MXPA97009462A - Heterociclic acrylonitriles as inhibitors of the proliferation of muscle cells - Google Patents

Abstract

Disclosed herein are compounds of the formula (I) wherein Ar1 and Ar2 are, independently, pyridinyl, quinolinyl, dihydro-1,4-benzodioxinyl, pyrrolyl, azaindolyl or carbazolyl or a pharmaceutically acceptable salt thereof, which are useful as inhibitors of muscle cell proliferation li

Description

ACRYLONITRILES HETEROCICUCOS AS INHIBITORS OF THE PROLIFERATION OF SMOOTH MUSCLE CELLS This invention relates to diheterocyclic styryl nitriles which are 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 and conditions associated with the proliferation of muscle cells. excess smooth, such as restinosis, and to a process for the preparation of such compounds. The proliferation and direct migration of vascular smooth muscle cells are vascular occlusive components, important in such procedures as vascular remodeling induced by hypertension, vascular restinosis, and atherosclerosis (Gibbons, GH; Dzau, VJ; NE.JM, 1994; 330; : 1431). The total disease procedure is referred to as hyperproliferative vascular disease based on the etiology of the disease procedure. Vascular occlusion is preceded by stenosis resulting from intimal, smooth muscle cell hyperplasia REF: 26214 (Clo is, A.W., Reidy, M.A .; J. Vasc. Surg., 1991, 13: 885). The preceding cause of intimal smooth muscle cell hyperplasia is vascular smooth muscle cell damage that leads to the disruption of the endothelium and the extracellular matrix (Schwartz, SM, Human Pathology, 1987; 18: 240; Fingerle , J., Arteriesclerosis, 1990; 10: 1082). Normally, the cells of the arterial wall are under closed negative control and in a state of low basal proliferation or in a non-proliferative, quiescent state. After vascular damage, the release of growth factors and cytokines results in the proliferation and migration of smooth muscle cells (Fagin, JA; Forrester, JS, Trends in Cardiovascular Med., 1992; 2; 90; Shiratini, M; Yui, Y; Kawai, C, Endothelium, 1993; 1: 5). The vascular damage that leads to intimal hyperplasia can be induced immunologically or by invasive cardiovascular procedures. Atherosclerosis is a common form of biologically vascular damage that progresses to stenosis. Abnormal proliferation of vascular smooth muscle cells is a characteristic of atherosclerotic plaques responsible for obstructive neo-intimal lesions at the site of intimate damage (Ross, R., Nature, 1993: 362; 801; Cascells, W., Circulation, 1992; 86: 723). The mechanical damage that leads to intimal hyperplasia can occur following the procedures of angioplasty, transprtertectomy-cte '"organs- -other invasive, vascular procedures that disrupt vascular integrity (Clowes, AW., Reidy, MA, J. Vasc Surg., 1991; 13: 885; Isik, FF; McDonald, TO; Ferguson, M .; Yana, E., Am., J. Pathol., 1992; 141: 1139.) Transluminal coronary angiosplasty, percutaneous Achieved wide acceptance for the treatment of coronary artery stenosis In this procedure the endothelium is damaged and exposed to a variety of chemoattractants and mitogens that are either carried by the blood or released at the site of damage. agents, the platelet derived growth factor (PDGF) is thought to play a significant role in the smooth muscle cell proliferation and chemotaxis procedure (Reidy, MA; Fingerle, J .; Lindner, V .; Ci ' rculation, 1993: 86 (suppl III): 111-4 3, Ferns, G.A.A .; Raines, E.W .; Sprugel, K.H .; Montani, A.S .; Reidy, M.A .; Ross, R .; Science, 1991; 253: 1129; Jawien, A., et al., J. Clin. Invest., 1992; 89: 507; Nabel, E.G. and collaborators, J. Clin. Invest., 1993; 91: 1822). Within 3 to 6 months after the angioplasty, a significant reduction in blood flow occurs in approximately 30-40% of patients as a result of restenosis caused by the response to vascular damage during this 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). Therefore, the agents that limit the restenosis procedure 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 hyperproliferative, vascular disorders (Molloy, CJ, Drug Dev. Res., 1993; 29: 148; Newby, AC; George, SJ, Cardiovasc. Res, 1993; 27: 1173). Patent WO 9218418 describes 3-heteroaryl-2-phenyl-2-propenenitriles as EGF receptor tyrosine kinase inhibitors useful for the inhibition of cell proliferation. WO 9116305 describes some mono and some 2, 3-diheterocyclic propane nitriles as cellular antiproliferative agents. This invention relates to the use of diheterocyclic styryl nitrile derivatives as inhibitors of the proliferation of smooth muscle cells and as therapeutic compositions for the treatment of diseases and conditions characterized by the proliferation of smooth, excess muscle cells such as restenosis. . In accordance with this invention a compound of the formula I is provided: wherein Ari and Ar2 are, independently, pyridinyl, quinolinyl, dihydro-1,4-benzodioxinyl, pyrrolyl, azaindolyl or carbazolyl optionally substituted with alkyl of 1 to 4 carbon atoms, or a pharmaceutically acceptable salt thereof. Particularly preferred compounds are those where Ari is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, quinolinyl, dihydro-1,4-benzodioxinyl, pyrrolyl, pyrrol- [2, 3-b] pyridin- 3- ilo) or carbazolyl and those where Ar2 is pyridin-3-yl. When the carbazolyl group is substituted with alkyl of 1 to 4 carbon atoms, it is preferably replaced with methyl or ethyl and is preferably substituted in the 9-position, in particular 9-ethyl. The compounds of the invention can exist as stereoisomers. A particularly preferred isomeric form is the Z-form. Particularly preferred compounds are: • Z-2- (pyridin-3-yl) -3- (pyridin-4-yl) -acrylonitrile or a pharmaceutically acceptable salt thereof. • 2-pyridin-3-yl-3-quinolin-4-yl-acrylonitrile or a pharmaceutically acceptable salt. • 3- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -2-pyridin-3-yl-acrylonitrile or a pharmaceutically acceptable salt thereof. • 2-pyridin-3-yl-3-pyridin-2-yl-acrylonitrile or a pharmaceutically acceptable salt thereof. • 2,3-di-pyridin-3-yl-acrylonitrile or a pharmaceutically acceptable salt thereof. • 2- (pyridin-3-yl) -3- (lH-pyrrolo [2, 3-b] pyridin-3-yl) -acrylonitrile or a pharmaceutically acceptable salt thereof. • (Z) -3- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -2- (1H-pyrrol [2, 3-b] pyridin-3-yl) -acrylonitrile or a pharmaceutically acceptable salt thereof. • (Z) -3- (9-ethyl-9H-carbazol-3-yl) -2- (pyridin-3-yl) acrylonitrile or a pharmaceutically acceptable salt thereof. • 2- (pyridin-3-yl) -3- (1H-pyrrol-2-yl) -acrylonitrile or a pharmaceutically acceptable salt thereof.

The diheterocyclic styryl nitriles were prepared by the condensation of an appropriate heterocyclic aldehyde (Ari) with an appropriate heterocyclic acetonitrile (Ar2). The condensation is carried out in ethanol using piperidine or sodium methoxide as a base.

Ar, CHO + Ar2CH2CN ° "» '»S?' BASE CN When Ar is 7-azaindole, 7-azaindole acetonitrile (3) is prepared by reacting 7-azaindole with dimethylamine and formaldehyde in refluxing butanol to obtain 7- (3-di-methylaminomethyl) azaindole (2) . Quaternization of (2) with dimethyl sulfate in tetrahydrofuran, followed by reaction with potassium cyanide in water gives acetonitrile (3). Thus, in accordance with a further aspect of the present invention there is provided a process for the preparation of a compound of the formula I as defined herein, which comprises condensing an aldehyde of the formula AriCHO with an acetonitrile of the formula Ar2CH2CN where Ari and Ar2 are previously defined to form the compound of the formula I; and optionally forms the pharmaceutical salt thereof. Accordingly, even a further aspect of the present invention provides a process for the preparation of Ar2CH2CN wherein Ar2 is 7-azaindole which comprises reacting 7-azaindole with dimethylamine to give the compound of formula 2 as defined herein. of quaternizing the compound of formula 2 followed by the reaction with a cyanide to form Ar2CH2CN.

The pharmaceutically acceptable salts are those derived from such organic and inorganic acids as; acetic, lactic, citric, fumaric, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methane sulfonic, methylbenzene sulphonic, and similarly acceptable, known acids. This invention includes pharmaceutical compositions comprised of diheterocyclic styryl nitriles of the invention either alone or in combination with excipients (ie, pharmaceutically acceptable materials without pharmacological effect). Such compositions are useful in the treatment of diseases that are characterized by the proliferation of smooth, excess muscle cells, most frequently arising from vascular reconstructive surgery and transplantation, eg, balloon angioplasty, vascular graft surgery, bypass surgery of the coronary artery, and transplantation of the heart. Other disease states in which there is unwanted vascular proliferation include hypertension, asthma and congestive heart failure. In this way, the compounds of this invention are useful for the treatment of these diseases and conditions.

The compounds of this invention can be administered systemically, for example by intravenous injection, typically ranging from 0.1 to 10 mg / kg / h for 5-30 days, by subcutaneous injection at lower doses or by oral administration at more doses. high than the intravenous injection. The localized delivery of the compounds of this invention can also be achieved by means of. routes of transmembrane, transdermal or other topical administration routes using appropriate continuous release devices such as a support matrix, where 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 that can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binding substances or tablet disintegrating agents or an encapsulating material. In the powders, the carrier is a finely divided solid that is mixed with the active ingredient, finely divided. 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 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidine, low melting point waxes and resins of ion exchange Liquid carriers can be used in the preparation of 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 both or oils or fat pharmaceutically acceptable. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, dulsifiers, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives such as the above for example cellulose derivatives, preferably sodium carboxymethyl cellulose solution), 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 can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in liquid form, sterile compositions for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used by, for example, intramuscular, intraperitoneal or subcutaneous injection. The Sterile solutions can also be administered intravenously. Oral administration can be either liquid or solid composition form. Preferably the pharmaceutical composition is in dosage unit form, for example, as tablets or capsules. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example powders, vials, ampoules, pre-filled syringes or sachets containing liquids, packed. The unit dose form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Thus, in accordance with a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The dose to be used in the treatment of a specific patient suffering from a disease that involves the proliferation of cells The smooth muscle must be subjectively determined by the attending physician or practitioner. The variables involved include the specific disease status and the size, age and response pattern of the patient. A compound of formula I as defined herein for use in the treatment of mammals, in particular for use in the treatment of diseases or conditions related to the proliferation of smooth muscle cells. The ability of the compounds of the present invention to inhibit the proliferation of smooth muscle cells was established using porcine aortic smooth muscle cells isolated in a modification of the procedure of Castellot et al. J. Biol. Chem 257 (19) 11256 (1982 ), as follows: Fresh porcine aortas, scrupulously cleansed of fatty tissue, are rinsed in saline buffered with phosphate, sterile with 2% antibiotic-antifungal fluid (lOOx) (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). The tissue is then digested in 10-15 mL of an enzyme solution containing type I collagenase, 165 U / mL; Type II elastase, 15 U / mL; BSA, 2 mg / mL; and soybean trypsin inhibitor, 0.375 mg / mL, followed by incubation at 37 ° C under a 5% C02 atmosphere for 10 to 15 minutes. After this treatment, the adventitia of the outer surface is removed by peeling with a forceps. The aorta is then cut longitudinally and opened and the endothelial layer is removed by scraping. The middle layer of cells is rinsed in the enzyme solution, and placed in a 100 mm dish, new with 10 mL of enzyme solution. The medium cell layer is chopped using a pair of fine scissors and digested for 2-3 hours at 37 ° C in 30 mL of fresh enzyme solution. After digestion, the medium tissue is homogenized using a sterile Pasteur pipette with a fire-polished nozzle or "an Eppendorf pipette with a sterile pipette nozzle 200-1000 μL. The suspension is then centrifuged for 10 minutes at 8000 rpm and the pellets are suspended in 4-6 mL of fresh enzyme solution and placed in 4-6 100-mm flasks with caps with ventilation holes. 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 antibodies to the SMC actin. The cells are tested in the first steps (in general step 3-7) under subconfluent conditions. Cultures are grown in 16-well multiple wells (24 wells) culture plates in 199 mediums supplemented with 10% fetal bovine serum and 2% antibiotic / anti-icotic. In the subconfluence, the cells are placed in a defined serum-free lymphocyte medium (AIM-V, Gibco) for 24-48 hours before initiating the experimental protocol. The normal test procedure is initiated by the addition of the test compound, 3H-thymidine and serum or a specific growth factor to the serum deprived of synchronized cells. The growth factor and serum stimulations are optimized for each type of cell. The test compounds are added to each well in 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 routinely assayed under the conditions of each cell preparation at a concentration of 5 μM. At the completion 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 vial containing 0.4 N HCl (500 μL / vial to neutralize NaOH) and each well is rinsed twice with water (500 μL) for a total volume of 2 mL / vial. The data are expressed in quantitative terms by holding the flasks to a scintillation counter, in triplicate, for both control and experimental samples. The control data (100%) is obtained from maximally stimulated cells, as the result of stimulation with the growth factor or serum. The data Experiments are obtained from the cells maximally stimulated with the growth factor or serum and treated with a test compound. (The platelet derived growth factor used in the assay was human recombinant PDGF-AB obtained from Upstate Biotechnology Inc., Lake Placid, NY). The data is expressed as one percent of the control from which the CI5oa are determined. To distinguish cytotoxicity from the ability of a compound to prevent proliferation, the test compounds were examined using a commercial modification of the MTT assay. In summary, the cells were developed in 24-well plates at the confluence of 70-80%. The cells were deprived of serum for 24-48 hours before the initiation of the experimental protocol. To ensure that the MTT assay monitored the toxicity preferably than the proliferation, the cells were incubated with the 50 mM test compound in a fresh medium without serum for 24 hours at 37 ° C in a humidified C02 incubator. At the completion of the treatment of the compound, an MTT indicator dye was added for 4 hours at 37 ° C. The cells were then solubilized and the aliquots from each well were transferred to a 96-well plate.

Wells for analysis. Absorbance at 570 mm wavelength with a reference wavelength of 630 nm was recorded using an ELISA plate reader. The results are reported as viable percent using norms without drug (viable at 100%) and pres-solubilization (viable at 0%). The compounds of the present invention are effective inhibitors of the proliferation of smooth muscle cells as shown by the data presented in Table I. Table I The following examples are presented by way of illustration preferably that the limitation for the production of representative compounds of the invention.

EXAMPLE 1 Z-2- (Pyridin-3-yl) -3- (pyridin-4-yl) -acylonitrile 3-pyridylacetonitrile was dissolved (1.18 g, 0.01 mol) and 4-pyridyl carboxyaldehyde (1.07 g, 0.01 mol) in ethanol (75 mL). Then sodium methoxide was added (2.16 g of methanol solution to the %, 0.01 mol). The mixture was allowed to stand at room temperature for a period of 1 hour. The crystalline solid that formed was collected by filtration, washed with fresh ethanol and dried to give the title compound (1.0 g, 48% yield) as an off-white solid, m.p. 150-152 ° C. Analysis Calculated for C? 3H9N3: C, 75.33; H, 4.38; N, 20.28. Found: C, 75.01; H, 4.58; N, 20.19. Mass spectrum (El; M +) m / z 207. XE-NMR (DMSO-d6; 400 MHz) d 9.0 (s, 1H), 8.78 (d, 2H), 8.68 (d, 1H), 8.21 (s, 1H) ), 8.17 (m, 1H), 7.8 (d, 2H), and 7.58 ppm (m, 1H).

EXAMPLE 2 2-Pyridin-3-yl-3-quinolin-4-yl-acrylonitrile Quinoline-4-carboxaldehyde was dissolved (4.71 g, 0.03 mol) and 3-pyridylacetonitrile (3.54 g, 0.03 mol) were dissolved in ethanol (100 mL). Sodium methoxide (2 mL of 25% methanol solution) was added. The reaction mixture was heated to reflux for a period of 2.5 hours. The mixture was cooled to room temperature. After 18 hours, the precipitated solid was collected, suspended in ethanol and saturated with hydrogen chloride gas. The mixture of cooled and the solid was collected by filtration. The solid was crystallized from methanol to give the title compound (5.8 g, 57% yield) as a dihydrochloride, three quarts of hydrate, yellow solid, m.p. 250 ° C (dec.). Calculated Analysis for CnHuN3-HCl-3/4 H20; C, 59.40; H, 4.25; N, 12.23. Found: C, 59.75; H, 4.10; N, 11.93. Mass spectrum (El; M +) m / z 257. H-NMR (DMSO-d6; 400 MHz) d 9.40 (s, 1H), 9.38 (d, 1H), 9.15 (s, 1H), 8.93 (d, 1H) ), 8.74 (d, 1H), 8.56 (d, 1H), 8.46 (d, 1H), 8.32 (d, 1H), 8.13 (t, 1H), 8.00 (q, 1H), 7.95 (t, 1H), and 7.70 ppm (broad s, 4H).

EXAMPLE 3 3- (2,3-Dihydro-benzo [1,4] dioxin-6-yl) -2-pyridin-3-yl-acrylonitrile It was added to the solution of 2,3-dihydro-benzo [1,4] dioxin-6-carboxaldehyde (4.92 g; 0.03 mole) and 3-pyridylacetonitrile (3.54 g, 0.03 mole) in ethanol (100 mL), sodium methoxide (6.48 g, 25% methanol solution, 0.03 mole). The mixture was allowed to stand at room temperature for 18 hours. The mixture was concentrated to half the volume. The solid was collected by filtration and dried to give 7.0 g (88.4% yield) of the title compound as an off-white solid, m.p. 158-159 ° C. Analysis Calculated for C? 6H? 2N2? 2 C, 72.72; H, 4.58; N, 10.60. Found: C, 72.53; H, 4.48; N, 10.97. Mass spectrum (DEI, M +) m / z 264. H-NMR (DMSO-d6; 400 MHz) d 8.91 (d, 1H), 8.59 (d, 1H), 8.08 (d, 1H), 8.00 (s, 1H) ), 7.57 (d, 1H), 7.47-7.53 (m, 2H), 7.02 (d, 2H), and 4.31 ppm (m, 4H).

EXAMPLE 4 2-Pyridin-3-yl-3-pyridin-2-yl-acrylonitrile The title compound was prepared by the procedure described in Example 1 using 2.14 g (0.02 mol) of 2-pyridylcarboxyaldehyde and equivalent amounts of all other reagents. After standing at room temperature for a period of 18 hours, the crystalline solid was collected by filtration and dried to give the title compound (3.0 g, 72.5% yield) as a yellow solid, m.p. 115-117 ° C. Analysis Calculated for C 3 H 9 N 3: C, 75.34; H, 4.38; N, 20.28. Found: C, 75.31; H, 4.32; N, 20.28. Mass spectrum (El: M +) m / z 207. XH NMR (DMSO-d6, 400 MHz) d 9.01 (d, 1H), 8.76 (d, 1H), 8.66 (dd, 1H), 8.19 (m, 1H) ), 8.15 (s, 1H), 7.97 (td, 1H), 7.76 (d, 1H), 7.56 (q, 1H), and 7.49 ppm (m, 1H).

EXAMPLE 5 2, 3-Di-pyridin-3-yl-acrylonitrile The title compound was prepared by the procedure described in Example 1, using 2.14 g (0.02 mole) of 3-pyridylcarboxyaldehyde and equivalent amounts of all the other reagents. After standing at room temperature for 4 hours, the crystalline solid was collected by filtration, washed with ethanol and dried to give 1.6 g (37% yield) of the title compound as an off-white solid, m.p. 136-137 ° C. Analysis Calculated for C? 3H9N3; C, 75.34; H, 4.38; N, 20.28. Found: C, 75.31; H, 4.30; N., 20.49. Mass spectrum (El; M +) m / z 207. NMR: H (DMSO-d6; 400 MHz) d 8.99 (dd, 2H), 8.67 (qd, 2H), 8.38 (m, 1H), 8.23 (s, 1H), 8.16 (m, 1H), and 7.58 ppm (, 2H).

EXAMPLE 6 2- (Pyridin-3-yl) -3- (lH-pyrrol [2, 3-b] pyridin-3-yl) -acrylonitrile 4H-Pyrrole [2, 3-b] pyridin-3-yl-carboxyaldehyde (1.46 g, 0.01 mole), 3-pyridyl-acetonitrile (1.18 g, 0.01 mole) and sodium methoxide (2.16 g of solution) were refluxed. of 25% methanol, 0.01 mole) in ethanol (50 mL) for 4 hours. The solvent was evaporated to the point of precipitation. The mixture was then filtered and the solid collected and dried. The solid was suspended in water and stirred for 1 hour. The solid was then collected by filtration and dried under vacuum for 18 hours to give 1.4 g (57% yield) of the title compound as a yellow solid, m.p. 295-297 ° C (desc.). Analysis Calculated for C? SH? ON4: C, 73.16; H, 4.09; N, 22.75. Found: C, 72.99; H, 3.86; N, 22.68. Mass spectrum (+ INN, [M + H] + m / z 247. XH-NMR (DMSO-de; 400 MHz) d 12.63 (broad s, 1H), 8.99 (d, 1H), 8.56 (m, 2H) , 8.45 (s, 1H), 8.39 (s, 1H), 8.36 (dd, 1H), 8.18 (M, 1H), 7.52 (q, 1H), and 7.27 ppm (q, 1H).

EXAMPLE 7 Step 1 Dimethyl- (lH-pyrrol [2, 3-b] pyridin-3-ylmethyl) -amine A mixture of 1H-pyrrole [2,3-b] pyridine (59 g, 0.5 mol), dimethylamine hydrochloride (44.83 g, 0.55 mol) and paraformaldehyde (16.5 g, 0.55 mol) in n-butanol was heated to reflux. 700 mL) for 20 minutes. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and dried. The solid was then dissolved in water (800 mL), a few drops of HCl were added to complete the solution. The aqueous solution was washed with diethyl ether. The solid potassium carbonate was then added to the aqueous phase until it was basic. The precipitated solid was collected, washed with water and dried to give 43.5 g (50% yield) of the title compound as an off-white solid, m.p. 161-162 ° C. Analysis Calculated for C? 0H? 3N3: C, 68.54; H, 7.48; N, 23.95. Found: C, 68.28; H, 7.75; N, 23.99. Mass spectrum (DEI, M +) m / z 175. XH-NMR (DMSO-de 400 MHz) d 12.45 (broad s, 1H), 8.14 (dd, 1H), 7.97 (d, 1H), 7.32 (s, 1H), 7.01 (q, 1H), 3.51 (s, 2H), and 2.12 ppm (s, 6H).

Step 2 ÍH-Pyrrol [2, 3-b] pyridin-3-yl-acetonitrile A solution of dimethyl sulfate (32.7 g, 0.25 mol) in THF (50 L) was added dropwise while the solution of dimethyl- (1H-pyrrole [2,3-b] pyridinylmethyl) was added. -amine (42 g, 0.24 mol) in THF (800 mL). After the addition was completed, the mixture was heated at 80 ° C for 10 minutes then cooled to room temperature. The solvent was decanted and the residual gum was titrated with acetone / methanol (1: 1 mixture) while heating. The solid formed was collected by filtration. The solid was then dissolved in water (500 ml). Potassium cyanide (22g, 0.32 moles) was added. The mixture was stirred at room temperature for 15 minutes, heated to reflux for 30 minutes, then cooled to room temperature. After 2 hours, the solid was collected by filtration and washed "with water then dried to give 21 g (56% yield) of the title compound as a whitish solid, m.p. 141-142 ° C which was used for the reaction described in step 3.

Step 3 (Z) -3- (2,3-Dihydro-benzo [1,4] dioxin-6-yl) -2- (1H-pyrrol- [2, 3-b] pyridin-3-yl) -acrylonitrile A mixture of 1-H-pyrrole [2,3-b] pyridinyl-acetonitrile (3.14 g, 0.02 mol), 2,3-dihydro-benzo [1,4] dioxin-6-carboxyaldehyde (3.3 g, 0.02 mol) and sodium methoxide (4.32 g, 25% methanol solution, 0.02 mole) was heated to reflux in ethanol (50 mL) over a period of 1 hour. The mixture was concentrated to half its volume. The solid formed was collected by filtration. The solid was washed with water and dried. Then it was suspended in ethyl acetate / methanol (1: 1, 100 mL) and the resulting mixture was saturated with hydrogen chloride. The mixture was cooled to room temperature while stirring. The solid was collected by filtration and dried to give 2.3 g (40% yield) of the title compound as a mono-hydrochloride, yellow solid, m.p. 280-283 ° C (dec.). Analysis Calculated for C? 8H? 3N30 -HCl: C, 63.63; H, 4.16; N, 12.37. Found: C, 68.83; H, 3.95; N, 12.31.

Mass spectrum (+ DCI, [M + H] +) m / z 304. XH NMR (DMS0-d6; 400 MHz) d 12.55 (s broad, 1H), 9.35 (s broad, 1H), 8.6 (dd, 1H), 8.39 (dd, 1H), 7.91 (s, 1H), 7.71 (s, 1H), 7.53 (d, 1H), 7.45 (dd, 1H), 7.31 (q, 1H), 7.0 (d, 1H), and 4.30 ppm (m, 4H).

EXAMPLE 8 (Z) -3- (9-Ethyl-9H-carbazol-3-yl) -2- (pyridin-3-yl) acrylonitrile 9-Ethyl-9H-carbazol-3-yl-carbaxaldehyde (4.46 g, 0.02 mole) and 3-pyridyl-acetonitrile (2.36 g, 0.02 mole) were dissolved in ethanol (25 mL).

Sodium methoxide (1 mL of 25% methanol solution) was added. The mixture was then allowed to stand at room temperature for 24 hours. The formed precipitate was collected by filtration and dried to give 2.4 g (37% yield) of the title compound as a yellow solid, m.p. 131-133 ° C. Analysis Calculated for C22H17N3: C, 81. 71; H, 5.30; N, 12.99. Found: C, 81.38; H, . 49; N, 12.48. Mass spectrum (El; M +) m / z 323.

NMR * H (DMSO-de; 400 MHz) d 8.98 (d, 1H), 8.75 (d, 1H), 8.60 (dd, 1H), 8.28 (s, 1H) 1, 8.18 (dd, 1H), 8.12-8.16 (m, 2H), 7.8 (d, 1H), 7.68 (d, 1H), 7.51- 7. 56 (m, 2H), 7.29 (t, 1H), 4.49 (q, 2H), and 1.34 ppm (t, 3H).

EXAMPLE 9 2- (Pyridin-3-yl) -3- (lH-pyrrol-2-yl) -acylonitrile A mixture of pyrrole-2-carboxaldehyde (2.85 g, 30 mmol), 3-pyridylacetonitrile (3.54 g, 30 mmol), and piperidine (2 mL) in methanol (50 mL) was heated at reflux for 18 hours. The dark precipitate formed was separated by filtration. The dark solid was treated with charcoal in hot methanol to obtain 2.8 g (48%) of the title compound as a yellow solid, m.p. 139-142 ° C. Analysis Calculated for Ci2H9N3: C, 73.83; H, 4.65; N, 21.52. Found: C, 73.71; H, 4.57; N, 21.76. Mass Spectrum: (El; M +) m / z 195. XH NMR (DMSO-de; 200 MHz) d 11.5 (s, 1H), 8.8 (d, 1H), 8.5 (d, 1H), 7.92-7.96 ( m, 1H), 7.8 (s, 1H), 7.43-7.52 (m, 1H), 7.2 (d, 2H), 6.38-6.4 ppm (q, 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, the content of the following claims is claimed as property.

Claims (16)

1. A compound of the formula: characterized in that Ari and Ar2 are independently pyridinyl, quinolinyl, dihydro-1,4-benzodioxinyl, pyrrolyl, azaindolyl or carbazolyl optionally substituted with alkyl of 1 to 4 carbon atoms or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, characterized in that Ari is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, quinolinyl, dihydro-1, -benzodioxinyl, pyrrolyl, pyrrole- [2, 3-b] ] pyridin-3-yl) or carbazolyl.

3. The compound according to claim 1 or claim 2, characterized in that Ar2 is pyridin-3-yl.

4. The compound according to claim 1, characterized in that it is Z-2- (pyridin-3-yl) -3- (pyridin-4-yl) -acrylonitrile or a pharmaceutically acceptable salt thereof, 2-pyridin-3-yl 3-pyridin-2-yl-acrylonitrile or a pharmaceutically acceptable salt thereof, 2,3-di-pyridin-3-ylacrylonitrile or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, characterized in that it is 2-pyridin-3-yl-3-quinolin-4-yl-acrylonitrile or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, characterized in that it is 3- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -2-pyridin-3-yl-acrylonitrile or a pharmaceutically acceptable salt thereof .

7. The compound according to claim 1, characterized in that it is 2- (pyridin-3-yl) -3- (1 H -pyrrol [2, 3-b] -pyridin-3-yl) -acrylonitrile or a pharmaceutically acceptable salt thereof. same.

8. The compound according to claim 1, characterized in that it is (Z) -3- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -2- (1H-pyrrole [2, 3-b] ] pyridin-3-yl) -acrylonitrile or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, characterized in that it is (Z) -3- (9-ethyl-9H-carbazol-3-yl) -2- (pyridin-3-yl) acrylonitrile or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, characterized in that it is 2- (pyridin-3-yl) -3- (1-pyrrol-2-yl) -acrylonitrile or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition, characterized in that it comprises a compound of the formula I according to any of claims 1 to 10, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

12. A compound of the formula I according to any of claims 1 to 10 characterized in that it is for use in the treatment of mammals.

13. A compound of formula I according to claim 12, characterized in that it is for use in the treatment of diseases or conditions related to the proliferation of smooth muscle cells.

14. A method for preventing the proliferation of smooth muscle cells in a mammal, characterized in that it comprises administering to said mammal, orally or parenterally, a compound of the formula: where Ari and Ar2 are as defined in any of claims 1 to 10.

15. A method according to claim 14, characterized in that the proliferation of smooth muscle cells manifests by itself the restinosis after angioplasty.

16. A process for the preparation of a compound of the formula I as defined in any of claims 1 to 10, characterized in that it comprises (a) condensing an aldehyde of the formula AriCHO with an acetonitrile of the formula Ar2CH2CN where Ari and Ar2 are as they are previously defined to form the compound of formula 1: and optionally form the pharmaceutically acceptable salt thereof.