MXPA97009647A - Derivatives of estirilbencimidazol as inhibitors of proliferation of muscle cells l - Google Patents

Abstract

The present invention relates to compounds of formula (I) or (II), in which R is phenyl or substituted phenyl, or R is furyl, pyridyl or quinolinyl, R and R are hydrogen, halogen, alkyl, alkoxy, nitro, carboxyl , alkoxycarbonyl or aryloxycarbonyl, R is hydrogen, alkyl, or a pharmaceutically acceptable salt thereof, which are both useful as muscle cell proliferation inhibitors li

Description

DERIVATIVES OF R.?TTPTT.BKNrTMTr)?7.0T. TM) PROLIFE ACIÓW DR rfTTTTTTTTTFTHY OF MLTSCOLO SMOOTH DESCRIPTION OF THE INVENTION The present invention relates to styrylbenzimidazole derivatives useful as inhibitors of smooth muscle cell proliferation, and to the use of these compounds and pharmaceutical compositions containing these compounds in the treatment of diseases or conditions related to proliferation of smooth muscle cells, and with a process for the preparation of such compounds. Proliferation and targeted migration of vascular smooth muscle cells are important vascular occlusive components and processes such as vascular remodeling induced by hypertension, vascular restenosis and atherosclerosis (Gibbons, G.H., Dzau, V.J., NEJM, 1994; 330: 1431). The process of total disease is known as hyperproliferative vascular disease based on the etiology of the disease process. Vascular occlusion is preceded by stenosis resulting from intimal smooth muscle cell hyperplasia (Clowes, A.; Reidy, M.A .; J. Vasc. Surg., 1991, 13: 885). The underlying cause of intimal smooth muscle cell hyperplasia is damage REF: 26199 of vascular smooth muscle cells leading to rupture of the endothelium and extracellular matrix (Shhwartz, S.M., Human Pathology, 1987; 8: 240; Fingerle, J., Arterosclerosis, 1990; 10: 1082). Normally, the cells of the arterial wall are under a narrow negative control and in a state of low basal proliferation or in a state of non-proliferation, at rest. After vascular damage, the release of growth factors and cytokines results in proliferation and migration of smooth muscle cells (Fagin, JA; Forrester, JS, Trends in Cardiovascular Med., 1992; 2; 90; Shiratani, M ,. Yui, Y .; Kawai, C., Endothelium, 1993; 1: 5). Vascular damage that leads to hyperplasia of the intima can be induced immunologically or by invasive cardiovascular procedures. Atherosclerosis is a common form of biologically mediated vascular damage that progresses to stenosis. Abnormal proliferation of vascular smooth muscle cells is a characteristic of the atherosclerotic plaques responsible for obstructive lesions of the neointima at the site of intimal damage (Ross, R., Nature, 1993: 362; 801; Cascells,., Circulation , 1992; 86: 723). The mechanical damage that leads to intimal hyperplasia can occur after angioplasty procedures, organ transplant surgery and other invasive vascular procedures that break the vascular integrity (Clowes, AW, Reidy, MA, J. Vasc. Surg., 1991; 13: 885; Isi, FF; McDonald, TO; Ferguson, M.; Yanaka, E., Am. J. Pathol., 1992; 141: 1139). Percutaneous transluminal coronary angioplasty has been widely accepted as a treatment for coronary artery stenosis. In this procedure the endothelium is damaged and exposed to various chemoattractants and mitogens which are either produced in the blood or released at the site of damage. Among these agents, platelet derived growth factor (PDGF) is considered to play a significant role in the smooth muscle cell proliferation and chemotaxis process (Reidy, MA; Fingerle, J.; Lindner, V .; Circulation, 1993: 86 (suppl III): 111-43, Ferns, GAA, Raines, EW, Sprugel, KH, Montani, AS, Reidy, MA, Ross, R., Science, 1991; 253: 1129; Jawien, A; ., et al., J. Clin. Invest., 1992; 89: 507; Nabel, EG, et al., J. Clin. Invest., 1993; 91: 1822). In the next 3 to 6 months after angioplasty, a significant reduction in blood flow occurs in approximately 30-40% of patients as a result of restenosis caused by response to vascular damage during this surgical procedure. These patients then require a second interventional procedure (Pepine, C, Circulation, 1990; 81: 1753; Hardoff, R.J., J. Am. Coil, Cardiol., 1990; 15: 1486). Consequently, agents that limit the process of restenosis would be of significant benefit. Agents that inhibit the proliferation of vascular smooth muscle cells, particularly proliferation stimulated by PDGF would be useful in the treatment of vascular hyperproliferative disorders (Molloy, CJ, Drug Dev. Res., 1993; 29: 148; Newby, AC.; George, SJ, Cardiovasc. Res., 1993; 27: 1173). DE 4,129,603 discloses fused heterocyclic compounds (benzimidazoles) as inhibitors of platelet aggregation induced by collagen and fibrinogen which are also useful in the "transluminal angioplasty treatment". No. 5,387,600 describes substituted 2-thio benzimidazoles for the treatment of atherosclerosis. No. 5,026,705 describes 2-styrylbenzimidazolylpyridazinones as positive inotropic agents useful in the treatment of congestive heart failure. The tuberculostatic activity of 2- [α-cyano-β-arylvinyl] benzimidazole derivatives has been described in Pol. J. Pharmacol: Pharm., 1981, 33, 217 (CA96: 293). WO 9116305 discloses diheterocyclic derivatives of propene and nitrile as cellular antiproliferative agents. US 5,196,446 describes propene indolyl nitriles as cellular antiproliferative agents.

Certain styrylbenzimidazoles are described in Zh. Obshch. Khim. 32, 2624-33 (1962) and Zhumal prikladnoi spektrokopii, Vol 2, No. 1, pp. 63-68 (1995) and Inorganica Chimica Acta, 191 (1992), 131-139. No biological or therapeutic activity is described. Certain 1-benzyl substituted benzimidazoles are described as anti-inflammatory agents in JP Kokai 7481369 and certain benzimidazoles with therapeutic activity are reported in J. Med. Chem. 1970, 13 (4), 784-6. In accordance with this invention, a compound of formula I or formula II is provided II wherein R is phenyl or phenyl substituted by halogen, hydroxyl, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, trifluoromethyl or R is furyl, pyridyl or quinolyl; R x and R 2 are hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, carboxyl, alkoxycarbonyl of 2 to 7 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms; R3 is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms or arylalkyl of 7 to 12 carbon atoms optionally substituted with alkoxycarbonyl of 2 to 6 carbon atoms; R4 and Rs are hydrogen or alkyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof, with the proviso that the compound of formula I is not any of the following: 1-benzyl-5 (6) methyl-2- (2,4-dichlorostyryl) benzimidazole; 5-chloro-2- [(p-chlorophenyl) vinyl] -1-methyl-benzimidazole; 2- [2- (p-chlorophenyl) inyl] -5-methoxy-1-methylbenzimidazole; 2- (p-chlorostyril) -1,5,6-trimethyl-benzimimidazole; 2- (3, 4-dimethoxystyryl) -1-methyl-benzimidazole; 2- [2- (4-chlorophenyl) ethenyl] -1-methyl-lH-benzimidazole; l-methyl-2-styryl-benzimidazole; 2- (p-fluorostyril) -1-methyl-benzimidazole; 2- (p-chlorostyril) -1-methyl-benzimidazole; 2- (p-Bromostyril) -1-methyl-benzimidazole; 2- (p-methoxystyryl) -1-methyl-benzimidazole; 2- (p-Methylstyryl) -1-methyl-benzimidazole; 2- (p-fluoro-styrene) -benzimidazole; 2- (p-chlorostyril) -benzimidazole; 2- (p-bromo-styryl) -benzimidazole, -2- (p-methoxystyryl) -benzimidazole; 2-styryl-benzimidazole; 2- (2-chlorostyril) -l-methyl-benzimidazole. In a further aspect of the present invention there is provided a pharmaceutically acceptable salt of a compound of formula I or II above in which R is phenyl or phenyl substituted by halogen, hydroxyl, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, trifluoromethyl or R is furyl, pyridyl or quinolinyl; R_ and R2 are hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, carboxyl, alkoxycarbonyl of 2 to 7 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms, - R3 is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms or arylalkyl of 7 to 12 carbon atoms optionally substituted with alkoxycarbonyl of 2 to 6 carbon atoms; and R4 and R5 are hydrogen or alkyl of 1 to 6 carbon atoms. According to one of the preferred embodiments of the present invention, there is provided a compound of formula I or II above, wherein R is furyl, pyridyl or quinolinyl; R t and R 2 are hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, carboxyl, alkoxycarbonyl of 2 to 7 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms; R3 is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms or arylalkyl of 7 to 12 carbon atoms optionally substituted with alkoxycarbonyl of 2 to 6 carbon atoms; R4 and R5 are hydrogen or alkyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present invention, there is provided a compound of formula I above, which is wherein R_ and R2 are hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, carboxyl, alkoxycarbonyl of 2 to 7 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms; or a pharmaceutically acceptable salt thereof. "According to a further preferred embodiment of the present invention, there is provided a compound of formula II above in which R is phenyl or phenyl substituted with halogen, hydroxyl, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 atoms of carbon, trifluoromethyl or R is furyl, pyridyl or quinolinyl, R_ and R2 are hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, carboxyl, alkoxycarbonyl of 2 to 7 carbon atoms carbon or aryloxycarbonyl of 7 to 12 carbon atoms: R3 is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms or arylalkyl of 7 to 12 carbon atoms optionally substituted with alkoxycarbonyl of 2 to 6 atoms of carbon, R 4 and R 5 are hydrogen or alkyl of 1 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof R is preferably furyl, pyridyl, phenyl or substituted phenyl Preferred substituents on phenyl are 1-alkoxy; to 6 á carbon atoms, particularly methoxy, preferably R.sup.1 and R.sup.2 are hydrogen, C.sub.1 -C.sub.6 alkoxy, particularly methoxy, nitro, carboxyl, alkoxycarbonyl having 2 to 7 carbon atoms, particularly carboxylic acid or aryloxycarbonyl methyl ester from 7 to 12 carbon atoms, particularly phenylmethanone. R3 is preferably hydrogen or benzyl substituted with alkoxycarbonyl of 2 to 6 carbon atoms, particularly benzoic acid methyl ester. R4 and R5 are preferably hydrogen or methyl.

Particularly preferred compounds are: • E) -2- [2- (3,4-diraetoxyphenyl) -vinyl] -1H-benzoimidazole or a pharmaceutically acceptable salt thereof. • 2- [2- (3, 4-dimethoxy-enyl) -vinyl] -5-methoxy-1H-benzoimidazole or a pharmaceutically acceptable salt thereof. • { 2- [2- (3, -dimethoxyphenyl) -vinyl] -lH-benzoimidazol-5-yl] phenyl-methanone or a pharmaceutically acceptable salt thereof. • 2- [2- (3, 4-dimethoxyphenyl) -vinyl] -4,7-dimethoxy-5,6-dimethyl-1H-benzoimidazole or a pharmaceutically acceptable salt thereof. • (E) -2- [2- (3, 4-dimethoxyphenyl) -vinyl] -lH-benzoimidazole-5-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof. • (E) -2- [2- (3,4-dimethoxyphenyl) -vinyl] -1H-benzoimidazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof. • (E) -2- [2- (3,4-dimethoxyphenyl) -vinyl] -5-nitro-lH-benzoimidazole or a pharmaceutically acceptable salt thereof. • 4-methyl ester. { 2- [2- (3, 4-dimethoxyphenyl) -vinyl] -4,7-dimethoxy-5,6-dimethylbenzoimidazol-1-ylmethyl} -benzoic acid or a pharmaceutically acceptable salt thereof. • 2- [2- (3,4-dimethoxyphenyl) -vinyl] -5,6-dimethyl-1H-benzoimidazole-4,7-dione or a pharmaceutically acceptable salt thereof. • (E) -5-nitro-2- (2-pyridin-4-yl-vinyl) -lH-benzoimidazole or a pharmaceutically acceptable salt thereof. • (E) -2- (2-furan-3-yl-vinyl) -5-nitro-lH-benzoimidazole or a pharmaceutically acceptable salt thereof. The compounds of the present invention are prepared according to the general sequence of reactions indicated in the following scheme: NaH / DMF / R ^ Bi II The iminoether hydrochloride (2) is prepared by reacting an appropriate nitrile with an alcohol and an excess of hydrogen chloride at 0 ° C. The reaction of (2) and the appropriate 1, 2-diaminobenzene in ethanol under reflux affords the corresponding 2-styrylbenzimidazole (4). Alkylation of (4) with an alkyl, aryl or arylalkyl halide in dimethylformamide using sodium hydride as a base provides the compounds of formula I. The compounds of formula II are obtained by oxidation of 1,4-dimethoxy derivatives of formula I with ammonium nitrate and cesium. 2 equivalents of ammonium nitrate and cesium are dissolved in 1: 4 water / acetonitrile and added dropwise to a solution of appropriate 1,4-dimethoxy styrylbenzimidazole and acetic acid. The mixture is heated at 40 ° C for 1 h to obtain the compounds of formula II.

Therefore, according to a further aspect of this invention there is provided a process for the preparation of a compound of formula I or II as defined herein which comprises: (a) reacting a nitrile of formula I as defined herein with an alcohol and hydrogen chloride to form the compound of formula 2, and (b) reacting the compound of formula 2 with a compound of formula 3 as defined herein, in the presence of an alcohol to form the compound of formula 4, and (c) reacting the compound of formula 4 with an R3-halide in the presence of an alkylating agent to form the compound of formula I as defined herein, (d) and optionally reacting the compound of formula 5 as defined herein with (NH4) 2Ce (N) 3) 6 in the presence of acetic acid to form the compound of formula II as defined herein. The pharmaceutically acceptable acid addition salts are those derived from organic or inorganic acids such as: acetic, lactic, citric, fumaric, tartaric; succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, methylbenzenesulfonic acid and similarly acceptable known acids. With those compounds that possess an acidic substituent such as carboxylic acids, pharmaceutically acceptable salts include alkali metal salts (sodium or potassium), alkaline earth metal salts (calcium or magnesium) and ammonium salts. This invention includes pharmaceutical compositions consisting of styrylbenzimidazoles either alone or in combination with excipients (i.e., pharmaceutically acceptable materials without pharmacological effect). Such compositions are useful for diseases which are characterized by excessive proliferation of smooth muscle cells that most frequently arise from vascular reconstructive surgery and transplants, eg, balloon angioplasty, vascular graft surgery, bypass surgery, artery and coronary artery and heart transplant. Other disease states in which unwanted vascular proliferation is observed include hypertension, asthma and congestive heart failure. The compounds of this invention are therefore useful for the treatment of these diseases and morbid states. The compounds of this invention can be administered systemically, for example, by intravenous injection, which usually varies between 0.1 and 10 mg / kg / h for 5-30 days, or by subcutaneous injection at a lower dose, by oral administration at a higher dose with respect to intravenous injection. The localized delivery of the compounds of this invention can also be carried out by transmembrane, transdermal or other topical routes of administration using continuous release devices such as support matrix, when applicable. The compositions of the invention can be formulated with conventional excipients such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and the like. These are formulated in a conventional manner. The compounds can be administered pure or with a solid or liquid pharmaceutical carrier to a patient in need of such treatment. Applicable solid carriers can include one or more substances which also act as flavoring agents, lubricants, solubilizers, suspension improving agents, fillers, glidants, compression aids, binders or tablet disintegrating agents, or a material encapsulant When administered in powder, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the desired shape and size. The powders and tablets preferably contain up to about 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, waxes with low melting point and ion exchange resins. . Liquid carriers can be used to prepare solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of pharmaceutically acceptable oils or fat. The liquid carrier may contain other pharmaceutically suitable additives such as solubilizers, emulsifiers, buffers, preservatives or preservatives, sweeteners, flavoring agents, suspension improving agents, thickening agents, colors, viscosity regulators, stabilizers and osmoregulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly that which contains additives as in the above, "for example, cellulose derivatives, preferably a solution of sodium carboxymethylcellulose), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and their derivatives, and oils (for example fractionated coconut oil and peanut oil.) For parenteral administration, the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate Sterile liquid carriers are used in compositions in sterile liquid form for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used, for example, for intraperitoneal or subcutaneous injection Sterile solutions may also be administered intravenously Oral administration may be in the form of a liquid or solid composition. preferable the pharmaceutical composition a is in unit dosage form, for example, as tablets or capsules. In such form, the composition is subdivided into a unit dose containing the appropriate amounts of the active ingredient; the unit dosage forms may be packaged compositions, for example, packaged powders, flasks, ampoules, pre-filled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be any appropriate amount of any such compositions in package form. Therefore, according to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula I or II as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The dosage to be used in the treatment of a specific patient suffering from a disease involving smooth muscle cell proliferation must be determined subjectively by the attending physician. The variables involved include the specific state of the disease and the size, age and pattern of response of the patient. The compounds are useful for preventing the proliferation of smooth muscle cells in a mammal. Therefore, according to the present invention there is provided a method for the treatment of a mammal, in particular to prevent the proliferation of smooth muscle cells in a mammal, which treatment comprises administering to the mammal, orally or parenterally, a composition of formula I or II as defined herein. Also provided is the use of the compounds of formula I or II as defined herein for the treatment of a mammal, in particular to prevent the proliferation of smooth muscle cells in a mammal, which treatment comprises administering to the mammal, orally or parenterally, a compound of formula I or II as defined herein. Also provided is the use of the compounds of formula I or II as defined herein for the manufacture of a medicament for the treatment of a mammal, in particular, to prevent the proliferation of smooth muscle cells in a mammal, which comprises administering to the mammal, orally or parenterally, a compound of formula I or II as defined herein. The ability of the compounds of the present invention to inhibit the proliferation of smooth muscle cells using porcine aortic smooth muscle cells isolated in a modification of the Castellot et al. J. Biol. Hem 252 (19) 11256 (1982), as follows: Fresh porcine aortas, carefully cleaned and removing the fatty tissue, are moistened in sterile saline buffered with phosphate, with 2% antibiotic-antifungal fluid (100X) (10,000 units of penicillin (base) 10,000 μg of streptomycin (base) and 25 μg of amphotericin B / ml using penicillin G (sodium salt), streptomycin sulfate, and amphotericin B as Fungizone "in 0.85% saline, available from Gibco Laboratories, Grand Island Biological Co., Grand Island, NY) Subsequently the tissue is digested in 10-15 ml of an enzyme solution containing type I collagenase, 165 U / ml; Elastase type III, 15 U / ml; BSA 2 mg / ml; and soybean trypsin inhibitor, 0.375 mg / ml, followed by incubation at 37 ° C under an atmosphere of 5% C02 for 10 to 15 minutes. After this treatment, the outer surface of the adventitia is removed by detachment with a forceps. The aorta is then cut longitudinally and placed open, and the endothelial layer is removed by scraping. The medium cell layer is moistened in the enzyme solution and placed in a new 100 mm container with 10 ml of enzyme solution. The medium cell layer is cut into small pieces using a pair of fine scissors and digested for 2'-3 h at 37 ° C in 30 ml of fresh enzyme solution. After digestion, the medium tissue is homogenized using a sterile Pasteur pipette with a burnished tip, or an Eppendorf pipettor with a sterile pipette tip of 200-1000 μl. The suspension is then centrifuged for 10 minutes at 8000 rpm and the pellet is suspended in 4-6 ml of fresh enzyme solution and sown in plates on 4-6 100 mm flasks with ventilated lids. The cells are then allowed to grow to confluence and divide using 0.25% trypsin. The cells are evaluated for purity and total quality using antibody to SMC actin. The cells are tested in an early passage (generally passage 3-7) under subconfluence conditions.

Cultures are grown in 16-mm multiple well culture vessels (24 wells) in medium 199 supplemented with 10% fetal bovine serum and 2% antibiotic / antifungal. In the subclonfluence, the cells are placed in a defined serum-free lymphocyte medium (AIM-V, Gibco) for 24-48 h before initiating the experimental protocol. The standard test procedure is initiated by addition of the test compound, 3H thymidine and serum or a specific growth factor to the synchronized cells lacking serum. The growth factor and the serum stimulation are optimized for each cell type. The test compounds are added to each well at a 50-fold dilution (20 μl / well) and the plates are incubated for 24-36 hours at 37 ° C in a 5% C02 atmosphere. The test compounds are dissolved in 50% ethanol and assayed at 1, 10 and 100 μM. As a control, RG 50872 (Bilder, G.A., et al., Am. J. Cell, Physiol., 1991; 260: C721) is systematically tested under the conditions of each cell preparation at a concentration of 5 μM. At the end of the experiment, the plates are placed on ice, washed three times with ice-cold PBS and incubated in ice-cold 10% trichloroacetic acid (TCA) for 30 minutes to remove the acid-soluble proteins. Each solution is transferred to a scintillation flask containing 0.4 N HCl (500 μl / vial to neutralize NaOH) and each well is moistened twice with water (500 ml) for a total volume of 2 μl / well. The data are quantified by submitting the flasks to a scintillation counter, in triplicate, both for the controls and for the experimental samples. Control data (100%) are obtained for maximally stimulated cells, as a result of growth factor or serum stimulation. Experimental data are obtained from cells maximally stimulated with growth factor or serum and treated with a test compound. The platelet-derived growth factor used in the assay was recombinant human PDGF-AB purchased from Upstate Biotechnology Inc., Lake Placid, NY. The data are expressed as hundreds of the control from which the ICS0 were determined. To differentiate cytotoxicity from the ability of a compound to prevent proliferation, the test compounds were examined using a commercial modification of the MTT assay. Briefly, the cells are grown in plates of "24 wells up to 70-80% confluence.The cells are deprived of serum for 24-48 hours before the initiation of the experimental protocol.To ensure that the MTT assay monitors toxicity instead of proliferation, the cells were incubated with 50 mM of test compound in fresh medium without serum for 24 hours at 37 ° C in a humidified incubator and with CO2.After completing the compound treatment, the MTT indicator dye was added for 4 h 37 ° C. The cells were then solubilized and aliquots were transferred from each well to a 96 well plate for analysis.The absorbance was recorded at 570 nm wavelength with a reference wavelength of 630 nm using a laser reader. ELISA plates The results are reported as viable percent without the use of a drug (100% viable) and viable pre-solubilization (0%) standards The compounds of the present invention are effective inhibitors. ions of smooth muscle cell proliferation as shown by the data presented in Table 1. Table I The following examples are provided by way of illustration rather than limitation, for representative compounds of the invention and methods for their production.

EXAMPLE 1 Stage 1 Methyl- (3,4-dimethoxy) -cinnamoy idato hydrochloride A suspension of 3,4-dimethoxycinnamonitrile (10 g, 52 mmol) in EtOH (150 ml) is cooled in an ice bath. Subsequently, the cold mixture is saturated with hydrogen chloride. The reaction solution is cooled for 18 h. The precipitate formed is collected by precipitation. The colorless solid provides 8.0 g (60% yield) of methyl- (3,4-dimethoxy) -cinnamoimidate hydrochloride which is used in the next reaction. XH NMR (DMS0-d6; 200 MHz) d 11.8 (broad s, 1H), 1.09 (broad s, 1H), 7.82-7.9 (d, 1H), 7.3 (d, 2H), 7.02-7.12 (d, 1H) ), 6.81-6.9 (d, 1H), 4.2 (s, 3H) and 3.76 (s, 3H), 3.82 ppm (s, 3H).

Stage 2 (E) -2- [2- (3,4-dimethaxyphenyl) -vinyl] -lH-benzoimidazole A mixture of 1,2-phenylenediamine (0.63 g; . 8 mmol) and methyl- (3,4-dimethoxy) -cinnamoimidate hydrochloride (1.5 g, 5.8 mmol) in methanol (35 ml) is stirred at room temperature for 18 hours. The methanol solution is concentrated to dryness. The residue is recrystallized from MeOH-diethyl ether to obtain 1.3 g (67% yield) of the title compound as a monohydrochloride hydrate, yellow solid, m.p. 248 ° C, decomposition. Analysis calculated for C17H16N202 HCl H20: C, 60.98, H, 5.12; N, 8.37. Found: C, 60.78; H, 5.12; N, 8.45. Mass Spectrum: (The; M +) m / z 280. NMR (DMSO-d6; 400 MHz) d 15.2 (broad s, 1H), 8.18-8.2 (d, 1H), 7.76-7.8 (m, 2H), 7.45-7.54 (m, 2H), 7.32 (d, 1H), 7.2-7.3 (m, 3H), 7.08-7.12 (d, 1H), 3.83 (s, H), 3.86 ppm (s, 3H): EXAMPLE 2 2- [2- (3,4-di? Netoxyphenyl) -vinyl] -5-p »taxi-lH-benzoip? Dazol A mixture of 4-methoxy-1,2-phenylenediamine dihydrochloride (1.55 g, 7.3 mmol) and methyl- (3,4-dimethoxy) -cinnamoimidate hydrochloride (1.9 g, 7.3 mmol) in methanol (50 ml) is stirred. at room temperature for 72 hours. The methanol is concentrated to 25 ml. A yellow solid is filtered off. The solid is suspended in MeOH (10 ml) and treated with hydrogen chloride. The formed precipitate is collected to obtain 515 mg (21% yield) of the title compound as a hydrate, monohydrochloride, yellow solid, m.p. 246-249 ° C. Analysis calculated for C13H18N203HC1 H20: C, 61.72, H. 5.20; N, 7.79. Found: C, 61.61; H, 5.37; N, 7.84. Mass Spectrum: (El; M +) m / z 310. l NMR (DMSO-d6; 400 MHz) 6 14.8 (s broad, 1H), 8.3-8.5 (d, 1H), 7.62-7.63 (d, 1H) , 7.3 (d, 1H), 7.21-7.23 (dd 1H), 7.2 (d, 2H), 7.07-7.16 (m, 3H), 3.86-3.88 (d, 6H), 3.82-3.84 ppm (s, 3H) .

EXAMPLE 3 . { 2- [2- (3,4-Dimethoxy-phenyl) -vinyl] -lH-benzoimidazol-5-yl} - phenyl-methanone A mixture of 3,4-diaminobenzophenone is stirred (1.7 g, 8.0 mmol) and methyl- (3,4-dimethoxy) -cinnamoimidate hydrochloride (2.0 g, 8.0 mmol) in methanol (50 ml) at room temperature for 48 hours. The methanol is concentrated to 25 ml. The yellow precipitate formed is filtered off. Recrystallization from MeOH gives 1.14 g (37% yield) of the title compound as a yellow solid, m.p. 211-214 ° C. Analysis calculated for C 24 H 20 N 2 O 3; C, 74.98, H, 5.24; 'N, 7.29. Found: C, 74.88; H, 5.12; N, 7.23. Mass spectrum: (BAR, M + H) m / z 385. XH NMR (DMSO-d6; 400 MHz) d 12.9-13.0 (broad s, 1H), 7.9 (s, 1H), 7.73-7.77 (d, 2H), 7.64 -7.69 (m, 4H), 7.55-7.6 (t, 2H), 7.3 (s, 1H), 7.16-7.22 (d, 2H), 7.0 (d, 1H), 3.83 (s, 3H), 3.8 ppm (s, 3H).

EXAMPLE 4 Step 1 2 3-Riimphthyl-5/6-dinitro-l / 4-dit-N-methoxybenzene A solution of 2,3-dimethyl-l, 4-dimethoxybenzene (16.6 g, 0.1 mol) in acetic acid (100 ml) is cooled in an ice bath, and then concentrated HN03 (40 ml) is added dropwise over 15 minutes. After the addition, the reaction mixture is stirred at room temperature for 3 hours, then heated at 50 ° C for 20 minutes. The solution is concentrated to 75 ml under vacuum and then poured into ice-H20 (350 ml). The yellow precipitate is collected (8.1 g). Recrystallization from EtOH affords 5.4 g (18.5% yield) of 2,3-dimethyl-5,6-dinitro-l, 4-dimethoxybenzene as a yellow solid, m.p. 147-150 ° C.

Stage 2 2/3-diptetyl-5,6-o! Ia i-o-l / 4-? Pwtco benzene Heat 2,3-dimethyl-5,6-dinitro-l, 4-dimethoxybenzene (4.0 g, 15 mmol) in EtOH (120 mL) to solution and add 10% palladium on activated charcoal (1.0 g). The reaction mixture is hydrogenated at 3.2 kg / cm2 (45 psig) for 3 hours. After the treatment, 2.41 g (83% yield) of 2,3-dimethyl-5,6-diamino-1,4-dimethoxybenzene are obtained as a yellow solid, m.p. 107-110 ° C.

Step 3 2- [2- (3,4-Dimethoxyphenyl) -vinyl] -4,7-dimethoxy-5,6-dimethyl-lH-benzoimidazole A mixture of 2,3-dimethyl-5,6-diamino-1,4-dimethoxybenzene (2.57 g, 10 mmol) and methyl (3,4-di ethoxy) -cinnamoimidate hydrochloride (1.96 g, 10 mmol) in Methanol (35 ml) is stirred at room temperature for 18 hours. The methanol solution is concentrated to 15 ml. The yellow precipitate is filtered off. Recrystallization from MeOH provides 2.1 g (58% yield) of the title compound as a yellow solid, m.p. 116-119 ° C. Analysis calculated for C21H24N204: C, 66.46, H, 6.57; N, 7.60. Found: C, 66.83; H, 6.64; N, 7.41. Mass Spectrum: (The; M +) m / z 368. ^ H NMR (DMSO-d6; 400 MHz) d 12.4-12.5 (s broad, 1H), 7.6 - 7.4 (d, 1H), 7.2 (d, 1H ), 7.07-7.16 (m, 2H), 7.0 (d, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 2.2 ppm (s, 3H).

EXAMPLE 5 Methyl ester of (E) -2- [2- (3,4-dimethoxyphenyl) -vinyl] -lH-benzoimidazole-5-carboxylic acid A mixture of 1,2-diamino-4-methylcarboxybenzene (3.6 g, 20 mmol) and methyl (3,4-dimethoxy) -cinnamoimidate hydrochloride (5.4 g, 20 mmol) in methanol (150 ml) are stirred at room temperature for 48 hours. The solution is concentrated to dryness. The residue recrystallized from MeOH to obtain 3.8 g (56% yield) of the title compound as a yellow solid, m.p. 185-188 ° C. decomposition. Analysis calculated for C19H1BN204. C, 67.45, H, 5.36; N, 8.28. Found: C, 67.25; H, 5.45; N, 8.28. Mass Spectrum: (El; M *) m / z 338. XH NMR (DMSO-d6; 400 MHz) d 12.9 (broad s, 1H), 8.1 (s, 1H), 7.63-7.69 (d, 1H), 7.57-7.62 (d, 1H), 7.33 (d, 1H), 7.17-7.21 (dd, 1H), 7.14-7.19 (d, 1H), 7.08-7.12 (d, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.79 ppm (s, 3H).

EXAMPLE 6 (E) -2- [2- (3 4-dimethoxyphenyl) -vinyl] -lH-benzoimidazole-5-carboxylic acid A mixture of 2- [2- (3, 4-dimethoxyphenyl) -vinyl] -lH-benzoimidazole-5-carboxylic acid methyl ester (3.5 g; 11 mmole) in MeOH (75 ml) and a 2.5N NaOH solution (7.5 ml) is refluxed for 3 hours. The reaction mixture is cooled to room temperature and stirred for 18 hours. The reaction mixture is concentrated to dryness. The residue is dissolved in H20 and acidified with 2N HCl. The precipitate is collected. Recrystallization from MeOH affords 600 mg (15%) of the title compound as a creamy solid, monohydrochloride, m.p. higher than 285 ° C. Analysis calculated for C18H16N204 HCl: C, 59.92, H, 4.75; N, 7.76. Found: C, 59.62; H, 4.80; N, 7.66. Mass Spectrum: (El; M *) m / z 324. XH NMR (DMSO-d6; 400 MHz) d 13.5 (broad s, 1H), 8.24 (d, 1H), 8.14-8.2 (d, 1H), 8.02-8.06 (dd, 1H), 7.8 (d, 1H), 7.34 (d, 1H), 7.26-7.28 (dd, 1H), 7.2-7.24 (d, 1H), 7.1 (d, 1H), 3.87 ( s, 3H), 3.83 ppm (s, 3H).

EXAMPLE 7 (E) -2- [2- (3,4-dimethoxyphenyl) -vinyl] -5-nitro-lH-benzoimidazole A mixture of 4-nitro-1,2-phenylenediamine (1.2 g, 8 mmol) and methyl (3,4-dimethoxy) -cinnamoimidate hydrochloride (2.0 g, 8 mmol) in methanol (70 ml) is refluxed for 18 hours. The solution is concentrated to dryness. The residue is recrystallized from MeOH to obtain 603 mg (23% yield) of the title compound as a yellow solid, m.p. 223-225 ° C. Analysis calculated for C 17 H 15 N 304 HCl: C, 62.76, H, 4.65; N, 12.92. Found: C, 62.67; H, 4.62; N, 13.05. Mass Spectrum: (The; M +) m / z 325. XH NMR (DMSO-d6; 400 MHz) d 13.2 (broad s, 1H), 8.4 (broad s, 1H), 8.1 (dd, 1H), 7.74 ( s, 1H), 7.62-7.72 (m, 1H), 7.35 (d, 1H), 7.19-7.23 (dd, 1H), 7.17 (S, 1H), 7.0 (d, 1H), 3.85 (s, 3H) 3.8 ppm (s, 3H).

EXAMPLE 8 Methyl ester of 4- acid. { 2- [2- (3,4-Dimethoxyphenyl) -vinyl] -4-dimethoxy-5-dimethyl-benzoimidazol-1-ylmethyl} - benzoic To a suspension of sodium hydride, 60% dispersion in oil (150 mg, 3.5 mmol) in 20 ml of DMF, is added dropwise for 5 minutes. { 2- [2- (3, 4-dimethoxyphenyl) -vinyl] -4,7-dimethoxy-5,6-dimethyl-lH-benzoimidazole (1.2 g, 3.25 mmol) in DMF (20 ml). After the addition, the reaction mixture is stirred at room temperature for 30 minutes, and then methyl 4- (bromomethyl) benzoate (745 mg, 3.25 mmol) in DMF (10 ml) is added. The reaction mixture is stirred at room temperature for 4 hours. DMF is concentrated to a residue and H20 is added. The solid is collected by filtration. Recrystallization from MeOH provides 620 mg (37% yield) of the title compound as a light yellow solid, hemihydrate, m.p. 111-114 ° C. Analysis calculated for C30H32N2O6 -0.5 H20; C, 68.56, H, 6.33; N, 5.33. Found: C, 68.51; H, 6.27; N, 5.28. Mass Spectrum: (The; M +) m / z 516. XH NMR (DMSO-d6; 400 MHz) d 7.9 (d, 2H), 7.72-7.78 (d, 1H), 7.31 (d, 1H), 7.2- 7.26 (m, 4H), 6.95 (d, 1H), 5.9 (s, 2H), 4.12 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 353 (S3H),, 6H).

EXAMPLE 9 2- [2- (3,4-dimethoxyphenyl) -vinyl] -5,6-dimethyl-1H-benzoinrydazole-4,7-dione To a solution of 2- [2- (3, 4-dimethoxyphenyl) -vinyl] -4,7-dimethoxy-5,6-dimethyl-lH-benzoimidazole (2.0 g, 5.4 mmol) in acetic acid (15 ml), Ammonium nitrate nitrate (7.25 g, 13 mmol) in 15 ml (H20 / CH3CN, 3/12) is added dropwise. The reaction mixture is heated at 40 ° C for 1 hour. After cooling, the solid is filtered off and the filtrate is concentrated to dryness, mixed with water and filtered. The red solid is dried at 60 ° C under vacuum, suspended in MeOH and treated with hydrogen chloride to provide 243 mg (13.5% yield) of the title compound as a dark brown solid, quarter hydrate, m.p. 248 ° C decomposition. Analysis calculated for C19H18N204 -0.25 H20: C, 66.68, H, 5.33; N, 8.22. Found: C, 66.84; H, . 32; N, 8.09. Mass Spectrum: (El; M +) m / z 338. XH NMR (DMSO-d6; 400 MHz) d 7.6-7.67 (d, 1H), 7.22 (d, 1H), 7.1- 7.14 (dd, 1H), 6.9-7.0 (d 1H), 6.94-6.98 (d, 1H) , 3.82 (s, 3H), 3.78 (s, 3H), 1.9 ppm (s, 6H).

EXAMPLE 10 (E) -5-Nitro-2- (2-pyridin-4-yl-vinyl) -lH-benzoi-idazole A mixture of 4-pyridylacrylic acid (1.6 g; mmol), 4-nitro-l, 2-phenylenediamine (1.5 g, 10 mmol) and polyphosphoric acid (15 g) is heated at 110 ° C for 2.5 hours. The reaction mixture is cooled to 50 ° C, then H20 (100 ml) is poured onto ice. The insoluble material is separated by filtration and the filtrate is basified to pH 8 with ammonium hydroxide. The solid (2.3 g) is subjected to flash chromatography on silica gel (CH2Cl2 / MeOH; 9: 1) to provide 735 mg (28% yield) of the title compound as a yellow solid, m.p. higher than 280 ° C. Analysis calculated for C 14 H 10 N 4 O 2: C, 63.15, H, 3.79; N, 21.04. Found: C, 69.92; H, 3.78; N, 21.08. Mass Spectrum: (El; M +) m / z 266. XH NMR (DMSO-d6; 400 MHz) d 13.44 (broad s, 1H) 8.63 (dd, 2H), 8.35-8.55 (broad d, 1H), 8.03 -8.18 (broad s, 1H), 7.69-7.83 (broad d, 2H), 7.65-7.7 (dd, 2H), 7.52-7.59 ppm (s, 1H).

EXAMPLE 11 Step 1 2-furanacryloimidate hydrochloride A solution of 2-furanacrylonitrile (10.9 g, 91 mmoles) in EtOH (75 ml) is cooled in an ice bath. Then the cold mixture is saturated with hydrogen chloride. The reaction solution is cooled for 18 hours. The reaction mixture is concentrated to 20 ml and diethyl ether is added. The brown solid provides 10.5 g (63% yield) of 2-furanacryloimidate hydrochloride which is used in the next reaction.

Stage 2 (E) -2- (2-furan-3-yl-vinyl) -5-nitro-lH-benzoimidazole A mixture of 4-nitro-1,2-phenylenediamine (1.53 g, 10 mmol) and 2-furanacryloimidate hydrochloride (2.21 g, 11 mmol) in ethanol (50 ml) is refluxed for 4 hours. The solution is concentrated to dryness. The residue is dissolved in MeOH and treated with activated carbon to obtain 660 mg (25% yield) of the title compound as a yellow solid, m.p. 230-233 ° C. Analysis calculated for C 13 H 9 N 303: C, 61.18, H, 3.55; N, 16.46. Found: C, 60.97;; H, 3.29; N, 16.15. Mass Spectrum: (El; M +) m / z 255. * H NMR (DMSO-d6, 400 MHz) ñ 13.2 (broad s, 1H), 8.4 (broad s, 1H), 8.1 (dd, 1H), 7.9 (d, 1H), 1. 62 - 1. 8 (m, 2H), 6.92-7.0 (d, 1H), 6.88 (d, 1H), 6.6 ppm (d, 1H).

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (23)

1. A compound characterized in that it is of formula I or II: II wherein: R is furyl, pyridyl, phenyl or phenyl substituted with alkoxy of 1 to 6 carbon atoms; R? and R2 are hydrogen, halogen, alkoxy of 1 to 6 carbon atoms, nitro, carboxyl, alkoxycarbonyl of 2 to 7 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms; is hydrogen, or benzyl, substituted with alkoxycarbonyl of 2 to 6 carbon atoms; R4 and R5 are hydrogen or methyl; with the proviso that in formula I, R1 # R2 and R3 are not all hydrogen, and with the proviso that when R is phenyl or pyridyl, one of R1 and R2 is not nitro when the other is hydrogen, with the proviso that the compound of formula I is not 2- [2- (3,4-dimethoxyphenyl) -vinyl] -1H-benzimidazole.

2, A compound characterized in that it is of formula I, which is: wherein R1 and R2 are hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, carboxyl, alkoxycarbonyl of 2 to 7 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms , R_, R2 and R3 are not all hydrogen and with the proviso that when R is phenyl or pyridyl, one of Rx and R2 are not nitro when the other is hydrogen; or a pharmaceutically acceptable salt.

3. A compound, characterized in that it is E) -2- [2- (3, 4-dimethoxyphenyl) -vinyl] -lH-benzoimidazole or a pharmaceutically acceptable salt thereof.

4. A compound, characterized in that it is 2- [2- (3,4-dimethoxyphenyl) -vinyl] -5-methoxy-1H-benzoimidazole or a pharmaceutically acceptable salt thereof.

5. A compound, characterized because it is. { 2- [2- (3, 4-dimethoxyphenyl) -vinyl] -lH-benzoimidazol-5-yl] phenyl-methanone or a pharmaceutically acceptable salt thereof.

6. A compound, characterized in that it is 2- [2- (3,4-dimethoxyphenyl) -vinyl] -4,7-dimethoxy-5,6-dimethyl-1H-benzoimidazole or a pharmaceutically acceptable salt thereof.

7. A compound, characterized in that it is (E) -2- [2- (3, 4-dimethoxyphenyl) -vinyl] -1H-benzoimidazole-5-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof.

8. A compound, characterized in that it is (E) -2- [2- (3, 4-dimethoxyphenyl) -vinyl] -lH-benzoimidazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof.

9. A compound, characterized because it is 4- methyl acid ester. { 2- [2- (3, 4-dimethoxyphenyl) -vinyl] -4,7-dimethoxy-5,6-dimethylbenzoimidazol-1-ylmethyl} -benzoic acid or a pharmaceutically acceptable salt thereof.

10. A compound, characterized in that it is 2- [2- (3, 4-dimethoxyphenyl) -vinyl] -5,6-dimethyl-lH-benzoimidazole-4,7-dione or a pharmaceutically acceptable salt thereof.

11. A compound, characterized in that it is (E) -5-nitro-2- (2-pyridin-4-yl-vinyl) -lH-benzoimidazole or a pharmaceutically acceptable salt thereof.

12. A compound, characterized in that it is (E) -2- (2-furan-3-yl-vinyl) -5-nitro-lH-benzoimidazole or a pharmaceutically acceptable salt thereof.

13. A compound characterized in that it is of formula I or II: II in which: R is phenyl or phenyl substituted with halogen, hydroxyl, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, trifluoromethyl or R is furyl, pyridyl or quinolyl; R? And R2 are hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, carboxyl, alkoxycarbonyl of 2 to 7 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms; R3 is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms or arylalkyl of T to 12 carbon atoms optionally substituted with alkoxycarbonyl of 2 to 6 carbon atoms; R4 and R5 are hydrogen or alkyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof, with the proviso that in formula I when R is phenyl, furan-3-yl or pyrid-3-yl, Rlf R2 and R3 are not all hydrogen, and when R is phenyl substituted and one of Rj or 2 is hydrogen, chlorine or nitro, and the other is hydrogen, then R3 is not hydrogen, methyl or benzyl, and with the additional proviso that when R3 is benzyl, R is not styrylbenzimidazole or 2,4-dichlorostyrylbenzimidazole , and with the proviso that when Rx or R2 is H, nitro or chlorine and R3 is hydrogen, then R is not phenyl substituted with chlorine, and with the proviso that when one of R or R2 is bromine and R3 is hydrogen, then R is not phenyl; and with the additional proviso that when R is 2 -furyl and one of R1 and R2 is nitro, then R3 is not hydrogen, for use in the treatment of mammals.

14. A compound, characterized in that it is of the formula: 2- [2- (3, 4-dimethoxyphenyl) -vinyl] -4,7-dimethoxy-5,6-dimethyl-lH-benzoimidazole; or methyl acid 4- ester. { 2- [2- (3,4-dimethoxyphenyl) -vinyl] -4,7-dimethoxy-5,6-dimethylbenzoimidazol-1-ylmethyl} -benzoic; or a pharmaceutically acceptable salt thereof, for use in the treatment of mammals.

15. The compound according to claim 13 or 14, characterized in that it is for use in the treatment of diseases or conditions related to proliferation of smooth muscle cells.

16. The compound according to claim 15, characterized in that the proliferation of smooth muscle cells manifests itself as restenosis after angioplasty.

17, The use of a compound of formula I or II II wherein: R is phenyl or phenyl substituted by halogen, hydroxyl, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, trifluoromethyl or R is furyl, pyridyl or quinolinyl; R_ and R2 are hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, carboxyl, alkoxycarbonyl of 2 to 7 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms; R3 is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl optionally substituted by alkoxycarbonyl of 2 to 6 carbon atoms; R4 and R5 are hydrogen or alkyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof, the use is characterized in that it is for the manufacture of a medicament for the prevention of proliferation of smooth muscle cells in a mammal.

18. The use of a compound characterized in that it is of the formula: 2- [2- (3, 4-dimethoxyphenyl) -vinyl] -4,7-dimethoxy-5,6-dimethyl-lH-benzoimidazole; or methyl acid 4- ester. { 2- [2- (3,4-dimethoxyphenyl) -vinyl] -4,7-dimethoxy-5,6-dimethylbenzoimidazol-1-ylmethyl} -benzoic; or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention of proliferation of smooth muscle cells in a mammal.

19. The use of a compound according to claim 17 or 18 characterized in that the proliferation of smooth muscle cells manifests itself as restenosis after angioplasty.

20. A pharmaceutical composition, characterized in that it comprises a compound of formula I or II, according to any of claims 1 to 13, and a pharmaceutically acceptable carrier.

21, The use of compounds of formula I or II, characterized in that they are for the manufacture of a medicament for the treatment of proliferation of smooth muscle cells in a mammal comprising administering to the mammal, orally or parenterally, a compound of formula I or II: II wherein: R is phenyl or phenyl substituted by halogen, hydroxyl, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, trifluoromethyl or R is furyl, pyridyl or quinolinyl; R? and R 2 are hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, carboxyl, alkoxycarbonyl of 2 to 7 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms; R3 is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl optionally substituted by alkoxycarbonyl of 2 to 6 carbon atoms; R4 and Rs are hydrogen or alkyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.

22 * Use in accordance with the claim 21, characterized for the manufacture of a medicament for the treatment of the proliferation of smooth muscle cells, which manifests itself as restenosis after angioplasty.

23. A process for the preparation of a compound of formula I or II: II in which : R is phenyl or phenyl substituted by halogen, hydroxyl, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, trifluoromethyl or R is furyl, pyridyl or quinolinyl; ? and R 2 are hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, carboxyl, alkoxycarbonyl of 2 to 7 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms; R3 is hydrogen, alkyl of 1 to 6 carbon atoms, or benzyl optionally substituted with alkoxycarbonyl of 2 to 6 carbon atoms; R4 and R5 are hydrogen or alkyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof, the process is characterized in that it comprises: (a) reacting a nitrile of formula 1 with an alcohol and hydrogen chloride to form the compound of formula 2: (b) reacting the compound of formula 2 with a compound of formula 3: in the presence of an alcohol to form the compound of formula 4: (c) reacting the compound of formula 4 with R3-halide in the presence of an alkylating agent to form the compound of formula I: (d) and option the compound of formula 5: with (NH4) 2Ce (N) 3) 6 in the presence of acetic acid to form the compound of formula II: II