Imidazole derivatives or their pharmaceutically acceptable salts

 

(57) Abstract:

Imidazole derivatives of the formula I, where Y Is H, alkyl, phenyl, phenylalkyl, pyridyl, pyridylethyl, AG1and AG2- phenylene, X and X1Is o, S, SO or SO2; R1Is h or alkyl; R2and R3is methylene, ethylene or propylene, have the ability to inhibit the enzyme lipoxygenase. The compounds of formula 1 are useful for the treatment of bronchial asthma, skin diseases and arthritis in mammals. 8 C.p. f-crystals.

This invention relates to new compounds of imidazole. Compounds of the present invention inhibit the action of the enzyme lipoxygenase and are suitable for the treatment or relief of inflammatory diseases, allergic and cardiovascular diseases in mammals, especially in humans.

The prior art.

It is known that arachidonic acid is the biological precursor of some group of biologically active endogenous metabolites. The first step in the metabolism of arachidonic acid is its release from membrane phospholipids through action of phospholipase A2. Next, arachidonic acid is converted in the course of metabolism under the influence of cyclooxygenase, direcis fatty acids, which can later be converted to leukotrienes.

Leukotrienes are extremely potent substances, which possess a variety of biological effects, often in the concentration range from nanomolar to picomolar. Peptide leukotrienes (LTC4, LTD4, LTE4) are important bronchoconstrictors and vasoconstrictors, and cause transudation plasma by increasing capillary permeability. LTB4a potent chemotactic agent that increases the flow of blood and stimulate their subsequent degranulation at the site of inflammation. Pathophysiological role of leukotrienes caused some painful human conditions, including asthma, rheumatoid arthritis and gout, psoriasis, respiratory distress syndrome in adults (ARDS), inflammatory intestinal diseases (e.g. Crohn's disease), bacterial endotoxin-toxic shock-induced ischemia violation of the myocardium. It is assumed that any tool, the inhibitory effect lipogenic could be of significant therapeutic interest in the treatment of acute and chronic inflammatory conditions.

Published several who, . Masamume and L. S. Melvin, Sr.: Annual Roports Medicinal Chemistry, 1989, 24, pp 71 - 80 (Academic Press), and B. J. Fitzsimmons and J. Rokach: Leukotrienes and Lipoxygenases, 1989, pp 427 - 502 (Elsevier).

Compounds with a similar structure to the compounds of the present invention, are disclosed in EP 488602 A1, EP 0409413 A2 and EP 0375404 A2.

These applicants worked for compounds able to inhibit the action of lipoxygenase, and after a wide range of studies have succeeded in the synthesis of a number of compounds, described in detail below.

Brief description of the invention.

The present invention provides new compounds of imidazole the following chemical formula 1:

< / BR>
and their pharmaceutically acceptable salts,

in which Y represents hydrogen, C1- C8-alkyl, galijasevic C1-C4-alkyl, phenyl, substituted phenyl, C7-C14-phenylalkyl, C7- C14-(substituted phenyl)alkyl, pyridyl, substituted pyridyl, C6-C13-pyridylethyl or C6- C13-(substituted pyridyl)alkyl, in which each Deputy independently represents halogen, nitro, cyano, C1- C4-alkyl, C1-C4-alkoxy, galijasevic C1-C4-alkyl, galijasevic C1- C4-alkoxy, NR4R5, CO21-C6-alkyl;

Ar1and Ar2each independently represents a phenylene, monosubstituted phenylene or disubstituted phenylene, in which the substituents independently denote halogen, C1- C4-alkyl, C1-C4-alkoxy, galijasevic C1-C4-alkyl or galijasevic C1- C4-alkoxy;

X and X1each independently represent O, S, SO or SO2;

R1denotes hydrogen or C1-C4-alkyl;

R2and R3each independently represents a methylene, ethylene or propylene.

A preferred group of compounds of the present invention consists of compounds of formula 1 in which Y is in position-2 of the imidazole ring; Ar2denotes 1,4-phenylene or monosubstituted 1,4-phenylene; Ar1means, 1,3-phenylene or monosubstituted 1,3-phenylene; X is O or S; X1represents O; and R2and R3each represent ethylene. In this preferred group is particularly desirable are those in which Y denotes a 2-alkyl; Ar1denotes 1,4-phenylene or 2-fluoro-1,4-phenylene; Ar2is 1,3-phenylene or 2-fluoro-1,3-phenylene or 5-fluoro-1,3-phenylene; X is O; and R1is methyl. Most specifically, Y represent the deposits of formula 1, in which Y represents 2-alkyl; Ar1denotes 1,4-phenylene or 2-fluoro-1,4-phenylene; Ar2represents 1,3-phenylene, 2-fluoro-1,3-phenylene or 5-fluoro-1,3-phenylene; X is O; X1- S; R1is methyl and R2and R3each are ethylene, In this second preferred group is particularly desirable compounds in which Y represents 2-methyl.

A third preferred group of compounds of the present invention consists of compounds of formula 1 in which Y is 2-alkyl; Ar1denotes 1,4-phenylene or monosubstituted 1,4-phenylene; Ar2is a 2.5 Diptera-1,3-phenylene; X and X1each represent O; R1is methyl; and R2and R3each represent ethylene. In this third preferred group is particularly desirable compounds in which Y is 2-methyl.

Detailed description of the invention.

This specification uses the following terms.

The term "halogen" is used to refer to fluorine, chlorine, bromine or iodine.

The term "alkyl" is used to denote a linear or branched hydrocarbon radicals, including, but not right restrictions, methyl, ethyl, n-propyl, isopropyl, n-butyl, and the like.

The term "galijasevic alkyl" refers to alkylation, as described above, substituted by one or more Halogens including, but not right restrictions, chloromethyl, bromacil, trifluoromethyl, etc., Preferred Alojamientos altergroup is trifluoromethyl.

The term "galijasevic alkoxy" is used to denote alkoxy radical as described above substituted by one or more Halogens including, but not right restrictions, chloromethoxy, bromoethoxy, deformedarse, triptoreline, etc. Preferred Alojamientos alkoxygroup is triptoreline.

The terms "substituted phenyl" or "substituted pyridyl" is used here to denote panelgroup and pyridium with up to three substituents, and these substituents may be either the same or different. However, the preferred monosubstituted phenyl or monosubstituted pyridyl.

The term "C7-C14(substituted phenyl)alkyl interval C7-C14refers to the number of carbons in the phenyl - and altergroup and has no relation to the carbon substituents. Similarly, "C6-C13(Osnovnye syntheses.

The compound of formula 1 or its pharmaceutically acceptable salt can be obtained by any synthetic method acceptable to the compounds corresponding to structures known to every expert in the relevant field of technology. For example, the compound of formula 1 are the reaction shown in scheme 1:

Circuit 1

< / BR>
in which Z denotes OH or a substituted group, and

Y, Ar1, Ar2X, X1, R1, R2and R3have the above values.

Method A.

In one version of the method the compound of formula II in which Z denotes a hydroxyl, combined with the compound of the formula III in which X represents O, by dehydration. Can be used a variety of dehydrating, but the usual way to perform this transformation is the use of diethylazodicarboxylate and triphenylphosphine in a reaction-inert solvent. Suitable solvents are dichloromethane, tetrahydrofuran and toluene. The reaction temperature is approximately in the interval 0oC to room temperature, but if necessary, can be used to lower or higher temperatures. The reaction time is usually from not the rum Z represents a substituted group (leaving group), combined with the compound of the formula III, preferably in the presence of a suitable base. Suitable substituted by a group Z is halogen or sulfonyloxy: for example, chlorine, bromine, iodine, tripterocalyx, methanesulfonate or p-toluensulfonate, all easily obtained from the corresponding alcohol according to standard techniques. Preferred bases for the reaction combinations are, for example, a hydroxide of an alkali metal or alkaline earth metal alcoholate, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, tert-butyl potassium, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride or an amine, such as triethylamine, diisopropylethylamine or dimethylaminopyridine. Preferred reaction inert solvents include, for example, acetone, acetonitrile, dichloromethane, N,N-dimethylacetamide, N, N-dimethylformamide, dimethylsulfoxide or tetrahydrofuran. The reaction temperatures are preferably in the range from room temperature to the boiling point of the solvent, but if necessary, can be used to lower or higher temperatures. The reaction time is usually from several vinyl or sulfonylurea, the compound of formula I in which X is S, can be oxidized in the usual ways. Suitable oxidants are, for example, hydrogen peroxide and nakilat, such as m-chlormadinone or peracetic acid, a sulfate of an alkali metal, such as Nationalrat potassium or the like. Preferred reaction solvents include, for example, acetone, dichloromethane, chloroform, tetrahydrofuran or water. The reaction temperature is approximately in the interval 0oto room temperature, but if necessary, can be used to lower or higher temperatures. The reaction time is usually from several minutes to several hours.

The initial product of the formula III can be obtained by conventional methods known to every expert in the relevant field of technology. For example, as described in J. Med. Chem., 1992, 35, 2600 - 2609, and EP 0375404 A2.

The initial product of the formula II can be obtained by conventional methods known to experts in the relevant field of technology. For example, the compound of formula II get reactions shown in scheme 2.

Scheme 2

< / BR>
in which W is a substituted group,

A - suitable electroactivity IV combined, preferably in the presence of a suitable base, with a compound of the formula

W-Ar1-A

order to obtain the compounds of formula V. Suitable substituted group is a halogen or sulfonyloxy, for example fluorine, chlorine, bromine, iodine or triftormetilfullerenov. Suitable electroactive group A is, for example, cyano, carboxaldehyde, carboxylic acid or ether carboxylic acid. The preferred base for the reaction combination is, for example, a hydroxide of an alkali metal or alkaline earth metal alcoholate, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, tert-butyl potassium, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or a metal alkyl, such as n-utility, etimani bromide, etc., the Preferred reaction inert solvents include, for example, methanol, ethanol, pyridine, N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidine-2-it, N,N-dimethylacetamide or tetrahydrofuran. The reaction temperature is approximately in the range from 50o150oC, but if necessary, can be used to lower or higher temperatures. The reaction time with the catalyst, for example tetrakis(triphenylphosphine)-palladium, bis(triphenylphosphine)-palladium(II) chloride, iodide monovalent copper, monovalent chloride or copper bromide monovalent copper.

The compound of formula V into a compound of formula II in which Z denotes a hydroxyl, by standard methods well known to the expert in the relevant field of technology. Thus, in stage 2 of the compound of formula II can easily get recovery with conventional reducing agents such as sodium borohydride, lithium aluminum hydride, diisobutylaluminium hydride, complex, borane-tetrahydrofuran, borane complex-metilsulfate or etc.

The products obtained in the above synthesis and shown in the experimental examples, can be isolated by standard methods and purification are achieved by conventional means, known to experts in the relevant field of technology, such as distillation, recrystallization and chromatography.

Since the compounds of the present invention are basic compounds, they are capable of producing a large variety of additive acid salts with various inorganic and organic acids. Additive acid salt new audinarayana acid in aqueous solvent or a suitable organic solvent, such as methanol or ethanol. Given the solid salt can be obtained by precipitation or by careful evaporation of the solvent.

To obtain pharmaceutically acceptable salts of the acid of joining the above-mentioned compounds of the present invention use those acids which form non-toxic acid salt of joining, such as hydrochloric, Hydrobromic, itestosterone, nitrate, sulfate, acetate, fumarate, tartrate, succinate, maleate, gluconatesee, benzoate, methanesulfonate, bansilalpet, p-toluensulfonate, pamoate (for example, 1,1-methylene-bis-(2-hydroxy-3-aftout)) of salt.

Compounds of the invention that have an acid group that can form basic salts with various pharmaceutically acceptable cations. Examples of such salts include salts of alkali and alkaline earth metals and, in particular, salts of sodium or potassium. All these salts receive by standard methods. As a chemical bases that are used as reagents to obtain pharmaceutically acceptable basic salts of this invention are used those which form non-toxic basic salts. In particular, these non-toxic basic salts include proiso be obtained by processing the above-mentioned compounds, aqueous solution, contain pharmaceutically acceptable cation, and then evaporation of the resulting solution to dryness, preferably under reduced pressure. Or else, they can be obtained by blending lower alkanovykh solutions of the acidic compounds and specified alcoholate of alkali metals and the subsequent evaporation of the resulting solution to dryness in the above manner. In any case, it is preferable to use stoichiometric amounts of reactants in order to achieve complete reaction and the maximum output of a given end-product

Compounds of the present invention inhibit the activity of the enzyme 5-lipoxygenase. This inhibition can be demonstrated by in vitro tests (in vitro) using the resident cells of the abdominal cavity of rats (RPC) (Japanese Journal of Inflammation, 1987, 7, 145 - 150) and heparinized whole human blood (HWB) (Br. J. of Pharmacol.: 1990, 99, 113 - 118), in both cases, we determined the effects of these compounds on the metabolism of arachidonic acid. All compounds given in the examples below, have passed the above tests, which showed that they are effective in the inhibition of lipoxygenase activity. Some predpochtitel is vomited from 0.001 to 1 μm. The ability of the compounds of the present invention to inhibit the enzyme lipoxygenase makes them useful for dealing with symptoms caused by endogenous metabolites formed from arachidonic acid in mammals, especially in humans. In addition, the compounds are of value in the prevention or the treatment of painful conditions in which the accumulation of metabolites of arachidonic acid is a causal factor, such as allergic bronchial asthma, skin diseases, rheumatoid arthritis and osteoarthritis.

In particular, the compounds of the present invention and their pharmaceutically acceptable salts are suitable for use in the treatment or relief of inflammatory diseases in humans.

For the treatment of various of the above-described States of the compounds and their pharmaceutically acceptable salts can be administered to a person either in pure form or preferably in combination with pharmaceutically acceptable carriers or solvents in the pharmaceutical composition in accordance with generally accepted pharmaceutical practice. The compounds can be administered orally or parenterally in the usual way.

When connections are assigned cheloveku 0.1 to 10 mg/kg of body weight of the patient per day, preferably from about 0.1 to 4 mg/kg / day as a single dose or divided doses. If it is desirable parenteral administration, the effective dose will be from about 0.05 mg/kg of body weight of the patient per day. In some cases it may be necessary to use dosages outside these limits, since the dosage must be changed in accordance with age, weight and individual susceptibility of the patient, as well as with the severity of symptoms and effectiveness of assigned connections.

For oral administration the compounds of the invention and their pharmaceutically acceptable salts can be administered, for example, in the form of tablets, powders, cakes, syrups or capsules or in the form of aqueous solutions or suspensions. In the case of tablets for oral use commonly used carriers include lactose and corn starch. In addition, usually added lubricants such as magnesium stearate. In the case of capsules useful diluents include lactose and dried corn starch. When oral administration is required aqueous suspensions of the active ingredient is mixed with emulsifying or suspendresume means. Can Wadi use is usually prepared sterile solutions of the active ingredient and pH of the solutions should be properly selected and maintained using buffers. Intravenous total concentration of dissolved substances should be controlled so that the drug was isotonic.

In addition, for the treatment of asthma the compounds of formula I of the invention can be administered to a patient by inhalation. For this purpose they are provided in the form of aerosols or sprays according to the standard method.

The present invention is further illustrated by the following examples. However, it should be clear that the invention is not limited to the specific details of these examples. Range of proton nuclear magnetic resonance (NMR) measured at 270 MHz, unless otherwise noted, and the position of peaks expressed in ppm (M. D.) in the lower pane from tetramethylsilane. Forms peaks have the following designations: s - singlet, d - doublet, t - triplet, q - Quartet, quint quintet, m - multiplet, br - broad.

Example 1. 4-[3-[4-(1-Imidazolyl)benzyloxy]-phenyl]4-methoxy - 3,4,5,6-tetrahydro-2H-Piran.

To a stirred solution of 4-(1-imidazolyl)benzyl alcohol (Eur. J. Med. Chem. , 1992, 27, 219) (0,87 g, 5.0 mmol), 4-(3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-Piran (J. Med. Chem., 1992, 35, 2600) (1,03 g, 4.9 mmol) and triphenylphosphine (1.55 g, 5.9 mmol) in THF (30 ml), cooled to 0oC, dabao completion of the addition the mixture was stirred at 0oC for 30 minutes and allowed to warm to room temperature, and then remove the volatile products under reduced pressure. Chromatographic purification of the residue (SiO2230 g; gradient elution from 15% to 30% acetone in dichloromethane) to give 0.27 g specified in the title compound in the form of a resin which solidifies upon standing at room temperature. Fractions contaminated with triphenylphosphine, unite, concentrate to dryness, transferred to the solid state by rubbing with diisopropyl ether and recrystallized from a mixture of diisopropyl ether/ethyl acetate, getting 0.16 g specified in the title compounds. The combined solids purified by recrystallization from a mixture of diisopropyl ether/ethyl acetate, giving specified in the title compound in the form of tiny colorless needles (0,30 g, 17%).

So pl. 129o- 130,5oC.

IR (KBr) cm-1: 2960, 2875, 1607, 1579, 1524, 1480, 1306, 1281, 1251, 1073, 1061, 1026.

NMR (CDCl3) : 7.78 (t, 1H, J = 1 Hz), 7.56 (d, 2H, J = 8 Hz), 7.43 (d, 2H, J = 8 Hz), 7.32 (t, 1H, J = 8 Hz), 7.28 (dd, 1H, J = 1.8 Hz), 7.22 (t, 1H, J = 1 Hz), 7.08 - 7.98 (m, 2H), 6.94 - 6.88 (m, 1H), 5.12 (s, 2H), 3.92 - 3.81 (m, 4H), 2.98 (s, 3H), 2.10 - 1.92 (m, 4H).

Elemental analysis for C22H24N2O3:

Calculated: C, 72.51, H 6.64, N, 7.69;

Found: C, 72.37, H 6.74, . -(2-Mei-1-yl)benzyl alcohol.

To a suspension of NaH (0,612 g of 15.3 mmol, 60% suspension in oil) in dry DMF (10 ml), cooled to 10oC add DMF (8 ml) solution of 2-methylimidazole (1,23 g, 15 mmol) under nitrogen atmosphere and the mixture is stirred for 30 minutes at room temperature. To the reaction mixture 4-forbindelse (1,90 g of 15.3 mmol) and the resulting solution was stirred for 14 hours. The reaction mixture was poured into ice saturated aqueous solution of NH4Cl (100 ml) and extracted with ethyl acetate (100 ml x 2). The organic layer was washed with water (100 ml) and salt solution (80 ml), dried over MgSO4and the solvent is removed under reduced pressure. The resulting residue is purified column chromatography (SiO2, hexane : ethyl acetate = 1 : 1, then ethyl acetate) and obtain raw 4-(2-Mei-1-yl)benzaldehyde (1.0 g), which is used without further purification.

To a stirred solution of crude 4-(2-Mei-1-yl)benzaldehyde (1.0 g) in methanol (15 ml), cooled to 0oC add NaBH4(0.2 g, 5.2 mmol) in portions over 15 minutes and stirred for 1 hour. To the reaction mixture is added saturated aqueous solution of NH4Cl (50 ml) and everything is extracted with ethyl acetate (100 ml x 2). Organiczna pressure. The crude product is washed with a mixture of Et2O/ethyl acetate (3 : 1, 15 ml), getting mentioned in the title compound (0.51 g, 50%) as a white powder.

NMR (CDCl3) : 7.5 (d, 2H, J = 8 Hz), 7.28 (d, 2H, J = 8 Hz), 7.01 (d, 1H, J = 1 Hz), 6.99 (d, 1H, J = 1 Hz), 4.78 (s, 2H), 2.35 (s, 3H).

b. 4-Methoxy-4-[3-[4-(2-Mei-1-yl)benzyloxy] - phenyl] -3,4,5,6-tetrahydro-2H-Piran.

Specified in the title compound is obtained from 4-(2-Mei-1-yl)benzyl alcohol and 4-(3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-Piran according to the method described for 4-[3-[4-(1-imidazolyl)benzyloxy]phenyl] - 4-methoxy-3,4,5,6-tetrahydro-2H-Piran (example 1).

So pl. 135,5o- 137oC.

IR (KBr) cm-1: 1520, 1416, 1248, 1073.

NMR (CDCl3) : 7.57 (d, 2H, J = 8 Hz), 7.30 - 7.36 (m, 3H), 7.00 - 7.07 (m, 4H), 6.93 (ddd, 1H, J = 8.3 Hz), 5.14 (s, 2H), 3.82 - 3.91 (m, 4H), 2.98 (s, 3H), 2.38 (s, 3H), 1.92 - 2.09 (m, 4H).

Example 3. 4-Methoxy-4-[3-[4-(4-Mei-1-yl)benzyloxy]- phenyl]-3,4,5,6-tetrahydro-2H-Piran.

Specified in the title compound gain, using 4-Mei and 4-forbindelse according to the method described for 4-methoxy-4-[3-[4-(2-Mei-1-yl)benzyloxy]phenyl]- 3,4,5,6-tetrahydro-2H-Piran (example 2).

So pl. 120o- 121oC.

IR (KBr) cm-1: 1525, 1251, 1076.

NMR 87 (m, 4H), 2.98 (s, 3H), 2.31 (s, 3H), 1.92 - 2.04 (m, 4H).

Example 4. 4-Methoxy-4-[3-[4-(2-phenylimidazol-1-yl)benzyloxy]- phenyl]-3,4,5,6-tetrahydro-2H-Piran.

a. 4-(2-Phenylimidazol-1-yl)benzonitrile.

A mixture of 4-perbenzoate (3,63 g, 30 mmol), 2-phenylimidazole (and 3.72 g, 30 mmol) and anhydrous K2CO3(4.15 g, 30 mmol) in dry DMSO (30 ml) is heated at 100oC 20 hours in nitrogen atmosphere. After cooling to room temperature the reaction mixture was poured into ice saturated aqueous solution of NH4Cl (100 ml) and the whole is extracted with Et2O (150 ml x 2). The combined extracts washed with water (100 ml) salt solution (80 ml), dried over MgSO4and the solvent is removed under reduced pressure. The resulting residue is purified column chromatography (SiO2; dichloromethane : ethyl acetate : ethanol = 20 : 1 : 1), obtaining mentioned in the title compound (3,61 g, 49%).

IR (KBr) cm-1: 2220.

NMR (CDCl3) : 7.74 (d, 2H, J = 8 Hz), 7.27 - 7.38 (m, 8H), 7.20 (s, 1H).

b. 4-(2-Phenylimidazol-1-yl)benzyl alcohol.

To a solution of 4-(2-phenylimidazol-1-yl)benzonitrile (3.2 g, 13 mmol) in dichloromethane (30 ml) and toluene (20 ml), cooled to -78oC, is added dropwise diisobutylaluminium hydride (13 ml, 13 mmol : 1.02 M solution (20 ml) cautiously add then to the reaction mixture and the mixture is allowed to warm to room temperature. Received gelatinousness the mixture is filtered through a layer of celite, rinsing with ethyl acetate (220 ml). The filtrate is washed with 0.3 N. HCl solution (100 ml), water (200 ml) and salt solution (100 ml) and the organic layer is dried over MgSO4. Removal of the solvent under reduced pressure gives the crude product (2.5 g) which is dissolved in methanol (30 ml) and cooled to 0oC. Add portions NaBH4(0.3 g, 8 mmol) and the reaction mixture is stirred for 30 minutes. To the reaction mixture is added saturated aqueous solution of NH4Cl (30 ml) and everything is extracted with ethyl acetate (20 ml x 3). The organic layer was washed with water (10 ml), a solution of salt (10 ml), dried over MgSO4and the solvent is removed under reduced pressure. The obtained crude product is washed with ethyl acetate (35 ml), getting mentioned in the title compound (0,81 g, 25%) as white solid powder.

NMR (CDCl3) : 7.37 - 7.41 (m, 4H), 7.18 - 7.29 (m, 6H), 7.15 (t, 1H, J = 1 Hz), 4.75 (s, 2H), 2.6 (br, 1H).

c. 4-Methoxy-4-[3-[4-(2-phenylimidazol-1-yl)-benzyloxy]phenyl]- 3,4,5,6-tetrahydro-2H-Piran.

Specified in the title compound receive according to the method similar to that described for 4-methoxy-4-[3-[4-(2-Mei - 1-yl)benzyloxy] phenyl] -3,4,5,6-tetrahydro-2H-Piran (example 2).

So pl. 117o- 117,5o

Example 5. 4-Methoxy-4-[3-[4-(4-phenylimidazol-1-yl)benzyloxy]- phenyl]-3,4,5,6-tetrahydro-2H-Piran.

Specified in the title compound is obtained from 4-vinylimidazole and 4-forventelige according to the General method described for 4-methoxy-4-[3-[4-(2-Mei-1 - yl)benzyloxy] phenyl]-3,4,5,6-tetrahydro-2H-Piran (example 2).

So pl. 98o- 100,5oC.

IR (KBr) cm-1: 1526, 1456, 1289, 1072.

NMR (CDCl3) : 7.91 (d, 1H, J = 1 Hz), 7.85 (dd, 2H, J = 7 Hz, 1 Hz), 7.60 (d, 2H, J = 8 Hz), 7.58 (s, 1H), 7.28 - 7.50 (m, 6H), 7.06 (d, 1H, J = 2 Hz), 7.02 (d, 1H, J = 8 Hz), 6.92 (dd, 1H, J = 8, 2 Hz), 5.14 (s, 2H), 3.83 - 3.87 (m, 4H), 2.99 (s, 3H), 1.92 - 2.09 (m, 4H).

Example 6. 4-[5-fluoro-3-[4-(2-Mei-1-yl)benzyloxy]- phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran.

Specified in the title compound receive according to the method similar to example 2, part b, but using 4-(5-fluoro-3 - hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-Piran as source material.

So pl. 168o- 168,5oC.

IR (KBr) cm-1: 1590, 1520, 1416, 1138, 1072.

NMR (CDCl3) : 7.56 (d, 2H, J = 8 Hz), 7.34 (d, 2H, J = 8 Hz), 7.04 (d, 1H, J = 1 Hz), 7.01 (d, 1H, J = 1 Hz), 6.38 (brs, 1H), 6.75 (ddd, 1H, J = 10, 2, 2 Hz), 6.64 (ddd, 1H, J = 10, 2, 2 Hz),- phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran.

Specified in the title compound receive according to the method similar to example 2, using as starting material ethyl-2,4-differentat and 2-Mei.

So pl. 121o- 122oC.

IR (KBr) cm-1: 1585, 1515, 1299, 1249, 1073, 900.

NMR (CDCl3) : 7.67 (dd, 1H, J = 8, 8 Hz), 7.34 (dd, 1H, J = 8, 8 Hz), 7.15 (dd, 1H, J = 8, 2 Hz), 7.01 - 7.11 (m, 3H), 6.94 (dd, 1H, J = 8, 3 Hz), 5.19 (s, 2H), 3.83 - 3.91 (m, 4H), 2.99 (s, 3H), 2.40 (s, 3H), 1.92 - 2.10 (m, 4H).

The compounds of examples 8 to get 24 by methods similar to those described in examples 1 to 7 using the appropriate starting materials. In some cases, the product after separation turned into hydrochloric salt.

Example 8. 4-Methoxy-4-[3-[4-(2-benzoimidazol - 1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-Piran.

So pl. oil.

IR (KBr) cm-1: 2955, 1606, 1586, 1519, 1485, 1437, 1306, 1260, 1079.

NMR (CDCl3) : 7.74 - 6.85 (m, 15H), 5.12 (s, 2H), 4.03 (s, 2H), 3.94 - 3.76 (m, 4H), 2.98 (s, 3H), 2.10 - 1.89 (m, 4H).

Example 9. 4-[3-[4-(2-Ethylimidazole-1-yl)benzyloxy] phenyl]- 4-methoxy-3,4,5,6-tetrahydro-2H-Piran.

So pl. oil.

IR (neat.) cm-1: 1519, 1429, 1306, 1255, 1073.

NMR (CDCl3) : 7.57 (d, 2H, J = 8 Hz), 7.33 (dd, 1H, J = 8, 8 Hz), 7.32 (d, 2H, J = 8 Hz), 7.07 (d, 1H, J = 1 Hz), 7.06 (d, 1H, J = 3 Hz), 7.02 (d, 1H, J = 8 Hz), 6.98 (d, 1H, J = 1 Metoxy-4-[3-[3-methyl-4-(2-Mei-1 - yl)benzyloxy] phenyl]-3,4,5,6-tetrahydro-2H-Piran.

So pl. 121,5o- 122oC.

IR (neat.) cm-1: 1584, 1305, 1251, 1072.

NMR (CDCl3) : 7.44 (s, 1H), 7.38 (d, 1H, J = 8 Hz), 7.33 (dd, 1H, J = 8, 8 Hz), 7.21 (d, 1H, J = 8 Hz), 7.06 - 7.07 (m, 2H), 7.02 (d, 1H, J = 8 Hz), 6.93 (dd, 1H, J = 8, 2 Hz), 6.86 (d, 1H, J = 1 Hz), 5.10 (s, 2H), 3.82 - 3.88 (m, 4H), 2.99 (s, 3H), 2.19 (s, 3H), 2.08 (s, 3H), 1.97 - 2.04 (m, 4H).

Example 11. 4-Methoxy-4-[3-[4-(2-(pyridine-2 - yl)imidazol-1-yl)benzyloxy] phenyl]-3,4,5,6-tetrahydro-2H-Piran.

So pl. 103o- 105oC.

IR (neat.) cm-1: 3360, 1598, 1515, 1455, 1267.

NMR (CDCl3) : 8.32 (d, 1H, J = 4 Hz), 7.92 (d, 1H, J = 8 Hz), 7.70 (dd, 1H, J = 1.8, 8 Hz), 7.47 (d, 2H, J = 8.4 Hz), 7.39 - 7.24 (m, 4H), 7.21 - 7.11 (m, 2H), 7.08 - 6.98 (m, 2H), 6.96 - 6.87 (m, 1H), 5.12 (s, 2H), 3.94 - 3.77 (m, 4H), 2.98 (s, 3H), 2.10 - 1.90 (m, 4H).

Example 12. 4-[3-[3-Fluoro-4-(2-Mei-1 - yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran.

M weight (Molek. weight 396,46).

So pl. 101,5o- 102oC.

IR (KBr) cm-1: 1584, 1542, 1434, 1304, 1351, 1073.

NMR (CDCl3) : 7.41 - 7.29 (m, 4H), 7.07 (d, 1H, J = 1 Hz), 7.05 - 7.02 (m, 2H), 6.96 (br, 1H), 6.91 (dd, 1H, J = 7, 3 Hz), 5.13 (s, 2H), 3.91 - 3.82 (m, 4H), 2.99 (s, 3H), 2.31 (s, 3H), 2.1 - 1.9 (m, 4H).

Example 13. 4-[5-fluoro-3-[2-fluoro-4-(2-Mei - 1-yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran.

M weight: 414,46.

So pl. 133,5o- 134oC.

IR (KBr) is .05 (d, 1H, J = 2 Hz), 7.01 (d, 1H, J = 2 Hz), 6.85 (br, 1H), 6.76 (d, 1H, J = 10 Hz), 6.65 (ddd, 1H, J = 10, 2, 2 Hz), 5.16 (s, 2H), 3.9 - 3.8 (m, 4H), 3.00 (s, 3H), 2.40 (s, 3H), 2.1 - 1.8 (m, 4H).

Example 14. 4-[3-[4-fluoro-2-(2-Mei-1 - yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran.

M weight: 396,46.

So pl. oil.

IR (neat.) cm-1: 1612, 1603, 1508, 1253, 1217, 1073.

NMR (CDCl3) : 7.69 (dd, 1H, J = 9, 4 Hz), 7.3 - 7.2 (m, 2H), 7.1 - 6.9 (m, 4H), 6.88 (t, 1H, J = 2 Hz), 6.73 (dd, 1H, J = 8, 2 Hz), 4.70 (s, 2H), 3.9 - 3.8 (m, 4H), 2.95 (s, 3H), 2.25 (s, 3H), 2.1 - 1.8 (m, 4H).

Example 15. 4-[3-[2-Chloro-4-(2-Mei-1 - yl)benzyloxy]-5-forfinal]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 467,37.

So pl. 204o- 205oC.

IR (KBr) cm-1: 1613, 1602, 1441, 1303, 1146, 1039.

NMR (CDCl3) : 7.89 (d, 1H, J = 8 Hz), 7.51 (br, 1H), 7.45 (d, 1H, J = 1 Hz), 7.40 (d, 1H, J = 8 Hz), 7.20 (d, 1H, J = 1 Hz), 6.87 (br, 1H), 6.79 (ddd, 1H, J = 10, 2, 2 Hz), 6.65 (ddd, 1H, J = 10, 2, 2 Hz), 5.22 (s, 2H), 3.9 - 3.8 (m, 4H), 3.02 (s, 3H), 2.80 (s, 3H), 2.0 - 1.8 (m, 4H).

Example 16. 4-[3-[2-Chloro-4-(2-Mei-1 - yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 449,38.

So pl. 224o- 225oC.

IR (KBr) cm-1: 1606, 1305, 1243, 1066, 1046, 1038, 755.

NMR (CDCl3) : 7.93 (d, 1H, J = 8 Hz), 7.48 (d, 1H, J = 2 Hz), 7.45 (d, 1H, J = 2 Hz), 7.4 - 7.3 (m, 2H), 7.19 (d, 1H, J = 2 Hz), 7.1 is telemedical-1 - yl)benzyloxy]-phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 446,95.

So pl. 207o- 280oC.

IR (KBr) cm-1: 1624, 1591, 1528, 1439, 1151, 1073.

NMR (CDCl3) : 7.70 (d, 1H, J = 9 Hz), 7.42 (d, 1H, J = 2 Hz), 7.3 - 7.2 (m, 2H), 7.17 (d, 1H, J = 2 Hz), 6.85 (br, 1H), 6.87 (ddd, 1H, J = 9, 2, 2 Hz), 6.65 (ddd, 1H, J = 10, 2, 2 Hz), 5.10 (s, 2H), 3.9 - 3.8 (m, 4H), 3.02 (s, 3H), 2.76 (s, 3H), 2.49 (s, 3H), 2.0 - 1.8 (m, 4H).

Example 18. 4-[5-fluoro-3-[4-(2-Mei-1-yl)-2 - trifluoromethyl-benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 500,92.

So pl. 198,5o- 199,5oC.

IR (KBr) cm-1: 1595, 1314, 1176, 1125, 1062.

NMR (CDCl3) : 8.11 (d, 1H, J = 9 Hz), 7.78 (br, 2H), 7.48 (d, 1H, J = 2 Hz), 7.24 (d, 1H, J = 2 Hz), 6.85 (br, 1H), 6.80 (d, 1H, J = 10 Hz), 6.61 (ddd, 1H, J = 10, 2, 2 Hz), 5.34 (s, 2H), 3.9 - 3.8 (m, 4H), 3.01 (s, 3H), 2.81 (s, 3H), 2.0 - 1.8 (m, 4H).

Example 19. 4-Methoxy-4-[3-[4-(2-Mei-1-yl)-2 trifluoromethyl-benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 482,93.

So pl. 213o- 215oC.

IR (KBr) cm-1: 1442, 1315, 1172, 1123, 1065, 1054.

NMR (CDCl3) : 8.15 (d, 1H, J = 8 Hz), 7.8 - 7.6 (m, 2H), 7.48 (d, 1H, J = 2 Hz), 7.35 (dd, 1H, J = 8, 8 Hz), 7.23 (d, 1H, J = 2 Hz), 7.1 - 7.0 (m, 2H), 6.90 (dd, 1H, J = 7, 3 Hz), 5.37 (s, 2H), 3.9 - 3.8 (m, 4H), 3.00 (s, 3H), 2.80 (s, 3H), 2.1 - 1.9 (m, 4H).

Example 20. 4-[2,4-Debtor-3-[4-(2-Mei-1 - yl)benzyloxy]phenyl] -4-methoxy-3,4,5,6-tetrahydro-2H-Piran Hydra is 5, 1281, 1094, 1023, 818.

NMR (CDCl3) : 7.75 (d, 2H, J = 8 Hz), 7.5 - 7.4 (m, 3H), 7.20 (d, 1H, J = 2 Hz), 7.09 - 6.91 (m, 2H), 5.25 (s, 2H), 3.9 - 3.8 (m, 4H), 3.05 (s, 3H), 2.76 (s, 3H), 2.2 - 2.1 (m, 4H).

Example 21. 4-[5-fluoro-3-[2-methoxy-4-(2-Mei-1 - yl)benzyloxy] phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 462,95.

So pl. 197,5o- 198,5oC.

IR (KBr) cm-1: 1612, 1590, 1440, 1329, 1242, 1150, 1042.

NMR (CDCl3) : 7.70 (d, 1H, J = 7 Hz), 7.42 (br, 1H), 7.21 (d, 1H, J = 2 Hz), 7.1 - 6.9 (m, 2H), 6.86 (br, 1H), 6.75 (d, 1H, J = 9 Hz), 6.64 (d, 1H, J = 10 Hz), 5.14 (s, 2H), 3.97 (s, 3H), 3.9 - 3.8 (m, 4H), 3.01 (s, 3H), 2.79 (s, 3H), 1.9 - 2.0 (m, 4H).

Example 22. 4-[3-[4-(2-Ethylimidazole-1-yl)benzyloxy] -5 - forfinal]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 446,95.

So pl. 210o- 211oC.

IR (KBr) cm-1: 1624, 1596, 1523, 1148, 1073, 1038.

NMR (CDCl3) : 7.71 (d, 2H, J = 8 Hz), 7.47 (d, 1H, J = 2 Hz), 7.42 (d, 2H, J = 8 Hz), 7.15 (d, 1H, J = 2 Hz), 6.85 (br, 1H), 6.77 (ddd, 1H, J = 10, 2, 2 Hz), 6.63 (ddd, 1H, J = 10, 2, 2 Hz), 5.17 (s, 2H), 3.9 - 3.8 (m, 4H), 3.06 (q, 2H, J = 8 Hz), 3.01 (s, 3H), 2.0 - 1.9 (m, 4H), 1.41 (t, 3H, J = 8 Hz).

Example 23. 4-[2,5-Debtor-3-[4-(2-Mei-1 - yl)benzyloxy]-phenyl] -4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 450,92.

So pl. 228o- 231oC (decomp.).

IR (KBr) cm-1: 1527, 1484, 1335, 1103, 853, 771.

Example 24. 4-[6-fluoro-2-[4-(2-Mei-1 - yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran.

M weight: 396,46.

So pl. 149o- 150,5oC.

IR (KBr) cm-1: 1606, 1518, 1554, 1418, 1305, 1282, 1071.

NMR (CDCl3) : 7.62 (d, 2H, J = 9 Hz), 7.33 (d, 2H, J = 8 Hz), 7.23 (ddd, 1H, J = 8, 8, 6 Hz), 7.04 (d, 1H, J = 2 Hz), 7.02 (d, 1H, J = 2 Hz), 6.79 (d, 1H, J = 8 Hz), 6.73 (ddd, 1H, J = 13, 8 Hz), 5.17 (s, 2H), 4.0 - 3.9 (m, 2H), 3.8 - 3.7 (m, 2H), 3.12 (s, 3H), 2.5 - 2.4 (m, 2H), 2.39 (s, 3H), 2.4 - 2.3 (m, 2H).

Example 25. 4-[5-fluoro-3-[4-(2-Mei-1 - yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran.

4-(5-fluoro-3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-Piran receive, as described in EP 0385662 A2, in the form of a white solid.

So pl. 130o- 132oC.

NMR (CDCl3) : 6.70 - 6.61 (m, 2H), 6.50 (dt, 1H, J = 10 and 2 Hz), 6.30 (s, 1H), 3.88 - 3.84 (m, 4H), 3.02 (s, 3H), 2.05 - 1.90 (m, 4H).

IR (KBr) cm-1: 3250, 1620, 1610, 1440, 1320, 1130.

Elemental analysis for C12H15FO3:

Calculated: C, 63.70, H 6.70%;

Found: C, 63.72, H 6.83%.

a. Ethyl 4-(2-Mei-1-yl)benzoate.

A mixture of 2-methylimidazole (50 g, 0.6 mol), ethyl 4-perbenzoate (100 g, 0.6 mol) and potassium carbonate (415 g, 3 mol) in dry DMCO (1.5 l) is heated at 120oC for 66 hours in Atmel) and extracted with Et2O (750 ml x 2). The organic phase is washed with water (500 ml) and salt solution (500 ml), dried (MgSO4) and evaporated. The remaining solid product is recrystallized from a mixture of ethyl acetate-hexane, obtaining 4-(2-Mei-1-yl)benzoate (47 g, 33%) as yellow needle crystals.

So pl. 72o- 73oC.

NMR (CDCl3) : 8.22 - 8.12 (m, 2H), 7.43 - 7.33 (m, 2H), 7.10 - 6.99 (m, 2H), 4.42 (q, 2H, J = 7 Hz), 2.42 (s, 3H), 1.43 (t, 3H, J = 7 Hz).

IR (KBr) cm-1: 1720, 1610, 1520, 1420, 1280.

Elemental analysis for C13H14N2O2:

Calculated: C, 67.80, H 6.10, N 12.20%;

Found: C, 67.97, H 6.17, N 12.20%.

b. 4-(2-Mei-1-yl)benzyl alcohol.

To a solution of ethyl 4-(2-Mei-1-yl)benzoate (46 g, 0.2 mol) in dry CH2Cl2(1 l), cooled to -75oC, in nitrogen atmosphere gently for 30 minutes add diisobutylaluminium (540 ml, 0.93 M in hexane) and the mixture is allowed to slowly warm to ambient temperature. After stirring for 5 hours the reaction mixture was cooled in an ice bath and carefully add methanol (30 ml). Add 30% aqueous solution of Rochelle salt (500 ml) and the mixture is stirred at room ambient temperature for 16 hours. The insoluble part (the core is Privat. The joint formed solid products are recrystallized from ethanol (approximately 300 ml) to give 4-(2-Mei-1-yl)benzyl alcohol (33.6 g, 95%) as white needle crystals.

So pl. 167o- 168oC.

NMR (DMCO-d6) : 7.50 - 7.33 (m, 4H), 7.25 (d, 1H, J = 1.5 Hz), 6.90 (d, 1H, J = 1.1 Hz), 5.33 (t, 1H, J = 6 Hz), 4.56 (d, 2H, J = 6 Hz), 2.73 (s, 3H).

IR (KBr) cm-1: 3200, 1520, 1420, 1310, 1060.

Elemental analysis for C11H12N2O:

Calculated: C, 70.20, H 6.40, N 14.90%;

Found: C, 70.12, H 6.41, N 14.81%.

c. 4-(2-Mei-1-yl)benzylchloride hydrochloride.

4-(2-Mei-1-yl)benzyl alcohol (1.28 g, 6.8 mmol) in SOCl2(5 ml) is stirred for 30 minutes at ambient temperature and then the volatile products are removed under reduced pressure. The resulting crude product is washed with a minimum amount of dry Et2O and dried in vacuum, obtaining 4-(2-Mei-1-yl)benzylchloride hydrochloride (1.65 g, quantitative.) in the form of a white solid product.

For free base:

NMR (CDCl3) : 7.56 - 7.47 (m, 2H), 7.34 - 7.25 (m, 2H), 7.03 (s, 1H), 7.00 (s, 1H), 4.65 (s, 2H), 2.37 (s, 3H).

d. 4-[5-fluoro-3-[4-(2-Mei-1-yl)benzyloxy] phenyl]- 4-methoxy-3,4,5,6-tetrahydro-2H-Piran.

A mixture of 4 is drochloride (1.65 g, 6.8 mmol) and potassium carbonate (7.2 g, 68 mmol) in dry DMF (10 ml) was stirred at 120oC for 2 hours. The mixture was poured into water (100 ml) and extracted with a mixture of ethyl acetate-benzene (300 ml, 2:1 V/V). The organic phase is washed with water (100 ml) salt solution (100 ml), dried (MgSO4) and evaporated. Cleaning the remaining yellow solid product column chromatography on silica gel (100 g) with elution with a mixture of CH2Cl2/methanol = 10 : 1 and recrystallization from a mixture of ethyl acetate-hexane gives 4-[5-fluoro-3-[4-(2-Mei - 1-yl)benzyloxy] phenyl] -4-methoxy-3,4,5,6-tetrahydro-2H-Piran (1.0 g, 39%) as not quite white solid product.

So pl. 168o- 168,5oC.

NMR (CDCl3) : 7.56 (d, 2H, J = 8 Hz), 7.34 (d, 2H, J = 8 Hz), 7.04 (d, 1H, J = 1 Hz), 7.01 (d, 1H, J = 1 Hz), 6.83 (br.s, 1H), 6.75 (ddd, 1H, J = 10, 2 and 2 Hz), 6.64 (ddd, 1H, J = 10.2 and 2 Hz), 5.11 (s, 2H), 3.86 - 3.81 (m, 4H), 2.99 (s, 3H), 2.38 (s, 3H), 1.99 - 1.88 (m, 3H).

IR (KBr) cm-1: 1590, 1520, 1416, 1138, 1072.

Elemental analysis for C23H25FN2O3:

Calculated: C, 69.68, H 6.36, N 7.07, 7.79%;

Found: C, 69.62, H 6.39, N 7.02, 4.62%.

The compounds of examples 26 to 40 is obtained from the relevant imidazolidinethione and phenols according to the General method of example 25, part d. In some cases, the product is transformed into far is-4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 460,97.

So pl. 140o- 143oC.

IR (KBr) cm-1: 1620, 1590, 1520, 1300, 1150.

NMR (DMCO-d6) : 7.86 (d, 1H, J = 2.2 Hz), 7.83 (d, 1H, J = 2.2 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.68 (d, 2H, J = 8.4 Hz), 6.95 - 6.77 (m, 3H), 5.28 (s, 2H), 3.78 - 3.59 (m, 4H), 3.15 - 3. 00 (m, 1H), 2.89 (s, 3H), 2.00 - 1.80 (m, 4H), 1.31 (d, 6H, J = 7.0 Hz).

Example 27. 4-[5-fluoro-3-[4-(2-propylimidazol-1 - yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 460,97.

So pl. 142o- 146oC.

IR (KBr) cm-1: 1620, 1590, 1530, 1440, 1290, 1140.

NMR (DMCO-d6) : 7.89 (d, 1H, J = 1.8 Hz), 7.82 (d, 1H, J = 2.2 Hz), 7.88 - 7.63 (m, 4H), 6.95 - 6.77 (m, 3H), 5.27 (s, 2H), 3.77 - 3.59 (m, 4H), 2.89 (s, 3H), 2.86 (t, 2H, J = 7.7 Hz), 2.00 - 1.80 (m, 4H), 1.70 - 1.52 (m, 2H), 0.79 (t, 3H, J = 7.3 Hz).

Example 28. 4-[2,3-Debtor-5-[4-(2-Mei-1 - yl)benzyloxy]phenyl] -4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 450,92.

So pl. > 200oC.

IR (KBr) cm-1: 1600, 1520, 1480, 1220, 880.

NMR (DMCO-d6) : 7.90 (d, 1H, J = 1.8 Hz), 7.79 (d, 1H, J = 1.8 Hz), 7.77 - 7.62 (m, 4H), 7.26 - 7.15 (m, 1H), 6.84 - 6.75 (m, 1H), 5.24 (s, 2H), 3.79 - 3.60 (m, 4H), 2.98 (s, 3H), 2.54 (s, 3H), 2.10 - 1.90 (m, 4H).

Example 29. 4-[2-Fluoro-5-[4-(2-Mei-1 - yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 432,93.

So pl. > 200oC.

IR (KB14 (dd, 1H, J = 8.8, 11.7 Hz), 7.07 - 6.91 (m, 2H), 5.22 (s, 2H), 3.78 - 3.60 (m, 4H), 2.95 (s, 3H), 2.55 (s, 3H), 2.10 - 1.90 (m, 4H).

Example 30. 4-[2,6-Debtor-3-[4-(2-Mei-1 - yl)benzyloxy]phenyl] -4-methoxy-3,4,5,6-tetrahydro-2H-Piran.

M weight: 414,45.

So square of butter.

IR (film) cm-1: 2950, 1580, 1480, 1420, 1300, 1250.

NMR (CDCl3) : 7.57 (d, 2H, J = 8.4 Hz, m), 7.33 (d, 2H, J = 8.4 Hz), 7.04 (d, 1H, J = 1.5 Hz), 7.01 (d, 1H, J = 1.5 Hz), 6.97 (ddd, 1H, J = 4.8, 8.8, 8.8 Hz), 6.88 - 6.75 (m, 1H), 5.13 (s, 2H), 4.00 - 3.70 (m, 4H), 3.13 (s, 3H), 2.37 (s, 3H), 2.40 - 2.20 (m, 4H).

Example 31. 4-[2-Fluoro-3-[4-(2-Mei-1 - yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran.

M weight: 396,46.

So pl. oil.

IR (film) cm-1: 1520, 1460, 1420, 1270, 1070.

NMR (CDCl3) : 7.62 - 7.54 (m, 2H), 7.38 - 7.29 (m, 2H), 7.12 - 6.92 (m, 3H), 5.18 (s, 2H), 3.98 - 3.78 (m, 4H), 3.09 (s, 3H), 2.38 (s, 3H), 2.29 - 2.05 (m, 4H).

This product is converted into its p-toluensulfonate salt by the procedure analogous to example 43.

M weight: 568,67.

So pl. 170o- 171oC.

IR (KBr) cm-1: 1620, 1530, 1480, 1280, 1240, 1160.

NMR (DMCO-d6) : 7.91 (d, 1H, J = 2.2 Hz), 7.81 - 7.62 (m, 5H), 7.52 - 7.43 (m, 2H), 7.32 - 7.06 (m, 4H), 7.01 - 6.91 (m, 1H), 5.28 (s, 2H), 3.80 - 3.61 (m, 4H), 2.95 (s, 3H), 2.53 (s, 3H), 2.28 (s, 3H), 2.13 - 1.90 (m, 4H).

Example 32. 4-Methoxy-4-[4-[3-(2-Mei-1 - yl)benzyloxy]phenyl]-3,4,5,6-Tetra is 7, 1230, 1183, 1072, 1008.

NMR (CDCl3) : 7.56 - 7.21 (m, 6H), 7.06 - 6.93 (m, 4H), 5.14 (s, 2H), 3.94 - 3.75 (m, 4H), 2.95 (s, 3H), 2.34 (s, 3H), 2.10 - 1.90 (m, 4H).

Example 33. 4-Methoxy-4-[4-[4-(2-Mei-1 - yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-Piran.

M weight: 378,47.

So pl. 150o- 151oC.

IR (KBr) cm-1: 1610, 1520, 1510, 1420, 1305, 1245, 1210, 1075, 1000.

NMR (CDCl3) : 7.57 (d, 2H, J = 8.4 Hz), 7.39 - 7.28 (m, 4H), 7.06 - 6.95 (m, 4H), 5.13 (s, 2H), 3.95 - 3.75 (m, 4H), 2.96 (s, 3H), 2.10 - 1.90 (m, 4H).

Example 34. 4-[5-fluoro-3-[3-(2-Mei-1 - yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran.

M weight: 396,46.

So pl. oil.

IR (film) cm-1: 2960, 1595, 1500, 1445, 1305.

NMR (CDCl3) : 7.58 - 7.44 (m, 2H), 7.39 (br.s, 1H), 7.33 - 7.21 (m, 1H), 7.08 - 6.98 (m, 2H), 6.86 - 6.56 (m, 3H), 5.12 (s, 2H), 3.93 - 3.73 (m, 4H), 2.98 (s, 3H), 2.36 (s, 3H), 2.12 - 1.85 (m, 4H).

Example 35. 4-[5-fluoro-3-[4-(2-cryptomaterial-1 - yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran.

M weight: 450,44.

So pl. 96o- 98oC.

IR (KBr) cm-1: 1695, 1440, 1190, 1130.

NMR (CDCl3) : 7.57 (d, 2H, J = 8.8 Hz), 7.41 (d, 2H, J = 8.4 Hz), 7.24 (d, 1H, J = 1.5 Hz), 7.16 (d, 1H, J = 1.1 Hz), 6.85 - 6.60 (m, 3H), 5.14 (s, 2H), 3.90 - 3.80 (m, 4H), 2.98 (s, 3H), 2.05 - 1.85 (m, 4H).

Example 36. 4 Ethoxy-4-[5-fluoro-3-[4-(2-Mei-1 - yl)benzyloxy]phenyl]-3,4,5,6-tism-1: 3235, 2905, 2870, 1621, 1516, 1417, 1382, 1335, 1299, 1145.

NMR (DMCO-d6) : 7.87 (d, 1H, J = 1.8 Hz), 7.77 (d, 1H, J = 2.1 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.68 (d, 2H, J = 8.4 Hz), 6.92 - 6.77 (m, 3H), 5.26 (s, 2H), 3.70 - 3.65 (m, 4H), 3.02 (q, 2H, J = 7.0 Hz), 2.56 (s, 3H), 1.97 - 1.81 (m, 4H), 1.05 (t, 3H, J = 7.0 Hz).

Example 37. 4-[5-fluoro-3-[4-(2-Mei-1 - yl)benzyloxy]phenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-Piran.

M weight: 382,44.

So pl. 190o- 191oC.

IR (KBr) cm-1: 3235, 2905, 2870, 1621, 1593, 1516, 1417, 1382, 1335, 1299, 1145.

NMR (CDCl3) : 7.57 - 7.53 (m, 2H), 7.35 - 7.31 (m, 2H), 7.02 (d, 1H, J = 1.5 Hz), 7.01 (d, 1H, J = 1.5 Hz), 6.96 (m, 1H), 6.85 (ddd, 1H, J = 1.5, 2.2, 9.5 Hz), 6.63 (ddd, 1H, J = 2.2, 2.6, 9.9 Hz), 5.11 (s, 2H), 3.99 - 3.83 (m, 4H), 2.37 (s, 3H), 2.21 - 2.08 (m, 2H), 1.97 (br.s, 1H), 1.70 - 1.61 (m, 2H).

Example 38. 4-[5-fluoro-3-[4-(2-Mei-1 - yl)benzyloxy]phenyl]-4-methylthio-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 448,99.

So pl. 216o- 217oC.

IR (KBr) cm-1: 2600, 1620, 1590, 1530, 1430, 1140.

NMR (DMCO-d6) : 7.89 (d, 1H, J = 2.2 Hz), 7.78 (d, 1H, J = 2.2 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.66 (d, 2H, J = 8.4 Hz), 6.89 (s, 2H), 6.85 (d, 1H, J = 1.8 Hz), 5.26 (s, 2H), 3.85 - 3.75 (m, 2H), 3.62 - 3.53 (m, 2H), 2.54 (s, 3H), 2.14 - 2.05 (m, 4H), 1.63 (s, 3H).

Example 39. 4-[5-fluoro-3-[4-(2-Mei-1 - yl)benzyloxy]phenyl]-4-methylsulfinyl-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 464,99.

So pl. 175,1d, 1H, J = 1.8 Hz), 7.78 (s, 1H), 7.74 (d, 2H, J = 8.2 Hz), 7.67 (d, 2H, J = 8.2 Hz), 7.02 (d, 1H, J = 11.0 Hz), 6.95 - 6.87 (m, 2H), 5.29 (s, 2H), 3.92 (d, 1H, J = 11.6 Hz), 3.80 (d, 1H, J = 11.6 Hz), 3.40 - 3.18 (m, 2H), 2.55 (s, 3H), 2.38 - 2.20 (m, 2H), 2.19 - 1.96 (m, 2H), 1.91 (s, 3H).

Example 40. 4-[5-fluoro-3-[4-(2-Mei-1 - yl)benzyloxy]phenyl]-4-methylsulphonyl-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 480,99.

So pl. 230,1o- 230,9oC.

IR (KBr) cm-1: 2850, 1625, 1590, 1530, 1330, 1290, 1270, 1140, 1130, 1100.

NMR (DMCO-d6) : 7.87 (d, 1H, J = 2.2 Hz), 7.78 (d, 1H, J = 2.2 Hz), 7.75 (d, 2H, J = 8.4 Hz), 7.65 (d, 2H, J = 8.4 Hz), 7.11 (s, 2H), 7.07 (s, 2H), 5.29 (s, 2H), 3.89 - 3.82 (m, 2H), 3.18 - 3.02 (m, 2H), 2.67 (s, 3H), 2.62 - 2.48 (m, 2H), 2.54 (s, 3H), 2.29 - 2.14 (m, 2H).

Example 41. 4-[5-fluoro-3-[4-(2-Mei-1 - yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

To a solution of 4-[5-fluoro-3-[4-(2-Mei-1-yl)benzyloxy]phenyl]- 4-methoxy-3,4,5,6-tetrahydro-2H-Piran (0.5 g, 1.3 mmol) in dry CH2Cl2(5 ml) is added Hydrogen Chloride; Methanol Reagent 10" (4 ml, Tokyo Chemical Industries)- "HCl; methanol reagent 10", Chemical industries, Tokyo) at ambient temperature. After stirring for 10 minutes the solvent is removed under reduced pressure. The crude product is recrystallized from isopropyl alcohol (4 ml) - ethanol (3 ml) to give 4-[5-fluoro-3- [4-(2-Mei-1-yl)gasoline is
- 234oC.

NMR (CDCl3) : 7.71 (d, 2H, J = 8 Hz), 7.43 (d, 1H, J = 2 Hz), 7.42 (d, 2H, J = 8 Hz), 7.19 (d, 1H, J = 2 Hz), 6.84 (br.s, 1H), 6.77 (ddd, 1H, J = 10.2 and 2 Hz), 6.62 (ddd, 1H, J = 10.2 and 2 Hz), 5.16 (s, 2H), 3.9 - 3.8 (m, 4H), 3.00 (s, 3H), 2.77 (s, 3H), 2.01 - 1.8 (m, 4H).

IR (KBr) cm-1: 1625, 1590, 1528, 1327, 1147.

Elemental analysis for C23H25FN2O3HCl:

Calculated: C, 63.81, H 6.05, N 6.47, Cl 8.19, F 4.39%;

Found: C, 63.63, H 6.17, N 6.42, Cl 8.18, F 4.32%.

Example 42. 4-[5-fluoro-3-[4-(2-Mei-1 - yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran fumarate.

To a solution of 4-[5-fluoro-3-[4-(2-Mei-1-yl)benzyloxy]phenyl]- 4-methoxy-3,4,5,6-tetrahydro-2H-Piran (150 mg, 0.38 mmol) in MeOH (3 ml) was added fumaric acid (44 mg, 0.38 mmol). The resulting solution was concentrated in vacuo. The remaining solid product is recrystallized from ethanol, getting 152 mg (77%) of 4-[5-fluoro-3-[4-(2-Mei-1-yl)benzyloxy]phenyl] -4-methoxy - 3,4,5,6-tetrahydro-2H-Piran fumarata in the form of a white powder.

So pl. 154o- 155oC.

IR (KBr) cm-1: 1626, 1595, 1529, 1329, 1290, 1144, 1075.

NMR (DMCO-d6) : 7.62 (brd, 2H, J = 8.4 Hz), 7.49 (brd, 2H, J = 8.4 Hz), 7.31 (d, 1H, J = 1.1 Hz), 7.00 - 6.74 (m, 4H), 6.62 (s, 2H), 5.21 (s, 2H), 3.80 - 3.58 (m, 4H), 2.89 (s, 3H), 2.30 (s, 3H), 2.00 - 1.80 (m, 4H).

Example 43. 4-[5-fluoro-3-[4-(2-Mei-1 - yl)resiliance] phenyl] - 4-methoxy-3,4,5,6-tetrahydro-2H-Piran p-toluensulfonate receive according to the method similar to example 42, using p-toluensulfonate acid instead of fumaric acid.

So pl. 168o- 171oC.

IR (KBr) cm-1: 1625, 1595, 1530, 1220, 1190.

NMR (DMCO-d6) : 7.90 (d, 1H, J = 2.2 Hz), 7.78 (d, 1H, J = 2.2 Hz), 7.74 (brd, 2H, J = 8.4 Hz), 7.66 (brd, 2H, J = 8.4 Hz), 7.47 (brd, 2H, J = 8.2 Hz), 7.11 (brd, 2H, J = 7.7 Hz), 6.95 - 6.75 (m, 3H), 5.26 (s, 2H), 3.80 - 3.60 (m, 4H), 2.89 (s, 3H), 2.52 (s, 3H), 2.28 (s, 3H), 2.00 - 1.80 (m, 4H).

Example 44. 4-[5-fluoro-3-[4-(2-Mei-1 - yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran L-tartrate.

4-[5-fluoro-3-[4-(2-Mei-1-yl)benzyloxy] phenyl] - 4-methoxy-3,4,5,6-tetrahydro-2H-Piran L-tartrate receive according to the method similar to example 42, using L-tartrate instead of fumaric acid.

So pl. 167o- 171oC.

IR (KBr) cm-1: 1614, 1528, 1439, 1300, 1075.

NMR (DMCO-d6) : 7.62 (brd, 2H, J = 8.4 Hz), 7.49 (brd, 2H, J = 8.4 Hz), 7.32 (brs, 1H), 7.08 - 6.73 (m, 4H), 5.21 (s, 2H), 4.28 (s, 2H), 3.78 - 3.55 (m, 4H), 3.40 (brs, 2H), 2.89 (s, 3H), 2.29 (s, 3H), 2.00 - 1.78 (m, 4H).

Example 45. 4-Methoxy-4-[3-[4-(2-Mei-1 - yl)benzilate]phenyl]-3,4,5,6-tetrahydro-2H-Piran.

So pl. 95,5o- 96oC.

IR (KBr) cm-1: 1518, 1421, 1303, 1070, 762.

NMR (CDCl3) : 7.38 (d, 2H, J = 8 Hz), 7.33 - 7.emer 46. 4-Methoxy-4-(hydroxyphenyl)-3,4,5,6-tetrahydro - 2H-Piran.

The compounds listed below, obtained from the corresponding phenols, using standard methods, according to the following reaction sequence:

(i) protection of the phenolic hydroxy-group in the form of her t-butyldimethylsilyl ether;

(ii) litrovaya second-butyllithium or n-butyllithium at -78oC;

(iii) condensation with tetrahydro-4H-Piran-4-one;

(iv) litrovaya tertiary hydroxy group, thus obtained, using sodium hydride or n-utility/under the conditions;

(v) removing silylamines group using tetrabutylammonium fluoride.

1. 4-(2,4-Debtor-3-hydroxyphenyl)-4-methoxy-3,4,5,6 - tetrahydro-2H-Piran.

Derived from 2,6-differenoe.

M weight: 244,26.

NMR (CDCl3) : 6.7 - 6.9 (m, 2H), 3.8 - 4.0 (m, 4H), 3.06 (s, 3H), 2.0 - 2.2 (m, 4H).

2. 4-(2-Fluoro-3-hydroxyphenyl)-4-methoxy-3,4,5,6 - tetrahydro-2H-Piran.

Is obtained from 2-terfenol.

M weight: 226,27.

NMR (CDCl3) : 7.07 - 6.92 (m, 2H), 6.88 - 6.79 (m, 1H), 5.71 (d, 1H, J = 5.5 Hz), 4.00 - 3.78 (m, 4H), 3.08 (s, 3H), 2.27 - 2.02 (m, 4H).

3. 4-(2-Fluoro-3-hydroxyphenyl)-4-methoxy-3,4,5,6 - tetrahydro-2H-Piran.

Obtained from 4-terfenol.

M weight: 226), 3.10 (s, 3H), 2.26 - 2.03 (m, 4H).

4. 4-(2,3-Debtor-5-hydroxyphenyl)-4-methoxy-3,4,5,6 - tetrahydro-2H-Piran.

Derived from 3,4-differenoe.

M weight: 244,26.

NMR (CDCl3) : 6.70 - 6.50 (m, 2H), 3.98 - 3.76 (m, 4H), 3.11 (s, 3H), 2.25 - 2.00 (m, 4H).

5. 4-(2,6-Debtor-3-hydroxyphenyl)-4-methoxy-3,4,5,6 - tetrahydro-2H-Piran.

Derived from 2,4-differenoe.

M weight: 244,26.

NMR (CDCl3) : 6.94 (ddd, 1H, J = 4.8, 9.2, 9.2 Hz), 6.78 (ddd, 1H, J = 2.2, 9.2, 11.3 Hz), 5.24 (d, 1H, J = 6.3 Hz), 4.00 - 3.70 (m, 4H), 3.13 (s, 3H), 2.39 - 2.17 (m, 4H).

6. 4-(4-Hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-Piran

Obtained from 4-bromophenol.

M weight: 208,28

NMR (CDCl3) : 7.30 - 6.21 (m, 2H), 6.87 - 6.78 (m, 2H), 5.45 (s, 1H), 3.95 - 3.76 (m, 4H), 2.95 (s, 3H), 2.11 - 1.90 (m, 4H).

Example 47. 4-(3-Hydroxy-5-forfinal)-4-methylsulfinyl-3,4,5,6 - tetrahydro-2H-Piran.

To a stirred solution of 4-(3-hydroxy-5-forfinal)-4 - methylthio-3,4,5,6-tetrahydro-2H-Piran (749 mg, 3.1 mmol) (EP 462830 A2, 1991) in a mixture of methanol-water (1 : 1, V/V; 20 ml), cooled to 0oC add NaO4(710 mg, 3.3 mmol), the ice bath removed and the mixture is stirred at room temperature for 2 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (50 ml). The organic extract was washed with water (50 ml the internal chromatography on silica gel (SiO2, 150 g, ethyl acetate), obtaining mentioned in the title compound as a white solid product.

NMR (CDCl3) : 8.93 (s, 1H), 6.77 (s, 1H), 6.60 (d, 1H, J = 9.9 Hz), 6.53 (d, 1H, J = 10.3 Hz), 4.09 - 3.88 (m, 2H), 3.66 - 3.48 (m, 2H), 2.50 - 2.29 (m, 2H), 2.20 - 2.00 (m, 2H), 2.06 (m, 3H).

Example 48. 4-5-Fluoro-(3-hydroxyphenyl)-4-methylsulphonyl-3,4,5,6 - tetrahydro-2H-Piran.

To a stirred solution of 4-(5-fluoro-3-hydroxyphenyl)-4 - methylthio-3,4,5,6-tetrahydro-2H-Piran (660 mg, 2.7 mmol) in chloroform (20 ml) is added m-CPBA (m-chloroperbenzoic acid) (1,48 mg, 6.0 mmol) and the mixture is stirred at room temperature overnight. To the reaction mixture add the calcium hydride (3 mmol) and the reaction mixture is vigorously stirred. Insoluble products are removed by filtration and the filtrate concentrated. The remaining solid products column chromatography on silica gel (SiO2, 150 g, hexane/ethyl acetate 1 : 2) to give 545 mg (81%) specified in the title compound as a white solid product.

NMR (CDCl3) : 6.86 (dd, 1H, J = 2.2, 2.2 Hz), 6.82 (ddd, 1H, J = 10.2, 2.2, 2.2 Hz), 6.64 (ddd, 1H, J = 9.5, 2.2, 2.2 Hz), 5.55 (s, 1H), 4.08 - 3.97 (m, 2H), 3.49 - 3.36 (m, 2H), 2.66 - 2.50 (m, 2H), 2.53 (s, 3H), 2.41 - 2.30 (m, 2H).

Example 49.

The following (1-imidazolyl)benzyl alcohols are synthesized from the corresponding source matela esters).

1. 2-Chloro-4-(2-Mei-1-yl)benzyl alcohol.

Is obtained from 2-methylimidazole and ethyl 2-chloro-4-perbenzoate.

M weight: 222,67.

NMR (CDCl3) : 7.69 (d, 1H, J = 8 Hz), 7.32 (d, 1H, J = 2 Hz), 7.24 (dd, 1H, J = 8, 2 Hz), 7.01 (d, 1H, J = 1 Hz), 6.99 (d, 1H, J = 1 Hz), 4.86 (s, 2H), 3.1 (br, 1H), 2.36 (s, 3H).

2. 3-Methyl-4-(2-Mei-1-yl)benzyl alcohol.

Is obtained from 2-methylimidazole and ethyl 4-fluoro-3-methylbenzoate.

M weight: 202,26.

NMR (CDCl3) : 7.37 (br, 1H), 7.31 (d, 1H, J = 8 Hz), 7.17 (d, 1H, J = 8 Hz), 7.04 (d, 1H, J = 1 Hz), 6.86 (d, 1H, J = 1 Hz), 4.76 (s, 2H), 2.17 (s, 3H), 2.05 (s, 3H).

3. 3-Fluoro-4-(2-Mei-1-yl)benzyl alcohol.

Is obtained from 2-methylimidazole and ethyl 3,4-differenziata.

M weight: 206,22.

NMR (CDCl3) : 7.2 - 7.4 (m, 3H), 7.03 (d, 1H, J = 1 Hz), 6.95 (br, 1H), 4.80 (s, 2H), 3.3 (br, 1H), 2.28 (s, 3H).

4. 2-Methyl-4-(2-Mei-1-yl)benzyl alcohol.

Is obtained from 2-methylimidazole and ethyl 4-fluoro-2-methylbenzoate.

M weight: 202,26.

NMR (CDCl3) : 7.51 (d, 1H, J = 8 Hz), 7.1 - 7.2 (m, 2H), 7.00 (d, 1H, J = 1 Hz), 6.97 (d, 1H, J = 1 Hz), 4.77 (s, 2H), 2.40 (s, 3H), 2.35 (s, 3H).

5. 4-(2-Mei-1-yl)-2-cryptomaterial alcohol.

Is obtained from 2-methylimidazole and ethyl 4-fluoro-2-triftoratsetata.

M weight: 256,23.

6. 2-Fluoro-4-(2-Mei-1-yl)benzyl alcohol.

Is obtained from 2-methylimidazole and ethyl 2,4-differenziata.

M weight: 206,22.

NMR (CDCl3) : 7.60 (dd, 1H, J = 8,8 Hz), 7.14 (dd, 1H, J = 8, 2 Hz), 7.03 (dd, 1H, J = 10, 2 Hz), 7.05 (d, 1H, J = 1 Hz), 6.99 (d, 1H, J = 1 Hz), 4.85 (s, 2H), 2.6 (br, 1H), 2.38 (s, 3H).

7. 2-Methoxy-4-(2-Mei-1-yl)benzyl alcohol.

Is obtained from 2-methylimidazole and ethyl 2-methoxy-4-perbenzoate.

M weight: 218,25.

NMR (CDCl3) : 7.43 (d, 1H, J = 8 Hz), 7.02 (d, 1H, J = 1 Hz), 7.00 (d, 1H, J = 1 Hz), 6.88 (dd, 1H, J = 8, 2 Hz), 6.78 (d, 1H, J = 2 Hz), 4.74 (s, 2H), 3.89 (s, 3H), 2.7 (br, 1H), 2.36 (s, 3H).

8. 4-(4-Mei-1-yl)benzyl alcohol.

Obtained from 4-methylimidazole and ethyl 4-perbenzoate.

M weight: 250,30.

NMR (CDCl3) : 7.65 (br, 1H), 7.4 - 7.5 (m, 2H), 7.3 - 7.4 (m, 2H), 7.0 (br, 1H), 4.8 (s, 2H), 2.3 (s, 3H).

9. 4-(2-Phenylimidazol-1-yl)benzyl alcohol.

Obtained from 4-vinylimidazole and 4-forventelige.

NMR (CDCl3) : 7.8 - 7.9 (m, 3H), 7.4 - 7.6 (m, 7H), 7.25 - 7.3 (m, 1H), 4.8 (br, 2H).

10. 4-(2-Ethylimidazole-1-yl)benzyl alcohol.

Is obtained from 2-ethylimidazole and ethyl 4-perbenzoate.

M weight: 202,26.

NMR (CDCl3) : 7.50 (d, 2H, J = 8 Hz), 7.28 (d, 2H, J = 8 Hz), 7.02 (d, 1H, J = 1 Hz), 6.97 (d, 1H, J = 1 Hz), 4.80 (s, 2H), 2.63 (dq, 2H, J = 1, 8 Hz), 1,23 and ethyl 4-perbenzoate.

M weight: 216,29.

NMR (CDCl3) : 7.60 - 7.80 (m, 6H), 4.80 (s, 2H), 2.70 - 2.45 (m, 2H), 2.00 - 1.50 (m, 3H), 1.00 - 0.70 (m, 3H).

12. 4-(2-Isopropylimidazole-1-yl)benzyl alcohol.

Is obtained from 2-isopropylimidazole and ethyl 4-perbenzoate.

M weight: 216,29.

NMR (CDCl3) : 7.55 - 7.80 (m, 6H), 4.79 (s, 2H), 3.07 - 2.85 (m, 1H), 2.37 (brs, 1H), 1.24 (d, 6H, J = 6.9 Hz).

13. 4-(2-Benzoimidazol-1-yl)benzyl alcohol.

Is obtained from 2-benzylimidazole and ethyl 4-perbenzoate.

M weight: 264,33.

NMR (CDCl3) : 7.54 - 7.37 (m, 2H), 7.28 - 7.10 (m, 8H), 7.00 (d, 1H, J = 1.5 Hz), 4.77 (d, 2H, J = 4 Hz), 4.02 (s, 2H), 2.20 - 2.07 (br, 1H).

14. 4-2-(Pyridin-2-yl)imidazol-1-yl benzyl alcohol.

Is obtained from 2-(pyridin-2-yl)imidazole and 4-perbenzoate.

M weight: 251,28.

NMR (CDCl3) : 8.36 - 8.27 (m, 1H), 7.89 (d, 1H, J = 8.1 Hz), 7.70 (dd, 1H, J = 1.8, 8.1 Hz), 7.39 (d, 2H, J = 8.8 Hz), 7.30 - 7.07 (m, 5H), 4.76 (d, 2H, J = 4.8 Hz), 2.07 (br, 1H).

15. 4-(2-Cryptomaterial-1-yl)benzyl alcohol.

Is obtained from 2-cryptomaterial and 4-perbenzoate.

M weight: 242,2.

NMR (CDCl3) : 7.55 - 7.05 (m, 6H), 4.80 (brd, 1H), 1.95 (brt, 1H).

Example 50. 3-(2-Mei-1-yl)benzyl alcohol.

a. 3-(2-Mei-1-yl)benzonitrile.

To mix the solution is), CuO (1.5 g), Cu powder (1.5 g) and CuBr (1.5 g) in a nitrogen atmosphere. The resulting mixture is heated at boiling temperature for 64 hours. The reaction mixture was filtered through a layer of celite and the filtrate concentrated in vacuo. The residue is purified column chromatography on silica gel, elwira a mixture of dichloromethane-methanol (10 : 1), which gives 12,9 g (23%) of 3-(2-Mei-1-yl)benzonitrile in the form of a white solid product.

NMR (CDCl3) : 7.80 - 7.63 (m, 4H), 7.07 (d, 1H, J = 1.5 Hz), 7.02 (d, 1H, J = 1.5 Hz), 2.39 (s, 3H).

b. 3-(2-Mei-1-yl)benzyl alcohol.

3-(2-Mei-1-yl)benzonitrile reduced to 3-(2-Mei-1-yl)benzyl alcohol using diisobutylaluminium hydride according to the procedure of example 4, part b.

M weight: 188,23.

NMR (CDCl3) : 7.51 - 7.15 (m, 4H), 7.00 (s, 2H), 4.79 (s, 2H), 2.34 (s, 3H).

Example 51.

The following compounds of the invention receive essentially according to the methods described above.

1. 4-Methoxy-4-[3-[4-(2-Mei-1-yl)benzylthio] - phenyl]3,4,5,6-tetrahydro-2H-Piran.

M weight: 394,54.

So pl. 95,5o- 96oC.

IR (KBr) cm-1: 1518, 1421, 1303, 1070, 762.

NMR (DMSO-d6) : 7.38 (d, 2H, J = 8 Hz), 7.33 - 7.23 (m, 4H), 7.20 (d, 2H, J = 8 Hz), 7.02 (d, 1H, J = 1 Hz), 6.97 (d, 1H, J = 1 Hz), 4.16 (s, 2H), 3.85 - 3.Neal]-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 446,97.

So pl. 148o- 150oC (decomposition).

IR (KBr)ncm-1: 1605, 1520, 1300, 1135.

NMR (DMSO-d6) : 7.64 (d, 2H, J = 8.4 Hz), 7.49 (d, 2H, J = 8.4 Hz), 7.36 - 7.22 (m, 4H), 6.92 (d, 1H, J = 1.5 Hz), 5.30 (s, 2H), 3.80 (m, 4H), 2.89 (s, 3H), 2.29 (s, 3H), 2.05 - 1.89 (m, 4H).

3. 4-[2-Fluoro-5-methoxy-3-[4-(2-Mei-1-yl)- benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 462,95.

So pl. 211,3o- 212,2oC

IR (KBr)ncm-1: 3070, 2980, 2960, 2880, 2590, 1660, 1525, 1490, 1445, 1430, 1210, 1170, 1100, 1160.

NMR (DMSO-d6) : 7.90 (d, 1H, J = 1.8 Hz), 7.78 (d, 1H, J = 1.8 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.68 (d, 2H, J = 8.4 Hz), 6.85 (dd, 1H, J = 6.6, 2.9 Hz), 6.44 (dd, 1H, J = 5.1, 2.9 Hz), 5.29 (s, 2H), 3.76 (s, 3H), 3.75 - 3.61 (m, 4H), 2.98 (s, 3H), 2.56 (s, 3H), 2.12 - 1.92 (m, 4H).

4. 4-[5-Chloro-2-fluoro-3-[4-(2-Mei-1-yl)- benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 467,37.

So pl. > 200oC.

IR (KBr)ncm-1: 1525, 1475, 1430, 1210.

NMR (DMSO-d6) : 7.90 (d, 1H, J = 2.2 Hz), 7.80 - 7.62 (m, 5H), 7.42 (dd, 1H, J = 2.6, 7 Hz), 6.97 (dd, 1H, J = 2.2, 5.9 Hz), 5.32 (s, 2H), 3.77 - 3.59 (m, 4H), 2.98 (s, 3H), 2.55 (s, 3H), 2.10 - 1.90 (m, 4H).

5. 4-[5-fluoro-5-methyl-3-[4-(2-Mei-1-yl)- benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 446,95.

So plz), 7.81 - 7.62 (m, 5H), 7.15 - 7.05 (m, 1H), 6.80 - 7.72 (m, 1H), 5.25 (s, 2H), 3.80 - 3.60 (m, 4H), 2.95 (s, 3H), 2.55 (s, 3H), 2.30 (s, 3H), 2.11 - 1.89 (m, 4H).

6. 4-[2-Fluoro-3-[4-(2-Mei-1-yl)benzyloxy] -5 - triptoreline]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran hydrochloride.

M weight: 500,29.

So pl. > 239o- 240oC (decomposition).

IR (KBr)ncm-1: 1525, 1442, 1368, 1308, 1215, 1118.

NMR (DMSO-d6) : 7.85 (d, 1H, J = 2 Hz), 7.75 (d, 2H, J = 8 Hz), 7.6 - 7.7 (m, 4H), 7.2 - 7.3 (m, 1H), 5.39 (s, 2H), 3.7 (br, 4H), 2.99 (s, 3H), 2.1 (br, 4H).

1. Imidazole derivatives of the formula:

< / BR>
or their pharmaceutically acceptable salt,

where Y is hydrogen, C1- C8-alkyl, galijasevic C1- C4-alkyl, phenyl, pyridyl, benzyl;

Ar1and Ar2each independently represents a phenylene, mono - or disubstituted phenylene, in which the substituents independently denote galijasevic C1- C4alkyl or halogen;

X and X1each independently represents O, S, SO or SO2;

R1denotes hydrogen or C1- C4alkyl;

R2and R3each independently represents a methylene or propylene.

2. Connection on p. 1, in which Ar1and Ar2each represent a phenylene or monosubstituted Fe is Voznesenie 1,4-phenylene and Ar2denotes a 1,3-phenylene or monosubstituted 1,3-phenylene.

4. Connection on p. 3, in which Ar1represents 1,4-phenylene or 2-fluoro-1,4-phenylene, Ar2represents 1,3-phenylene, 2-fluoro-1,3-phenylene or 5-fluoro-1,3-phenylene, X is O, R1is methyl, Y is alkyl, C1- C8.

5. Connection on p. 4, in which Y represents methyl.

6. Connection on p. 1, in which Ar1represents 1,4-phenylene or monosubstituted 1,4-phenylene and Ar2denotes a 2,5-debtor-1,3-phenylene.

7. Connection on p. 1, selected from the group consisting of 4-methoxy-4-[3-[4-(2-Mei-1-yl)benzyloxy] phenyl]-3,4,5,6-tetrahydro-2H-Piran, 4-[5-fluoro-3-[-4-(2-Mei-1-yl)benzyloxy] phenyl] -4-methoxy-3,4,5,6-tetrahydro-2H-Piran, 4-[3-[2-fluoro-4-(2 - Mei-1-yl)benzyloxy]phenyl] -4-methoxy-3,4,5,6-tetrahydro-2H-Piran, 4-[5-fluoro-3-[4-(2 - Mei-1-yl)benzyloxy] phenyl]-4-methylthio-3,4,5,6-tetrahydro-2H-Piran and 4-[2,5-debtor-3-[4-(2-Mei-1-yl)benzyloxy] phenyl] -4-methoxy-3,4,5,6-tetrahydro-2H-Piran.

8. Connection on p. 1, representing 4-[5-fluoro-3-[4-(2 - Mei-1-yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-Piran.

9. Connection on p. 1, representing 4-[5-fluoro-3-[4-(2 - Mei-1-yl)benzyloxy the

 

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