepared from N-phenyl-o-phenylenediarin and (E) -3- (4-? Iridyl) acrylic acid, according to the preparation of (E) -l-phenyl-2-C2- (2-pyridyl) vinyl] -lH-benzylnidazole (Example 24). Molecular weight: 297.36. P.f. 116, 0-117, 5 ° C. NMR-lH (CDC13) d: 8.60-8.56 (2H, m), 7.88-7.83 UH, m), 7.87 UH, d, J = 16, l Hz), 7, 70-7.56 (3H, m), 7.48-7.42 (2H, rn), 7.39-7.32 UH,), 7.31-7.19 (4H, rn), 7, 04 UH, d, J = 16, l Hz).

EXAMPLE 26 (E) -2-C2- (2-Oxazolyl) vinyl-3-l-phenyl-1H-benzimidazole 1) (E) -2- (1-Phenyl-1H-benzimidazol-2-yl) ethyl propenoate Ethyl (E) -2-U-phenyl-lH-benzimidazole-2-iD-propenoate was prepared from N-phenyl-o-phenylenediamine and ethyl 3-chlorocarbonylacrylate (Horne S., Taylor N., S. Colloins and Rodrigo RJ, Chern, Soc. Perkin Trans., I, 12, 1991, 3.047) according to the preparation of (E) -l-phenyl-2-styryl-lH-benzimidazole (Example 1).

NMR-lH (CDCI3) d: 7.88-7.83 UH, rn), 7.66-7.55 (3H, m), 7.42 UH, d, J = 15.4 Hz), 7, 41-7.19 (5H, rn), 7.15 UH, d, J = 15.4 Hz), 4.23 (2H, 1, J = 7.0 Hz), 1.30 (3H, t, J = 7.0 Hz). 2) Acid (E) -2- (l-phenyl-lH-benzimidazol-2-yl) propenoic acid To a solution of ethyl (E) -2-U-fem-lH-benzyl-dazol-2-idpropenoate (3.74 g, 12.8 mmol) in a mixture of methanol (18 rnl) and tetrahydrofuran ( 18 ml) was added a 4N aqueous solution of lithium hydroxide (6 rnl, 24 mmol) and the reaction mixture was warmed to room temperature for 3 hours. To the reaction mixture was added 4N hydrochloric acid (6 rnl; 24 nilirnols) at 0 ° C. The precipitated solids were collected by filtration and dried under reduced pressure yielding 2.70 g (80%) of (E) -2- (1-phenol-1H-benzylnitol-2-yl) acid) pro? o? co in the form of solid white. NMR-lH (DMSO-dβ) d: 7.89 UH, d, J = 7.3 Hz), 7.84-7.62 (5H, rn), 7.48-7.26 (4H, rn) , 6.97 UH, d, J = 15.4 Hz). 3) 3- (Fen? L-lH-benz? Midazol-2-yl) acrylamide To a stirred solution of 3- (1-pheyl-1H-benzamidazole-2?) Acrylic acid (1.06 g, 4 mmol) in dichloromethane (80 mmol), at 0 ° C and under an atmosphere of nitrogen, oxalyl chloride (3.05 g, 24 rnilirnoles) was added and the resulting suspension was stirred at 0 ° C for 20 minutes and then at room temperature for 2.5 hours. The volatiles were removed by evaporation and the residue was added in portions to a stirred aqueous solution of 25% ammonia (40 ml). After 130 minutes, the solids were collected by suction, washed with water and dried in vacuo at 50 ° C to give 1.04 g (98%) of the title compound as white-bone solid. NMR-lH (CDC13) d: 7.86-7.91 UH, rn), 7.66-7.55 (3H, m), 7.45 UH, d, J = 15.0 Hz), 7, 43-7.19 (6H, rn), 5.65 UH, br.s), 555 UH, br.s). 4) ÍE) -2-C2- (2-oxazolyl) vinyl-3-l-phenyl-lH-benzimidazole A mixture of 3-U-phenol-1H-benzamidazole-2 (1) acrylamide (0.62 g, 2.35 mmol), vinylene carbonate was stirred at 170 ° C. (0.26 g, 3.0 mmol) and polyphosphatic acid (6.2 g :). After 2 hours, ice was added and the mixture was basified with 10% aqueous potassium hydroxide solution (100 rnl) and extracted with dichloromethane / isopropyl alcohol 9/1 (150 rnl + 50 rnl). The combined organic layers were washed consecutively with water (2x100 ml) and brine (100 ml), dried (magnesium sulfate) and concentrated to dryness. Purification by column chromatography (silica gel, 100 g, ethyl acetate) gave 66 g of the product as pale green solids which were recrystallized from diisopropyl ether to give 36 mg (5%) of the title compound as of eolidoe of color toetado. Molecular weight: 287.32. P.f. 155, 5-156, 0 ° C. NMR-iH (CDC13) d: 7.89-7.84 UH, m), 7.73 UH, d, J = 16, l Hz), 7.68, 7-54 UH, rn), 7.47 -7.42 (2H, rn), 7.39-7.32 UH, m), 7.31-7.25 UH, m), 7.27 UH, d, J = 16, l Hz), 7 , 23-7.18 (2H, rn). The chemical structures of the compounds prepared in Examples 1 to 26 are summarized in the following table.

PICTURE 1 * phenyl (E CH = CH 2 phenyl (E CH = CH 4-F 3 phenyl (E CH = CH 3-F 4 phenlo (E CH = CH 2 -F phenyl (E CH = CH 4 -MeS 6 phenyl (E CH = CH 4 -MeS (0) 7 phenyl (E CH = CH 4 -MeS (0) 2 8 phenyl (EC (CH 3) = CH 9 phenyl (E CH = CH 6 -Cl 10 phenyl (E CH = CH 5 -Cl 11 phenyl (E CH = CH 4 -F 12 phenyl (E CH = CH 4 -F 4 -Month 13 phenyl (E CH = CH 4 -MeS 4-F 14 phenyl (E CH = CH 5 -N02 15 phenyl (E CH = CH 5 -NH 2 16 phenyl (E CH = CH 5-Br 17 phenyl (E CH = CH 5-CN 18 phenyl (E CH = CH 5-CONH 2 19 3-pyridyl (E CH = CH 20 cyclohexyl (E CH = CH 21 cyclopentyl (E CH = CH 22 phenyl C = C (• *) To be used in a pharmaceutical composition PICTURE (Continued) Ar Y X2 phenyl (Z) CH = CH 2 -pyridyl (E) CH = CH 4 -pyridyl (E) CH = CH oxazolyl (E) CH = CH

Claims (7)

1. NOVELTY OF THE INVENTION CLAIMS A compound of the following formula: and the pharmaceutically acceptable salts of the same, wherein Ar is phenyl, C3-8 cycloalkyl, C4-8 cycloalkenyl or heteroaryl which is connected to Y by a carbon atom, the heteroaryl being selected from pyridyl, furyl, thienyl, oxazolyl, thiazolyl , isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl and tetrazolyl; ? i is H, halo, C 1-4 alkyl, hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, (C 1-4 alkoxy) (C 1-4 alkyl), amino, (C 1-4 alkyl) arnino (alkyl) C1-4), (dialkyl C? - ") amino (alkyl C? -"), (C4-4 alkanoyl) amino, (dialkyl C1-4) arnino, (C1-4 alkyl) (C4 alkanoyl) ) arnino, (C 1-4 alkyl) eulphonylamino, C 1-4 alkanoyl, carboxyl, (C 1-4 alkoxy) carbonyl, aminocarbonyl, (C 1-4 alkyl) aminocarbonyl, (C 1-4 alkyl) arninocarbonyl, cyano, nitro, mercapto, ( C 1-4 alkyl) thio, (C 1-4 alkyl) sulphonyl, (C 1-4 alkyl) sulphonyl, ammonium sulphonyl, (C 1-4 alkyl) arnesulfonyl or (dialkyl C1) -4) ammosulfonyl; ? and 3 3 are independently C alquilo-alquilo alkyl), halo, halo-substituted C 1-4 alkyl, hydroxy, C 1-4 alkoxy, rnercapto, (C 1-4 alkyl) t? o, (C 1-4 alkyl) e? lf? n It, (C 1 - "alkyl) sulfonyl, C 1-4 alkanoyl, carboxyl, (C 1-4 alkoxy) carbonyl, to incarbonyl, (alkyl Ci-) aminocarbonyl, (dialkyl) C1 -4) arn? Nocarbomlo, cyano, nitro, arnino, (C 1-4 alkyl) arn? No, (dialkyl C? - < v) am? No or (alkyl Ci-) sulfon? Larn? No. Y is -CRi = CR2 - or -C = C ~, wherein R1 and R2 are independently H, methyl, ethyl or halo; 1 is 0, 1, 2, 3 or 4; ymyn are independently 0, 1, 2 or 3, with the proviso that when Ar is phenyl and 1, rn and n are zero, then Y is not -CH = CH -, - and when Ar is phenyl, 1 and m are zero, n is 1, and Y is -CH = CH-, then? it is not C 1-4 alkoxy linked to the 2-position of Ar or arnino, (C 1-4 alkyl) amine or (C 1-4 dialkyl) arn not attached to the 4-position of flr.
2. 2. A compound according to claim 1, wherein flr is phenyl, C3-8 cycloalkyl, C4-8 cycloalkylene, or heteroaryl selected from pindyl, pyrrolyl and oxazolyl; X2 and? 3 < they are independently C 1-4 alkyl, halo, halo-substituted C 1-4 alkyl, hydroxy, C 1-4 alkoxy, (C 1-4 alkyl) thio, (C 1-4 alkyl) s? or methyl (C 1-4 alkyl) sulfonyl; is H, halo, C 1-4 alkyl, hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkyl, C 1-4 alkyl hydroxy-substituted, arnino, (C 1-4 alkyl) amino, cyano or nitro; l is O or l; and m and n are independently O or 1.
3. 3. A compound according to claim 2, wherein Ar is phenyl or C3-8 cycloalkyl; X2 and X3 are independently halo, (C1-4 alkyl) thio, (C1-4 alkyl) eulfinyl or (C1-4 alkyl) eulphonyl; Xi is H, halo, amino, cyano or nitro, which is attached to the 5 or 6 position of the benzyl idazo ring system, - and Y is -CRi = CR2, wherein R1 and R2 are independently H or methyl.
4. 4. A compound according to claim 3, wherein Ar is phenyl, cyclopentyl or cyclohexyl; X2 and 33 are independently fluoro, methylthio, rnsulfinyl or ethylsulphonyl; i is H, fluoro, chloro, bromo, amino, cyano or nitro, which is attached to the 5-position of the benzylnidazole ring system; and Y is -CH = CH-.
5. 5. A compound according to claim 1, selected from (E) -2- (4-fluoroetheryl) -l-phenyl-lH-benzimidazole, hydrochloride of (E) -2- (2-fluoroetheryl) -1- phenyl-lH-benzimidazole, (E) -5-nitro-l-phenyl-2-styryl-lH-benzimidazole, (E) -5-mino-l-phenyl-2-styryl-lH-benzylnidazole dihydrochloride, (E ) -5-bromo-l-phenyl-2-etyryl-lH-benzylnidazole, (E) -S-cyano-l-phenyl-2-styryl-lH-benzimidazole, (E) -2- (2-cyclohexylvinyl) - l-phenyl-lH-benzimidazole, (E) -2- (2-cyclopentiivinyl) -l-phenyl-1H-benzimidazole hydrochloride and (E) -l-phenyl-2- [2- (2-pyridyl) vinyl] -lH-bencirnidazole.
6. 6. A compound according to claim 5, selected from (E) -5-nitro-l-phenyl-2-styryl-lH-benzylnidazole, (E) -5-c? Ano-l-phenyl-2- styrene-1H-benzimidazole and (E) -2- (2-c? clopentylvinyl) -l-femyl-lH-benzylnidazole hydrochloride.
7. 7. A pharmaceutical composition useful for the treatment of a medical disorder in which the prostaglandins are implicated as pathogens, comprising a compound of the following formula (I): and pharmaceutically acceptable salts of the same, wherein flr is phenyl, C3-8 cycloalkyl, C4-8 cycloalkenyl or heteroaryl which is connected to Y by a carbon atom, the heteroaryl being selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, irnidazolyl, pyrazolyl, oxadiazolyl, tnazolyl and tetrazolyl; Xi is H, halo, C1- alkyl, hydroxy, Ci-4 alkoxy, halo-substituted C1-4 alkyl, hydroxy-substituted C1-4 alkyl, (C1-4 alkoxy) (C1-4 alkyl), arnino, (C1-4 alkyl) arn? no, (C1-4 dialkyl) arn? no, arn? no (C1-4 alkyl), (C4-4 alkyl) amino (C1-4 alkyl), (C1-4 dialkyl), amino (alk) C 1-4 alkanoyl), (C 1-4 alkanoyl) arnino, (dialkanoyl C? -4) amino, (C 1-4 alkyl) (C 1-4 alkanoyl) arnino, (C 1-4 alkyl) eulphonylamino, C alkanoyl -4, carboxyl (C 1-4 alkoxy) carbonyl, aminocarbonyl, (C 1-4 alkyl) aminocarbonyl, (C 1-4 alkyl) arninocarbonyl, cyano, nitro, mercapto, (C 1-4 alkyl) thio, (C 1-4 alkyl) sulfinyl, to inosulfonyl, (C 1-4 alkyl) arnino-sulfonyl or (dialkyl-4) amino-ephonyl; X2 and 33 are independently C1-4alkyl, halo, halo-substituted C1-4alkyl, hydroxy, C1-4alkoxy, rnercapto, (C1-4alkyloxy), (C1-4alkyl) sulfinyl, (C1-4alkyl) eulphonyl, C1-4 alkanoyl, carboxyl, (C1-4 alkoxy) carbonyl, aminocarbonyl, (C1-4 alkyl) arninocarbonyl, (dialkylC4) arninocarbonyl, cyano, nitro, amino, (C1-4 alkyl) arnino, (dialkyl C1 -4) amino or (C 1-4 alkyl) eulphonylamino; Y is -CRi = CR 2 - or -CaC-, wherein R 1 and R are independently H, methyl, ethyl or halo; 1 is 0, 1, 2, 3 or 4, and rn and n are independently 0, 1, 2 or e, and a pharmaceutically inert carrier 8. A pharmaceutical composition according to claim 7, wherein flr is phenyl, C3-8 cycloalkyl or C4- cycloalkenyl. 8, or heter-oaryl selected from pyridyl, pyrrolyl and oxazolyl; and 3 are independently C 1-4 alkyl, halo, C 1-4 alkyl substituted, hydroxy, C 1-4 alkoxy, (C 1-4 alkyl) thio, (alkyl) C1-4) sulfinyl or (Ci-4 alkyl) sulfonyl; XI is halo, C 1-4 alkyl, hydroxy, C 1-4 alkoxy, C 1-4 alkyl substituted, C 1-4 hydroxy substituted alkyl, amino (C 1-4 alkyl) arnide, cyano or nitro; l ee O or l; and m and n independently 0 or 1. 9. A pharmaceutical composition according to claim 8, wherein flr is phenyl or C3-8 cycloalkyl; X 2 and X 3 are independently halo, (C 1-4 alkyl) thio, (C 1-4 alkyl) e? Lfinyl or (C 1-4 alkyl) sulfonyl; ? is H, halo, amino, cyano or nitro, which is attached to the 5 or 6 position of the ring seven of the benzimidazole; and Y ee -CR = CR2, wherein R1 and R2 are independently H or methyl. 10. A pharmaceutical composition according to claim 9, wherein flr is phenyl, cyclopentyl or cyclohexyl; X2 and 3 are independently fluoro, rethylthio, ethylsulfinyl or rnethylsulfonyl; X1 ee H, fluoro, chloro, bromo, amino, cyano or nitro, which is attached to the 5-position of the benzimidazole ring system; and Y is -CH = CH-. 11. A pharmaceutical composition according to claim 1, wherein the compound is selected from (E) -l-phenyl-2-styryl-1H-benzimidazole, (E) -2- (4-fluoroetheryl) -1. -phenyl-lH-benzylnidazole, (E) -2- (2-fl? oroestiryl) -l-phenyl-1H-benzimidazole hydrochloride, (E) -5-nitro-l-phenyl-2-styryl-lH- benzimidazole, (E) -5-arnino-l-phenyl-2-eetyryl-lH-benzylnidazole dihydrochloride, (E) -5-bromo-l-phenyl-2-styryl-lH-benzinidazole, (E) -5- cyano-l-feml-2-styryl-lH-benzylnidazole, (E) -2- (2-cyclohexylvinyl) -l-phenyl-lH-benzimidazole, (E) -2- (2-cyclo? entiivinyl) hydrochloride - L-phenol-lH-benzylnidazole and (E) -l-phenyl-2-C2- (2-? iridyl) vinyl] -lH-benzyl-dazole. h < 1, A composition according to claim 11 wherein the compound is selected from (F ") 1 fem 1? - < 11 ii - 1H- bencuru da,: ol, ( ! -) - - ni ti o- 1 - fen i 1 - 2 est iril 1H benc i roí < ta l, (I ") - 5- ci ano- 1 - foni 1 -? -its T. i r-i 1 - 1 H-benzyl dazol and hydrochloride of (F) 2- (2 ci elopenti 1 vi or 1) - 1 leml-lH bonc irn idazol. 13. - The use of the composition according to claim 7, in the preparation of a medicament for the treatment of a medial disorder in which la1--, pr or '? aglandin1, such as pathogens, are involved in a mammalian patient. 14. The use of a compound according to claim 1, in the preparation of compositions for the treatment of a medical disorder in which the p ros are involved.; agí andinas corno pat genos, in a mammalian patient. SUMMARY OF THE INVENTION This invention provides a compound of the following formula and pharmaceutically acceptable salts thereof, wherein Ar is phenyl, C3-8 cycloalkyl, C4-8 cycloalkenyl, or heteroaryl; X and 3 3 are independently C1-4 alkyl, halo, C1-4 alkyl unsubstituted, hydroxy, C1-4 alkoxy, rnercapto, (C1- alkyl) thio, (C1-4 alkyl) s1-linoyl, (Ci- 4 alkyl) eulphonyl or sirnilary groups; ? ee H, halo, C 1-4 alkyl, hydroxy, cyano, nitro, (C 1-4 alkyl), (C 1-4 alkyl) eulfinyl, (C 1 -alkyl) sulfonyl or similar groups, Y is -CR = CR 2 - or -CeC -, wherein R and R2 are independently H, methyl, ethyl or halo; 1 is 0, 1, 2, 3 or 4; and m and n are independently 0, 1, 2 or 3, with the proviso that when flr is phenyl , and 1, rn and n are zero, then Y is not ~ CH = CH-; and when flr is phenyl, 1 and m are zero, n is 1, and Y is -CH = CH-, then X3 is not C1-6 alkoxy. 4 bound to the 2-position of flr or amino, (C 1-4 alkyl) arnino or (C 1-4 dialkyl) arnino linked to the 4-position of flr, and a pharmaceutical composition useful for the treatment of a medical disorder in which they are involved the prostaglandins as pathogens. P97 / 1318 PF / gfr / a e