2,3-disubstituted pyridine derivative, the means of obtaining it, containing pharmaceutical composition and the intermediate product to obtain

 

(57) Abstract:

Describes the connection of the formula (I):

where And represents O, S, CH2or NH, X1and X2the same or different, and each of themrepresents H, halogen atom, cyano, and so forth, Y1represents N, Z1and Z2the same or different and each represents H, halogen atom, cyano, hydroxyl group, lower CNS group and so forth, and n is an integer from 2 to 4, its pharmaceutically acceptable salt, methods of its production, the pharmaceutical composition exhibiting inhibiting action against phosphodiesterase IV containing the compound of formula (I) as an active ingredient, and an intermediate connection for receiving it. The technical result - the compounds of formula (I) exhibit a potent inhibitory activity against PDE IV, and possess excellent bronchodilator activity, and therefore they can be widely used as inhibitors of PDE IV in the treatment and prevention of allergic inflammatory diseases or inflammatory diseases. 6 C. and 5 C.p. f-crystals, 5 PL.

Region the derivative of pyridine, showing inhibitory activity against phosphodiesterase IV (PDE IV), which can be applied as a medicinal product, and method of its production, to its containing pharmaceutical compositions and to the intermediate product to obtain it.

The level of technology

Currently, as a means to treat asthma using theophylline or different chemical antagonists of mediators, but these tools have disadvantages, for example they may not provide a sufficient inhibitory effect on bronchostenosis or sufficient action on inflammatory diseases of the respiratory tract, and, in addition, they do not show sufficient selectivity with respect to their adverse effects on the cardiovascular system. As a means for the treatment of asthma is also used steroids, but they have a powerful effect on inflammatory diseases of the respiratory tract, but their inhibitory effect on bronchostenosis weak, and, in addition, steroids are projected to experience severe side effects. Consequently, it is desirable to develop a new means of providing an inhibiting effect on bronchostenosis, and is also effective against inflammation of the respiratory tract.

Compounds of the following formula, for example, rolipram (U.S. patent No. 4193926), RP 73401 (WO 9212961), SB-207499 (WO 9319749), are given as examples of representative compounds with inhibitory activity against PDE IV:

In addition, in EP 773024 describes that connection, representing the N-substituted nicotinamide according to the following formula (A), has an inhibitory activity against PDE IV:

where R3is a 1-piperidyl, phenyl, benzyl, etc., Y represents hydrogen, fluorine or chlorine, and X represents hydrogen, fluorine, chlorine, methoxy, trifluoromethyl, cyano, carboxy, methylcarbamoyl, dimethylcarbamoyl or Carbo(C1-C4) alkoxy.

In addition, in WO 9845268 describes that connection, representing nicotinamide following formula (C), has an inhibitory activity against PDE IV:

where m submitted the defaults to a 0, 1, 2, or 3, r represents 0, 1, 2, 3 or 4, t represents 0 or 1, a represents an oxygen atom, >NH, and so on, represents an oxygen atom or NH, D represents an oxygen atom or NR9E represents CH2, an oxygen atom, NH or S(O)a, R1represents a hydrogen atom, (C1-C6) alkyl group, (C3-C7)heterocyclic group, etc., R2, R3and R4represent a hydrogen atom, hydroxyl group, etc., R5represents a heterocycle (C3-C7), R6, R7and R8represent a hydrogen atom, (C1-C6) alkyl group, etc.

However, conventional inhibitors of PDE IV may not provide sufficient bronchodilatory action, and in view of this circumstance it is desirable to develop a new inhibitor of PDE IV, which has a strong bronchodilatory effect and is effective against inflammation of the respiratory tract.

On the other hand, the compounds of the above formula (A) or (B), in which 3-Deputy pyridine ring is pyridylacetate, is not known.

The present invention is to obtain a new 2,3-disa the abuser activity against PDE IV.

The invention

The present invention relates to 2,3-disubstituted pyridine derivative of the formula (I) or its pharmaceutically acceptable salt, an inhibitor of phosphodiesterase IV, containing specified compound as an active ingredient, and containing pharmaceutical compositions of:

where a represents an oxygen atom, a sulfur atom, CHR1or NR2, R1and R2represent a hydrogen atom or a lower alkyl group;

X1and X2the same or different and each represents a hydrogen atom, a halogen atom, a nitro-group, a cyano, hydroxyl group, lower alkyl group, replacement of the lower alkyl group, halogen-substituted lower alkyl group, lower CNS group, lower cycloalkyl group, replacement of the lower CNS group, halogen-substituted lower CNS group, substituted lower CNS group lower CNS group, carboxyterminal lower CNS group, substituted lower alkoxycarbonyl group lower CNS group, carboxyl group, lower alkoxycarbonyl group, mono - or di-lower aminogroup, karbamoilnuyu group, 5-tetrazolyl group or a group which can be converted to a hydroxyl group in vivo;

Y1represents a hydrogen atom or a lower alkyl group;

Z1and Z2the same or different and each represents a hydrogen atom, halogen atom, cyano, hydroxyl group, lower alkyl group, replacement of the lower alkyl group, halogen-substituted lower alkyl group, lower CNS group, lower cycloalkyl group, replacement of the lower CNS group, halogen-substituted lower CNS group, substituted lower CNS group lower CNS group, carboxyterminal lower CNS group, substituted lower alkoxycarbonyl group lower CNS group, carboxyl group, lower alkoxycarbonyl group, mono - or di-lower alkylaminocarbonyl group, lower Allexinno group, amino group, mono - or di-lower alkylamino, lower allmenalp, lower alkoxycarbonyl, lower alkylsulfonyl, karbamoilnuyu group, 5-tetrazolyl group or a group that can be the Pharmaceutically acceptable salts include pharmaceutically acceptable acid additive salt, salt of alkali metal, alkali earth metal salt or a salt with an organic base. For example, an acid additive salt includes a salt with an inorganic acid such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc. or a salt with an organic acid, such as oxalate, maleate, fumarate, malonate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, p-toluensulfonate, gluconate, etc. Salt of an alkali metal includes, for example, a salt with an alkaline metal such as sodium salt, potassium salt, and the salt of the alkaline earth metal includes, for example, a salt of calcium salt of magnesium. Salt with organic base includes, for example, a salt with ammonia, methylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, dicyclohexylamine.

The connection according to the invention of formula (I) and its pharmaceutically acceptable salt may exist in the form of a hydrate and/or MES, and the present invention also includes these hydrate and solvate.

The compounds of formula (I) optionally may have one or more asymmetric carbon atoms, and the present invention also includes these stereoisomers and mixtures thereof.

If Z1and Z2predlitz, the compounds of formula (I) can be cetainly tautomer, and the present invention also includes these tautomers and their mixtures.

In connection with (I) a group which can be converted to a hydroxyl group in vivo, refers to a group that enzymatic or nonenzymatic can be destroyed to a hydroxyl group in vivo, for example, one in which the hydroxyl group allyawan, carbonyliron or carbonatation acetyl group, propionyloxy group, bentilee group, ethoxycarbonyl group, carbamoyl group, amino acid residue, and so on, Following compounds having such groups, sometimes called prodrugs.

The present invention also relates to intermediate compounds to obtain a 2,3-disubstituted pyridine derivative of the above formula (I), i.e. the derivative of pyridine following formula (II):

in which Z3represents a hydrogen atom, a lower alkyl group, lower cycloalkyl group, substituted lower CNS group, a lower alkyl group, lower acyl group, a benzyl group, benzoyloxy group or substituted mono - or di-lower CNS group is onilne group, lower Allexinno group, lower CNS group, substituted lower CNS group lower CNS group, amino group, lower alkoxycarbonyl or lower alkylsulfonamides.

Used in this description, the terms are explained below.

The term “lower alkyl group” includes an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyl, etc.

The term “halogen-substituted lower alkyl group includes an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, which is substituted by a halogen atom, for example triptorelin group.

The term “lower cycloalkyl group” includes cyclic alkyl group having 3 to 6 carbon atoms, such as cyclopentyl and cyclohexyl.

The term “lower acyl group” includes alkanoyloxy group with a straight or branched chain, having from 1 to 5 carbon atoms, for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl and pivaloyl.

The term “halogen atom” means a fluorine atom, chlorine, bromine or the second circuit, having from 1 to 6 carbon atoms, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, hexyloxy.

The term “lower cycloalkenyl group” includes cycloalkenyl group having from 3 to 6 carbon atoms, for example, cyclopentyloxy, cyclohexyloxy.

The term “lower Alchemilla group” includes alkenylphenol group with a straight or branched chain, having from 2 to 6 carbon atoms, for example allyl, 2-butenyl and 3-methyl-2-butenyl.

Among the compounds of formula (I) according to the present invention, preferred is a compound of formula (I) in which a represents an oxygen atom, a sulfur atom, CH2or NH, Z1and Z2are the same or different and each represents a hydrogen atom, halogen atom, hydroxyl group, lower CNS group, lower cycloalkyl group, replacement of the lower CNS group, halogen-substituted lower CNS group, substituted lower CNS group lower CNS group, carboxylterminal lower CNS group, substituted lower alkoxycarbonyl group lower CNS group, mo alkylamino, the lower allmenalp, lower alkoxycarbonyl, lower alkylsulfonyl, karbamoilnuyu group or a group which can be converted to a hydroxyl group in vivo, or their pharmaceutically acceptable salt.

More preferred are the compounds of formula (Ia) or their pharmaceutically acceptable salts:

where a1represents an oxygen atom, a sulfur atom, CH2or NH;

X11represents a hydrogen atom, a halogen atom, a nitro-group, a cyano, hydroxyl group, lower alkyl group, replacement of the lower alkyl group, halogen-substituted lower alkyl group, lower CNS group, replacement of the lower CNS group, halogen-substituted lower CNS group, lower alkoxycarbonyl group, mono - or di-lower alkylaminocarbonyl group or lower acyl group;

X21represents a hydrogen atom, halogen atom, lower alkyl group, lower CNS group, replacement of the lower CNS group, halogen-substituted lower CNS group;

Y1represents a hydrogen atom or a lower alket a hydrogen atom, halogen atom, hydroxyl group, lower CNS group, lower cycloalkyl group, replacement of the lower CNS group, halogen-substituted lower CNS group, substituted lower CNS group lower CNS group, carboxyterminal lower CNS group, substituted lower alkoxycarbonyl group lower CNS group, mono - or di-lower alkylaminocarbonyl group, lower Allexinno group, amino group, mono - or di-lower alkylamino, lower allmenalp, lower alkoxycarbonyl, lower alkylsulfonyl, karbamoilnuyu group or a group which can be converted to a hydroxyl group in vivo.

Particularly preferred are the following compounds or their pharmaceutically acceptable salts:

2 phenoxy-3-[3-(pyridin-4-yl)propoxy]pyridine;

2-(3-bromophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine;

2-(3-pertenece)-3-[3-(pyridin-4-yl)propoxy]pyridine;

2-(3-pertenece)-3-[3-(3-hydroxypyridine-4-yl)-propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridine-4-yl)-propoxy]pyridine;

2-(3-bromophenoxy)-3-[3-(3-hydroxypyridine-4-yl)-Ministers shall oxypyridine-4-yl)propoxy]pyridine;

2 phenoxy-3-[3-(3-acetoxyphenyl-4-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-acetoxyphenyl-4-yl)propoxy]-pyridine;

2-(3-chlorophenoxy)-3-[3-(3-chloro-5-hydroxypyridine-4-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridine-5-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-amino-5-hydroxypyridine-4-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-methylsulfonylamino-4-yl)propoxy]pyridine and

2-(3-pampanito)-3-[3-(pyridin-4-yl)propoxy]pyridine.

Representative compounds (I) according to the present invention are the compounds listed in table 1 or their pharmaceutically acceptable salts, in addition to the compounds described in the following examples.

Compounds (I) according to the present invention can be obtained, for example, using the following methods (a) and (b), as explained below.

Method (a)

The compound of formula (I) in which a represents an oxygen atom, a sulfur atom or CHR1you can obtain, if necessary, implementing a common way of introducing a protective group into the compound of the formula (III):

in which AND2is Soi of them represents a hydrogen atom, halogen atom, a nitro-group, a cyano, a lower alkyl group, halogen-substituted lower alkyl group, lower CNS group, lower cycloalkyl group, halogen-substituted lower CNS group, substituted lower CNS group lower CNS group, lower alkoxycarbonyl group, a lower acyl group or a lower Allexinno group, a R1and Y1have the meanings given above,

and in the compound of formula (IV):

in which Z12and Z22the same or different and each represents a hydrogen atom, halogen atom, cyano, hydroxyl group, lower alkyl group, lower CNS group, lower cycloalkyl group, substituted lower CNS group lower CNS group, lower alkoxycarbonyl group, lower Allexinno group, benzyloxy, benzoyloxy substituted mono - or di - lower CNS group benzoyloxy group, a substituted mono - or di - lower CNS group benzoyloxy, amino group, lower alkoxycarbonyl, lower alkylsulfonyl, and n has the meanings given above,

Dialkyldithiocarbamate includes, for example, diethylazodicarboxylate, diethylazodicarboxylate, diisopropylsalicylic, dibenzyldithiocarbamate, etc. in Addition, instead of triphenylphosphine, you can use trialkylphosphine, such as tri-n-butylphosphine and so on, the Reaction is preferably carried out at a temperature from-50C to 120C, preferably at a temperature of from 0C to 80C. The solvent can be used tetrahydrofuran, toluene, xylene, dichloromethane, etc.

The compound of formula (IV) may include the compound of the above formula (II), i.e. a compound of formula (IV), in which one of the substituents Z12and Z22attached in position 3 of the pyridine ring in the form of OZ3and the other of these substituents attached at position 4 or position 5 of the pyridine ring in the form Z4and hydroxyalkyloxy group, in which n represents 3 and attached including provision of 4 or 5 of the pyridine ring in which the above-mentioned Z42can be obtained by the reaction of compounds of formula (V):

in which L represents a halogen atom or a nitro-group, Z13and Z23the same or different and each represents a hydrogen atom, halogen atom, cyano, a lower alkyl group, lower CNS group, lower cycloalkyl group, substituted lower CNS group lower CNS group or lower alkoxycarbonyl group, a Y1and n have the meanings defined above, with a compound of formula (VI):

in which AND3represents an oxygen atom, a sulfur atom or NR2, a R2X12and X22have the meanings given above, in the presence of a base and a copper catalyst in a suitable solvent and, if necessary, removing the protective group of the obtained compound and then converting the substituents X12X22, Z13and Z23in other deputies in the usual way, if required. The base is preferably an alkali metal hydride, a carbonate of an alkali metal etc. Copper catalyst may preferably be present and (monovalent), bromide of divalent copper and so on, the Reaction is carried out at a temperature of from 80 to 220C, preferably at a temperature from 100C to 180C. The solvent preferably used dimethylformamide, dimethylimidazolidine, dimethylsulfoxide, dimethylacetamide, pyridine, toluene, xylene, etc.

The means of obtaining the source compounds for methods (a) and (b), i.e., compounds of formulas (II) to (VI) are described below.

The method of obtaining the compounds of formula (III):

The compound of formula (III), which is a source connection for the method (a) in which a represents an oxygen atom, i.e. a compound of the formula (1-4), can be obtained in accordance with the following scheme 1. Namely, conduct the reaction of the compound of formula (1-1) and compounds of formula (1-2) in the presence of a base and a copper catalyst in a suitable solvent, and then removing the protective group of the obtained compound of the formula (1-3), resulting in the compound of the formula (1-4).

Scheme 1

where Q represents a lower alkyl group, lower cycloalkyl group, substituted lower CNS group, a lower alkyl group, lower alkenylphenol group, benzyl group or tetrahed is of the formula (1-1) or (1-2) can be commercially available or can be obtained in the usual way. The base can be an alkali metal hydride, a carbonate of an alkali metal etc. Copper catalyst mainly can be a monovalent iodide copper bromide monovalent copper, chloride monovalent copper, copper powder, arised monovalent copper, ferrous bromide, copper and so on, the Reaction is carried out at a temperature of from 80 to 220C, preferably at a temperature from 100C to 180C. The solvent can be used dimethylformamide, dimethylimidazolidine, dimethylsulfoxide, dimethylacetamide, pyridine, toluene, xylene, etc.

The original connection for the method (a), the compound of formula (III) in which a represents a sulfur atom, i.e. a compound of formula (2-3), can be obtained in accordance with the following scheme 2. Namely, conduct the reaction of the compound of the formula (2-1) and the compounds of formula (2-2) in a suitable solvent, resulting in the compound of formula (2-3).

Scheme 2

where L, X12X22and Y1have the meanings given above

The compounds of formula (2-1) or (2-2) may be commercially available or can be obtained in the usual way. The reaction is carried out at a temperature of from 0C to 200C, preferably at temperaturerated, dimethylacetamide, toluene, xylene, tetrahydrofuran, etc.

The original connection for the method (a), the compound of formula (III) in which a represents a CHR1, i.e. the compound of the formula (3-6) or (3-8), can be obtained in accordance with the following scheme 3. Namely, the compound of the formula (3-1) is converted into compound lithium salt of the formula (3-1A), which then lead into interaction with the compound of the formula (3-2), with the compounds of formula (3-3). If R1represents a hydrogen atom, the compound of the formula (3-3) oxidised with obtaining the compounds of formula (3-4), which is then subjected to recovery with obtaining the compounds of formula (3-5). Then remove the protective group from compounds of formula (3-5), resulting in the compound of the formula (3-6). If R1represents a lower alkyl group, the compound of the formula (3-3) is subjected to restore, to obtain the compounds of formula (3-7), which then removes the protective group and get the connection formula (3-8).

Scheme 3

If R1represents a hydrogen atom

If R1represents a lower alkyl group

Compounds of formula (3-1) or (3-2) may be commercially available or can be obtained in the usual way. The compound of the formula (3-1) can be converted into its corresponding lithium salt by reaction with a base, such as n-utility, in a suitable solvent. The reaction is carried out at a temperature of-150C to 100C, preferably at a temperature of from 80 to 0C. The solvent can be used toluene, xylene, tetrahydrofuran, diethyl ether, dioxane, etc.

The compound of formula (3-2) are added to the reaction solution containing the thus obtained compound of the formula (3-1A), and conducting the reaction. The reaction is carried out at a temperature of-150C to 100C, preferably at a temperature of from 80 to 0C.

The compound of formula (3-4) obtained by the reaction of compounds of formula (3-3), in which R1represents a hydrogen atom, in the presence of an oxidising agent, such as activated manganese dioxide and so on, in a suitable solvent. The reaction is carried out at a temperature from-20C to 120C, preferably at a temperature of from 0C to 100C. The solvent can be used toluene, tetrahydrofuran, dioxane, methylene chloride, hexane, etc.

The base can be an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc. and the solvent may be ethylene glycol, diethylene glycol, etc. the Reaction is carried out at a temperature of from 0C to 220C, preferably at a temperature from 100C to 200C.

The compound of the formula (3-7) receive, subjecting the compound of the formula (3-3), in which R1represents a lower alkyl group, catalytic recovery in the presence of palladium on coal, and optionally in the presence of an acidic catalyst such as hydrochloric acid, acetic acid, Perlina acid, etc. in a suitable solvent in a hydrogen atmosphere. The reaction is carried out at a temperature from-40C up to 110S, preferably at a temperature of from 0C to 70C. The solvent may be methanol, ethanol, ethyl acetate, toluene, xylene, tetrahydrofuran, dioxane, etc.

The removal of the protective group from the compound (3-5) and compounds (3-7) is carried out in the presence of a suitable acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, camphorsulfonic acid, etc. in an appropriate solvent such as water, methanol, ethanol, isopropanol, acetic acid and other Reaction is carried out at temperly (II) or formula (IV):

The original connection for the method (a), i.e. the compound of formula (IV) can be found in the sale or obtain, in accordance with scheme 4. Similarly it is possible to obtain the compound of formula (II), which is covered by the volume formula of compound (IV), i.e. a compound of formula (IV), in which one of the substituents Z12or Z22is in position 3 of the pyridine ring in the form of OZ3and the other of these substituents occupies position 4 or 5 of the pyridine ring in the form Z4and hydroxyalkyloxy group, in which n represents 3, position 4 or 5 of the pyridine ring, free from substituent Z4.

Scheme 4

where E represents a bromine atom or an iodine atom, G represents a lower alkyl group, a substituted lower CNS group, a lower alkyl group, allyl group, benzyl group or tetrahydropyranyl group, Z14, Z24represent a halogen atom, Z15, Z25the same or different and each represent a halogen atom, cyano, lower CNS group, lower cycloalkyl group, lower alkoxycarbonyl group or benzyloxyphenyl group, and Z13, Z23Elah (IV), in which n represents 2 or 4, is obtained by the reaction of compounds of formula (4-1) with trimethylsilylmethylamine in a suitable solvent, converting the product obtained into a compound of formula (4-2), which places him at conditions with the required acidity, and then the compound of formula (4-2) is subjected to reaction hydroporinae, and then oxidation and hydrolysis to obtain the compounds of formula (4-3), and optionally followed by conversion of the Z13and Z23the usual way.

The compound of the formula (4-1) can be found on sale or get in the usual way. The reaction of the compound (4-1) with trimethylsilylmethylamine preferably carried out at a temperature from-150C to 100C, preferably at a temperature of from-70C to 0C. The solvent may be toluene, xylene, tetrahydrofuran, diethyl ether, dioxane, etc.

Thus obtained compound (4-2) are hydroborating in the presence hydroperiodide agent such as a complex of borane-pyridine complex borane-tetrahydrofuran or 6-borabicyclo[3.3.1]nonan and others, in a suitable solvent, and then subjected to oxidation with subsequent basic hydrolysis. The reaction hydroporinae carried out at tempuran, diethyl ether, dioxane, etc. the oxidation Reaction and subsequent hydrolysis is carried out by adding an aqueous solution of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc. to the reaction solution hydroporinae, and then with an aqueous solution of hydrogen peroxide. The reaction is carried out at temperatures from-100C to 100C, preferably at a temperature of from-70C to 50C.

Among the starting compounds (IV) for the method (a) compound of formula (IV) in which n represents 3, obtained by the reaction of the compound (4-4) with a salt of an alkali metal and trialkylphosphates in a suitable solvent to obtain the compound (4-5), which is then subjected to catalytic hydrogenerating, after which the compound obtained (4-6) is subjected to reduction with hydride, resulting in a receive connection (4-7), and optionally followed by conversion of the Z13, Z23the usual way.

The compound (4-4) can be found on sale or get in the usual way. The reaction of the compound (4-4) is carried out by performing the reaction of alkaline salts trialkylphosphates, which is obtained in the reaction of trialkylphosphates, such as trimethylphosphate solvent. The reaction is carried out at a temperature from-50C to 100C, preferably at temperatures from-20C to 70C. The solvent may be toluene, xylene, tetrahydrofuran, diethyl ether, dioxane, etc.

Thus obtained compound (4-5) can be converted to a compound of the formula (4-6) by catalytic reduction in the presence of palladium on coal in a hydrogen atmosphere. The reaction is carried out at a temperature from-40C up to 110S, more preferably at a temperature of from 0C to 70C. The solvent may be methanol, ethanol, ethyl acetate, toluene, xylene, tetrahydrofuran, dioxane, etc.

Further, the compound (4-6), subject to recovery by the use of such agent, as sociallyengaged and others, in a suitable solvent. The reaction is carried out at a temperature from-50C to 100C, preferably at a temperature of from 0C to 70C. The solvent may be toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, etc.

Among the starting compounds (IV) for the method (a) compound of formula (IV) in which n represents 3, can also be obtained by the reaction of compounds of formula (4-8) with ethylene oxide in the presence of a base to obtain the compounds of formula (4-7) and, if necessary, with subsequent dicit in the usual way. Connection (4-8) can be converted to a compound of the formula (4-7) by treatment with base, such as diisopropylamide lithium hexamethyldisilazide lithium, sodium amide, etc. in a suitable solvent, obtaining as a result of its corresponding salt of an alkali metal, followed by reaction with ethylene oxide. The reaction is carried out at a temperature of-120C to 100C, preferably at a temperature of from 80 to 20C. The solvent may be toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, etc.

Among the starting compounds (IV) for the method (a) compound of formula (IV) in which n represents 3, and in position 4 of the pyridine ring is propanamine group, can be obtained by the reaction of compounds of formula (4-9) with the compound of the formula (4-10) in the presence of a base and optionally followed by conversion of the 14the compounds of formula (4-11) in the usual way and the removal of the protective group to obtain the compounds of formula (4-12), and optionally converting the Z15and Z25the usual way.

The compound (4-9) and the compound (4-10) can be found on sale or get in the usual way. The compound of formula (4-11) can be obtained by processing soy is in a suitable solvent to obtain its salts with alkali metal followed by the reaction with the compound of the formula (4-10). The reaction is carried out at a temperature of-120C to 100C, preferably from 80 to 20C. The solvent may be toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, etc.

The method of obtaining the compounds of formula (V):

The original connection (V) for method (b), which represents the same compound as the compound of the formula (5-3), can be obtained in accordance with the following scheme 5. Namely, conduct the reaction of the compounds of formula (5-1) and the compounds of formula (5-2) in the presence of triphenylphosphine and dialkyldithiocarbamate in a suitable solvent to obtain the compound of formula (5-3).

Scheme 5

where L, Y1, Z13, Z23and p have the meanings defined above.

The compound (5-1) can be found on sale or get in the usual way. Dialkyldithiocarbamate includes diethylazodicarboxylate, diethylazodicarboxylate, diisopropylsalicylic, dibenzyldithiocarbamate etc. Instead of triphenylphosphine, you can use trialkylphosphine, such as tri-n-butylphosphine etc. the Reaction is carried out at a temperature from-50C to 120C, preferably at a temperature of from 0C to 80C. The solvent may be tetrahydrofuran, toluene, xylene, dichloro the emnd reaction, shown in figure 4, is similar to obtaining the compounds of formula (4-3), compounds (4-7) and the compound (4-12), as described above.

The method of obtaining the compounds of formula (VI):

The original compound (VI) to method (b) can be found on sale or get in the usual way.

Pharmacological experiments

Pharmacological experiments were performed on representative compounds according to the present invention. The results obtained and the pharmacological activity of the compounds according to the present invention are described below.

Experiment 1: Test the activity of inhibiting PDE IV

Test for the activity of inhibiting PDE IV was performed in accordance with the method of using the eosinophils obtained from the abdominal Guinea pigs (Souness, J. E. et al., Biochem. Pharmacol. vol. 42, p. 937 (1991)). In accordance with this method of homogenizing buffer (10 ml, components: 20 mm buffer Tris-HCl (pH 7.5); 2 mm magnesium chloride; 1 mm dithiothreitol; 5 mm disodium salt ethylenediaminetetraacetic acid (EDTA); 250 mm sucrose; 20 mm n-tosyl-1-lysine-chloromethylketone; 10 μg/ml leupeptin) was added to 5107cells and the resulting mixture was centrifuged. To the residue was added solubilizers buffer (10 ml, for the floor is tion: 100 mm) was added to the above homogenizing buffer) and the mixture was again centrifuged. The supernatant was subjected to ultrafiltration using a device Molcut-II (manufactured Japan Millipore Limited), and the fraction deposited on the membrane were collected by adding a homogenizing buffer (10 ml) and the thus obtained enzyme preparation. Inhibitory activity against this enzyme was determined by comparing the speed of hydrolysis of the substrate (camp produced Nacalai Tesque Inc.), caused by the above-mentioned fraction of the enzyme between the group treated with the test compound, and the group receiving only the media. In addition, the value of the 50% inhibitory concentration, i.e., IR50received from curve between concentration and activity of the tested compounds. Compounds of examples according to the present invention, listed in table 2, was used as the test compounds, and rolipram, RP 73401 SB-207499, which is known to have inhibitory activity against PDE IV, used as control compounds. The results are presented in table 2.

As can be seen from table 2, the compounds of formula (I) according to the present invention exhibit a potent inhibitory activity against PDE IV isolated from Guinea-pig eosinophils.

As can be seen from table 3, the compounds of formula (I) according to the present invention exhibit a potent inhibitory activity against bronchostenosis Guinea pigs induced by antigen.

From the above pharmacological experiments show that the compounds of formula (I) according to the present invented the x2">

In addition, these compounds of formula (I) according to the present invention viscotoxin. In the test for acute toxicity, for example, the compound of example 31 was never shown any toxicity even at a dose of 2000 mg/kg

The compounds of formula (I) according to the present invention can be entered as an inhibitor of PDE IV either orally or intraperitoneally, or rectally. Compounds of the present invention can also be entered by using the infiltration through the lungs, or by application to mucous membranes of the mouth or nose. The dose of the compounds of the present invention depends on the method of administration, the condition and age of the patient, etc. and also from the purpose of introduction, i.e. whether prevention or treatment, but it usually is in the range from 0.01 to 100 mg/kg/day, preferably in the range from 0.1 to 50 mg/kg/day.

The compounds of formula (I) according to the present invention is usually administered in the form of a pharmaceutical preparation which is prepared by mixing this compound with a pharmaceutically acceptable carrier or diluent. Pharmaceutically acceptable carrier or diluent may be any conventional carriers or diluents commonly used in the pharmaceutical industry and not reagir the carriers or diluents are, for example, lactose, glucose, mannitol, dextrin, starch, white sugar, aluminate-metasilicate magnesium, synthetic aluminum silicate, crystalline cellulose, carbometalation sodium, oxypropylene (modified) starch, ion exchange resin, methylcellulose, gelatin, gum Arabic based on the Arabian gum, oxypropylene cellulose, nizkozameshhennoj oxopropylidene cellulose, oxypropylation cellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, ester sorbitan and fatty acids, sodium lauryl sulfate, glycerin, esters of glycerin and fatty acids, purified lanolin, glycoregulation, Polysorbate, macrogol, vegetable oil, wax, nonionic surfactant, propylene glycol, water, etc.

The pharmaceutical preparation is, for example, tablets, capsules, granules, powders, syrups, suspensions, suppositories, gels, injections, inhalations, nasal drops, etc. These preparations can be produced by conventional means. When cooking liquids compound of the present invention can be dissolved or suspended is prepared in the usual way. As for preparations for injection, it is preferable to dissolve the compound of formula (I) in water, if necessary with the use of isotonic agent, followed by addition of a pH regulator, sautereau agent or preservative.

These preparations may contain a compound of the formula (I) according to the present invention in amount of at least 0.01 percent, preferably in amounts of 0.05-70%. These preparations can also contain other therapeutically effective compounds.

If necessary, these drugs can be used together with anti-allergic agent, a steroid,2stimulator, an anticholinergic agent.

The best option of carrying out the invention

Examples

The present invention is illustrated in more detail using the following examples, however, the scope of the invention, these examples are not limited. Identification of compounds is carried out using elemental analysis, by determining the spectrum of the proton nuclear magnetic resonance1H-NMR (TMR) and other

To simplify the description of the PMR uses the following abbreviations:

J: constant interaction

s: singlet

dt: double triplet

q: Quartet

m: multiplet

In sravnitelnyh examples and examples the main method chromatography on a column of silica gel was performed using the device Chromatorex NH, manufactured by Fuji Silysia Chemical Ltd.

Comparative example 1: Obtain 2-(3-pampanito)-3-pyridinol

2-Bromo-3-pyridinol (44 g, 250 mmol) and 3-bromothiophene (30 g, 160 mmol) is dissolved in tetrahydrofuran (THF) (100 ml) and dimethylformaldehyde (DMF) (100 ml) and the resulting mixture is heated in a flask under reflux for 5 hours. The mixture is cooled, then to it was added ethyl acetate (1000 ml), washed with 5% aqueous solution of sodium hydroxide (50 ml of 2) and saturated saline solution (100 ml of 2), and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to recrystallization from ethyl acetate, to deliver specified in the header of the example compound (35 g) in the form of colorless crystals with a melting point 125-S.

In the same manner as in comparative example 1, carried out the reaction of the corresponding starting compounds for preparing compounds of comparative examples 2 to 8.

Comparative example 2: 2-(2-bromfeild original

Melting point: 214-S.

Comparative example 4: 2-(3-cryptosecurity)-3-pyridinol

Melting point: 125-S.

Comparative example 5: 2-(3-forfinally)-3-pyridinol

Melting point: 147-S.

Comparative example 6: 2-(3-chlorophenylthio)-3-pyridinol

Melting point: 148-S.

Comparative example 7: 2-(3-methoxyphenyl)-3-pyridinol

Melting point: 116-117S.

Comparative example 8: 2-phenylthio-3-pyridinol

Melting point: 137-S.

Comparative example 9: Obtain 2-(3-hydroxyphenyl)-3-pyridinol

A mixture of 2-(3-methoxyphenyl)-3-pyridinol (2.0 g, 8.6 mmol) obtained in comparative example 7, and pyridinecarboxamide (17 g) was stirred at 200C for one hour. Mixture is allowed to cool, after which it was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (300 ml). The organic layer was washed with saturated saline solution (100 ml of 2), dried over anhydrous magnesium sulfate and concentrated to dry under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate), and the and the compound (1.24 g) as colorless crystals with a melting point 147-S.

Comparative example 10: Obtain 2-bromo-3-cyclopentenopyridine

Triphenylphosphine (94 g, 360 mmol) and Cyclopentanol (43 g, 500 mmol) dissolved in THF (500 ml) and to the resulting mixture while stirring diisopropylsalicylic (71 g, 350 mmol) at room temperature. To the mixture is added 2-bromo-3-pyridinol (50 g, 290 mmol) while cooling on ice, after which the mixture was stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure and the residue purified via chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver specified in the header of the example compound (51 g) as a pale yellow oil.

Comparative example 11: Obtain 2-(3-bromophenoxy)-3-pyridinol

(i) 2-Bromo-3-cyclopentenopyridine (20 g, 83 mmol) obtained in comparative example 10 and 3-bromophenol (26 g, 150 mmol) dissolved in DMF (50 ml) to the resulting mixture is added potassium carbonate (42 g, 300 mmol) and copper bromide (monovalent) (18 mg, 130 mmol) and the resulting mixture was stirred at 140 C for one hour. After the reaction mixture has cooled, it was poured into ice, add 48% Hydrobromic acid (50 ml) and the mixture is stirred in takeitem (500 ml 2). The organic layer was washed with saturated saline solution (100 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified using the main method chromatography on a column of silica gel (eluent: ethyl acetate/hexane) to give the result 2-(3-bromophenoxy)-3-cyclopentenopyridine in the form of a pale yellow oil.

(ii) the Oily product obtained as described above, is dissolved in acetic acid (250 ml), add to it 47% aqueous solution of Hydrobromic acid (100 ml) and the resulting mixture is heated in a flask under reflux for 4 hours. The reaction solution is concentrated under reduced pressure, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (500 ml 2). The organic layer was washed with saturated saline solution (100 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified using the main method chromatography on a column of silica gel (eluent: ethyl acetate/hexane) and then recrystallized from isopropyl ether/hexane, to deliver specified in the header of the example compound (15 g) as colorless crystals with temperatureui starting compounds for preparing compounds of comparative examples 12 to 14.

Comparative example 12: 2-phenoxy-3-pyridinol

Melting point: 92-93S.

Comparative example 13: 2-(3-pertenece)-3-pyridinol

Melting point: 84-85C.

Comparative example 14: 2-(3-chlorophenoxy)-3-pyridinol

Melting point: 86-90.

Comparative example 15: Getting 2-(3-cianfrocca)-3-methoxypyridine

3-Bromo-3-methoxypyridine (15 g, 68 mmol) and 3-cyanoprop (8,9 g, 75 mmol) dissolved in DMF (150 ml) to the resulting mixture is added potassium carbonate (28 g, 0.2 mmol) and copper bromide (monovalent) (10.7 g, 75 mmol), the mixture was heated in a flask under reflux at 140 C for 1.5 hours. After the reaction mixture has cooled to it was added ethyl acetate (1000 ml), the mixture was washed with saturated saline (200 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is recrystallized from isopropyl ether/hexane, to deliver specified in the header of the example compound (11.1 g) as pale-brown crystals with a melting point of 88-89S.

Comparative example 16: Getting 2-(3-cianfrocca)-3-pyridinol

2-(3-Cianfrocca)-3-methoxypyridine (10 g, 44 mmol),IDA boron in methylene chloride (170 ml, 170 mmol) under cooling on ice. The mixture is then stirred at room temperature for 36 hours, then the reaction quenched by adding saturated brine. The mixture is neutralized with sodium bicarbonate and extracted with chloroform (500 ml 2). The organic layer was washed with saturated saline (200 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified using the main method chromatography on a column of silica gel (eluent: chloroform/ethanol), to deliver specified in the header of the example compound (5.2 g) as colorless crystals with a melting point 130-S.

Comparative example 17: Getting 2-(3-acetylphenol)-3-pyridinol

2-(3-Cianfrocca)-3-pyridinol (3.0 g, 14 mmol) obtained in comparative example 16, was dissolved in THF (50 ml) to the resulting mixture add a solution metallice in diethyl ether (21,4 ml, 30 mmol) at a temperature of 70 C and the mixture is stirred for 30 minutes. The reaction is quenched by adding acetone (5 ml). The mixture is acidified with 10% aqueous hydrochloric acid (15 ml), then neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (300 ml 2). Organics under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver specified in the header of the example compound (3.0 g) as a pale yellow oil.

Comparative example 18: Getting 2-(3-ethoxycarbonylphenyl)-3-pyridinol

(i) 3-Benzyloxy-2-bromopyridine (8 g, 30 mmol) and ethyl-3-hydroxybenzoate (13.3 g, 80 mmol) dissolved in DMF (50 ml) and to the resulting mixture is added potassium carbonate (28 g, 0.2 mmol) and copper bromide (univalent) in (11.5 g, 80 mmol). The mixture is heated in a flask under reflux at 140 C for one hour. After the reaction mixture has cooled, it is acidified with 15% aqueous solution of hydrochloric acid (50 ml), then neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (300 ml 2). The organic layer was washed with saturated saline (200 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver 3-benzyloxy-2-(3-ethoxycarbonylmethoxy)pyridine as a pale yellow oil.

(ii) the Oily product obtained as described above, dissolved in atature for one hour in hydrogen atmosphere. The reaction solution is filtered, to remove insoluble substances, and concentrate under reduced pressure. The residue is purified using the main method chromatography on a column of silica gel (eluent: ethyl acetate/ethanol), and then recrystallized from diethyl ether/hexane, to deliver specified in the header of the example compound (5.4 g) as colorless crystals with a melting point 117-S.

Comparative example 19: Obtaining 2-(3-bromobenzoyl)-3-methoxypiperidine

2-Bromo-3-methoxypyridine (22 g, 100 mmol) dissolved in diethyl ether (500 ml) to the resulting mixture add a solution of n-utility in hexane (69 ml, 110 mmol) under cooling at-60C and stirred for 15 minutes. To the mixture add 3-bromobenzaldehyde (20 g, 110 mmol) and stirred for 10 minutes, then the reaction quenched with a saturated salt solution. The mixture is extracted with ethyl acetate (500 ml 2), washed with saturated salt solution (200 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in chloroform (100 ml) and hexane (300 ml) and add to it an activated manganese dioxide (200 g). The mixture is stirred at room temperature for real is using chromatography on a column of silica gel (eluent: ethyl acetate/hexane), and then recrystallized from isopropyl ether/hexane, to deliver specified in the header of the example compound (25 g) as colorless crystals with a melting point of 101 1 0 2.

Comparative example 20: Obtaining 2-(3-bromobenzyl)-3-pyridinol

2-(3-Bromobenzoyl)-3-methoxypiperidine (6.7 g, 21 mmol) obtained in comparative example 19 is dissolved in ethylene glycol (67 ml) to the resulting mixture add hydrazinoacetate (3.4 ml) and potassium hydroxide (5.0 g, 76 mmol) and the mixture is stirred at a temperature of 90 ° C for 5 hours. After the reaction mixture has cooled, add water (200 ml), extracted with ethyl acetate (150 ml 2), washed with saturated salt solution (200 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is recrystallized from isopropyl ether, to deliver specified in the header of the example compound (4.9 g) as pale-brown crystals with a melting point of 160-C.

Comparative example 21: obtaining the ethyl ester of 3-(3,5-dimethoxypyridine-4-yl)propanolol acid

3,5-Dimethoxypyridine (8,1 g, 58 mmol) dissolved in THF (100 ml) to the resulting mixture add a solution of n-utility in the on-S. To the mixture is added DMF (5.4 ml, 70 mmol), heated the mixture to 0C for 30 minutes. Then to the reaction solution was added a solution of salt, obtained from triethylphosphate (15.6 g, 69 mmol) and sodium hydride (60% in mineral oil, 2,78 g, 69 mmol) in THF (50 ml) at 0C, and the mixture was stirred for one hour. The reaction solution is poured into a mixture of ice water, extracted with ethyl acetate (200 ml of 2), washed with saturated salt solution (100 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol) and then recrystallized from isopropyl ether/hexane, to deliver specified in the header of the example compound (7,3 g) as colorless crystals with a melting point of 100 S.

Comparative example 22: obtaining the ethyl ester of 3-(3,5-dimethoxypyridine-4-yl)-propionic acid

Ethyl ester of 3-(3,5-dimethoxypyridine-4-yl)propanolol acid (6.5 g, 27 mmol) obtained in comparative example 21 were dissolved in ethanol (200 ml) to the resulting mixture is added 10% palladium on coal (1.0 g) and the mixture is stirred at room temperature in a hydrogen atmosphere. After t and the filtrate concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane) and recrystallized from hexane, to deliver specified in the header of the example compound (7,1 g) as colorless crystals with a melting point of 66 S.

Comparative example 23: Obtain 3-(3,5-dichloropyridine-4-yl)-1-propanol

(i) 3,5-Dichloropyridine (4.4 g, 30 mmol) dissolved in THF (100 ml) to the resulting mixture add a solution of n-utility in hexane (19 ml, 30 mmol) at-70C and the resulting mixture is stirred for 15 minutes. Then to the mixture was added 1-bromo-3-methoxymetopon (6.0 g, 33 mmol) and heated the mixture up to 0C for one hour. The reaction is quenched with a saturated saline solution (50 ml) and the mixture extracted with ethyl acetate (150 ml 2). The organic layer was washed with saturated saline solution (100 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane) to give the result of 1-(3,5-dichloropyridine-4-yl)-3-methoxymetopon (1.0 g) as oil.

(ii) the Oily product obtained as described above was dissolved in ethanol (20 ml) to the resulting mixture add 10% CE is th aqueous solution of sodium bicarbonate, extracted with ethyl acetate (100 ml), washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver specified in the header of the example compound (0,70 g) as a pale yellow oil.

Comparative example 24: obtaining the ethyl ester of 3-(3-methoxypiperidine-4-yl)-propanolol acid

3-Methoxypiperidine (17.5 g, 130 mmol) dissolved in THF (500 ml) add a solution of n-utility in hexane (88 ml, 140 mmol) at-30C. The mixture was stirred at 0C for 20 minutes and cooled to-70C. To the mixture is added DMF (11,0 g, 150 mmol) and the mixture is again stirred at 0C for 30 minutes. Then to this mixture a solution of salt, obtained from triethylphosphate (34,0 g, 150 mmol) and sodium hydride (60% in mineral oil, 6.0 g, 150 mmol) in THF (200 ml) at 0C, and the mixture is stirred for one hour. The reaction solution is poured into a mixture of ice water, extracted with ethyl acetate (400 ml 2) and the residue purified via chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver specified in the header of the example compound (22,0 the pyridine-4-yl)-propionic acid

Ethyl ester of 3-(3-methoxypiperidine-4-yl)propanolol acid (22,0 g, 93 mmol) obtained in comparative example 24 is dissolved in ethanol (200 ml), add 5% palladium on coal (2.0 g) and the mixture is stirred at room temperature in a hydrogen atmosphere. After you have spent theoretical quantity of hydrogen gas, the reaction solution is filtered, and the filtrate concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver specified in the header of the example compound (21,0 g) as a pale yellow oil.

Comparative example 26: Obtain 2-bromo-3-[3-(pyridin-3-yl)propoxy]pyridine

3-(Pyridin-3-yl)-1-propanol (12.3 g, 90 mmol) and triphenylphosphine (34,0 g, 130 mmol) dissolved in THF (200 ml), the mixture is gradually added with stirring diisopropylsalicylic (22,2 g, 110 mmol) and 2-bromo-3-hydroxypyridine (12.0 g, 69 mmol) under cooling on ice. The mixture is stirred at room temperature for 30 minutes and then the reaction solution is concentrated under reduced pressure. To the residue is added ethyl acetate (300 ml) and the mixture extracted with 10% aqueous solution of hydrochloric acid is atom (200 ml of 2). The organic layer was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver specified in the header of the example compound (18.3 g) as a colourless oil.

In the same manner as in comparative example 26, conduct the reaction of the corresponding starting compounds for preparing compounds of comparative examples 27 to 29.

Comparative example 27: 2-bromo-3-[3-(pyridin-4-yl)propoxy]-pyridine

Melting point: 78-S.

Comparative example 28: 2-chloro-3-[3-(3-methoxypiperidine-4-yl)propoxy]pyridine

Pale brown oil

Comparative example 29: 2-bromo-3-[3-(3-methoxypiperidine-4-yl)propoxy]pyridine

Pale brown oil

Comparative example 30: 3-(pyridin-3-yl)-1-butanol

(i) 3-(Pyridin-3-yl)propanal (10 g, 74 mmol) dissolved in THF (200 ml) to the resulting mixture add a solution of trimethylsilylmethylamine in diethyl ether (100 ml, 100 mmol) under cooling on ice and the resulting mixture is stirred for 15 minutes. REM salt solution (200 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue add THF (50 ml) and concentrated sulfuric acid (5 ml), then the mixture is heated in a flask under reflux for 20 minutes. The reaction the solution is allowed to cool, and then neutralize it with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (200 ml of 2). The organic layer was washed with saturated saline (200 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver 3-(3 butenyl)pyridine (6.5 g) as a pale yellow oil.

(ii) the Oily product obtained as described above was dissolved in THF (100 ml) to the resulting mixture add 9-borabicyclo[3.3.1]nonan (14.0 g, 57 mmol) under cooling on ice. The ice bath was removed and the mixture is stirred at room temperature for 30 minutes and then mix again carefully add 30% aqueous solution of the hydrochloride sodium (30 ml) and 30% aqueous hydrogen peroxide solution (25 ml) under cooling on ice. The reaction solution is extracted with chloroform (500 ml), the organic layer washed nanii. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), and then subjected to distillation on a Kugelrohr, to deliver specified in the header of the example compound (1.2 g) as a colourless oil.

Comparative example 31: Obtain 4-(pyridin-4-yl)-1-butanol

3-(Pyridin-4-yl)propanal treated the same way as described in comparative example 30, to deliver specified in the header of the example compound as a colourless oil.

Comparative example 32: Obtain 3 -(3-bromopyridin-4-yl)-1-propanol

Diisopropylamine (7,1 g, 70 mmol) dissolved in THF (100 ml) and to the resulting mixture add a solution of n-utility in hexane (35,7 ml, 60 mmol) at-70C, the resulting mixture is stirred for 15 minutes. Then to this mixture a solution of 3-bromo-4-methylpyridine (8.6 g, 50 mmol) in THF (30 ml). Ten minutes to the mixture of the ethylene oxide (2.6 g, 60 mmol) and the mixture is heated to 0C for one hour. The reaction is quenched with a saturated saline solution (50 ml) and the mixture extracted with ethyl acetate (150 ml 2). The organic layer was washed with saturated saline solution (100 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified with boegolovki example compound (8.5 g) as a pale yellow oil.

Comparative example 33: 3-cyano-4-methylpyridine

3-Bromo-4-methylpyridin (20,0 g, 116 mmol) was dissolved in DMF (100 ml) and added copper cyanide (monovalent) (11.6 g, 30 mmol), the mixture is then heated in a flask under reflux for 18 hours. After cooling, to the reaction solution was added 25% aqueous ammonia solution (200 ml) and saturated aqueous solution of ammonium chloride (200 ml), the mixture is then extracted with ethyl acetate (200 ml of 5). The organic layer was washed with saturated saline solution (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver specified in the header of the example compound (11,0 g) as colorless crystals with a melting point of 75 S.

Comparative example 34: 3-(3-cyano-4-yl)-1-propanol

Diisopropylamine (2.5 g, 25 mmol) dissolved in THF (30 ml) to the resulting mixture add a solution of n-utility in hexane (14,3 ml, 24 mmol) at-70C. The mixture is stirred for 15 minutes and then there was added a solution of 3-cyano-4-methylpyridine (2.4 g, 20 mmol) obtained in comparative example 33, in THF (20 ml). Ten is saturated saline solution (50 ml) and the mixture extracted with ethyl acetate (150 ml 2). The organic layer was washed with saturated saline solution (100 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver specified in the header of the example compound (1.2 g) as a pale brown oil.

Comparative example 35: Obtain 3-(3-ethoxycarbonylmethyl-4-yl)-1-propanol

3-Cyano-4-pyridin-1-propanol (1.2 g, 7.4 mmol) obtained in comparative example 34, was dissolved in ethanol (35 ml) to the resulting mixture is added an aqueous solution (15 ml) of sodium hydroxide (1.2 g, 30 mmol). The mixture was stirred at 45 CELSIUS for one hour, and after it has cooled, neutralized with concentrated hydrochloric acid (2.5 ml). The solvent is concentrated under reduced pressure and the remaining water is removed by azeotropic distillation with ethanol. Then the residue is dissolved in 30% solution of hydrochloric acid in ethanol (100 ml) and the mixture is heated in a flask under reflux for 5 hours. The reaction solution is concentrated under reduced pressure, poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (100 ml of 2). Organicheskoi reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver specified in the header of the example compound (1.22 g) as a pale yellow oil.

Comparative example 36: obtaining the ethyl ester of 3-(5-benzyloxypyridine-3-yl)propanolol acid

Sodium hydride (60% in mineral oil, 0.71 g, 18 mmol) suspended in THF (50 ml), add triethylphosphate (3.5 ml, 18 mmol) and the mixture was stirred at 0C for 20 minutes. To the mixture of 5-benzyloxy-3-pyridinylmethyl (2.50 g, 12 mmol) and continue stirring for another 45 minutes. The reaction solution was poured into ice water (200 ml), the mixture is extracted with ethyl acetate (100 ml of 2), washed with saturated salt solution (100 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane) and then recrystallized from isopropyl ether/hexane, to deliver specified in the header of the example compound (3.1 g) as pale-yellow crystals with a melting point of 76 S.

Comparative example 37: Obtain 1-(3,5-dichloropyridine-4-yl)-3-(tetrahydropyranyl-2-hydroxy)proyavlayut a solution of n-utility in hexane (57.6 ml, 95 mmol) at-70C. Ten minutes to the mixture is added dropwise within 15 minutes, a solution of 3,5-dichloropyridine (13,0 g, 88 mmol) in THF (50 ml), and during this operation the average bulk temperature should not rise above 60C, and then the mixture is additionally stirred for 20 minutes. Then to the mixture was added 1-bromo-3-(tetrahydropyranyl-2-oxy)propane (20,0 g, 90 mmol) and the mixture was stirred at-70C for 2 hours, then the temperature was brought to 0 ° C and incubated the mixture at this temperature for 5 hours. The reaction is quenched with saturated saline (200 ml) and the mixture extracted with ethyl acetate (300 ml 2). The extract was washed with saturated saline solution (100 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver specified in the header of the example compound (8.6 g) as a pale yellow oil.

Comparative example 38: Obtain 1-(3-chloro-5-methoxypyridine-4-yl)-3-(tetrahydropyranyl-2-oxy) propane

1-(3,5-Dichloropyridine-4-yl)-3-(tetrahydropyranyl-2-oxy)-propane (8.0 g, 28 mmol) obtained in comparative example 37, dissolved in N-methylpyrrolidinone (60 ml) and dopaminemediated when 110S for 3 hours. After the reaction solution has cooled, added 28% aqueous ammonia solution (30 ml) and water (200 ml), after which the mixture is extracted with ethyl acetate (300 ml 2). The extract was washed with saturated saline solution (100 ml × 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver specified in the title compound (4.1 g) as a pale yellow oil.

Comparative example 39: Obtain 1-(3,5-dibromopyridin-4-yl)-3-benzyloxypropionic

Diisopropylamine (of 5.1 g, 50 mmol) dissolved in THF (100 ml) and with stirring to the resulting mixture add a solution of n-utility in hexane (27,3 ml, 45 mmol) at-70C. Ten minutes to the mixture is added dropwise within 20 minutes, a solution of 3,5-dibromopyridine (10.0 g, 42 mmol) in THF (30 ml), and during this operation the average bulk temperature should not rise above 60C, then the mixture is stirred for another 5 minutes. Then to the mixture was added 1-bromo-3-benzyloxypropionic (10.0 g, 44 mmol) and stirred at-70C for 2 hours. The mixture is then heated to 20 ° C and kept at this temperature for 2 hours. The reaction extinguish the feast upon the m solution (100 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver specified in the title compound (9.0 g) as a pale yellow oil.

Comparative example 40: Obtain 1-(3-bromo-5-methoxypyridine-4-yl)-3-benzyloxypropionic

1-(3,5-Dibromopyridin-4-yl)-3-benzyloxypropionic (6.0 g, 16 mmol) obtained in comparative example 39, dissolved in N-methylpyrrolidinone (40 ml) and add to it the 28% solution of sodium methylate in methanol (20 ml) and copper bromide (monovalent) (2.0 g, 14 mmol). The mixture was stirred at 110S within one hour. After the reaction solution has cooled, added 28% aqueous ammonia solution (30 ml) and water (200 ml), after which the mixture is extracted with ethyl acetate (200 ml of 2). The extract was washed with saturated saline solution (100 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver specified in the title compound (2.7 g) as a colourless oil.

Comparative example 41: Obtain 1-(3-cyano-5-labels is received in comparative example 40, dissolved in N-methylpyrrolidinone (30 ml), the mixture added copper cyanide (monovalent) (0.9 g, 10 mmol) and the mixture is stirred at 180C for 4 hours. After the reaction solution has cooled, added 28% aqueous ammonia solution (30 ml) and water (100 ml), after which the mixture is extracted with ethyl acetate (100 ml of 2). The extract was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), to deliver specified in the title compound (2.2 g) as a pale yellow oil.

Example 1: Obtain 3-(3,5-dimethoxypyridine-4-yl)-1-propanol

Sociallyengaged (1.1 g, 30 mmol) suspended in THF (50 ml) and the resulting mixture with stirring ethyl ester 3-(3,5-dimethoxypyridine-4-yl)propionic acid (3.5 g, 15 mmol) obtained in comparative example 22, at 50C for 40 minutes. Then the mixture is heated in a flask under reflux for 30 minutes and successively added thereto water (1.1 ml), 15% aqueous sodium hydroxide solution (1.1 ml) and water (3.3 ml) to quench the reaction. The reaction solution is filtered, the technology Department is ecografia on a column of silica gel (eluent: chloroform/methanol), and then recrystallized from isopropyl ether/hexane, obtaining specified in the header of the example compound (2.9 g) as colorless crystals with a melting point of 88-89S.

Example 2: Obtain 3-(3-methoxypiperidine-4-yl)-1-propanol

Sociallyengaged (6.0 g, 0.16 mmol) suspended in THF (500 ml) and the resulting mixture with stirring ethyl ester 3-(3,5-methoxypiperidine-4-yl)propionic acid (21 g, 89 mmol) obtained in comparative example 25, at 50C for 30 minutes. Then the mixture is heated in a flask under reflux for 30 minutes and successively added thereto water (6 ml), 15% sodium hydroxide (6 ml) and again water (18 ml) to quench the reaction. The reaction solution is filtered to remove insoluble matter and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate), to deliver specified in the title compound (17.5 g) as a colourless oil.

1H-NMR (300 MHz, CDCl3, ppm): 1.83-1.93 (m, 2H), 2.75 (t, 2H, J=8Hz), 3.51 (s, 3H), 3.67 (t, 2H, J=6Hz), 5.25 (s, 2H), 7.10 (d, 1H, J=5Hz), 8.21 (d, 1H, J=5Hz), 8.40 (s, 1H).

Example 3: Obtaining 2-(3-pampanito)-3-[3-(pyridin-3-yl)propoxy]-pyridine what scientists mixture with stirring, add diisopropylethylamine (6,1 g, 30 mmol) and 2-(3-pampanito)-3-pyridinol (5.0 g, 18 mmol) obtained in comparative example 1, while cooling on ice. The mixture is then stirred at room temperature for 30 minutes and the reaction solution was concentrated under reduced pressure. To the residue is added ethyl acetate (300 ml) and the mixture extracted with 10% aqueous hydrochloric acid (150 ml 2). The pH value of the aqueous layer was adjusted to 12 with potassium carbonate and the mixture extracted with ethyl acetate (200 ml of 2). The organic layer was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane) and recrystallized from diethyl ether, to deliver specified in the header of the example compound (6.8 g) as colorless crystals with a melting point of 75 S.

1H-NMR (200 MHz, CDCl3, ppm): 2.08-2.22 (m, 2H), 2.86 (t, 2H, J=11Hz), 4.02 (t, 2H, J=8Hz), 6.98-7.08 (m, 2H), 7.19-7.29 (m, 2H), 7.45 (dd, 1H, J=1Hz, 3Hz), 7.49 (dd, 1H, J=1Hz, 3Hz), 7.51-7.58 (m, 1H), 7.69 (t, 1H, J=3Hz), 8.01 (dd, 1H, J=3Hz, 6Hz), 8.47 (dd, 1H, J=3Hz, 7Hz), 8.50 (dd, 1H, J=1Hz, 3Hz).

Examples 4 to 17

The corresponding starting compound is treated in the same manner as described in example 3, the floor is the significance of 2-(3-cyclopentylacetyl)-3-[3-(pyridin-4-yl)-propoxy]pyridine

Cyclopentanol (0.11 g, 1.3 mmol) and triphenylphosphine (of 0.47 g, 1.8 mmol) dissolved in THF (15 ml) and the resulting mixture under stirring consistently add diisopropylethylamine (0.26 g, 1.3 mmol) and 2-(3-hydroxyphenyl)-3-[3-(pyridin-4-yl)-propoxy]pyridine (0,30 g, 0.89 mmol) obtained in example 13. The mixture is then stirred at room temperature for 30 minutes and the reaction solution was concentrated under reduced pressure. The residue is extracted with 10% aqueous solution of hydrochloric acid (30 ml), the aqueous layer washed with chloroform (30 ml 2) and the pH value of the aqueous layer was adjusted to 12 with potassium carbonate. The mixture is extracted with ethyl acetate (50 ml of 2) and the organic layer was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol), to deliver specified in the title compound (0.26 g) as a colourless oil.

1H-NMR (200 MHz, CDCl3, ppm): 1.52-1.93 (m, 8H), 2.08-2.22 (m, 2H), 2.85 (t, 2H, J=8Hz), 4.01 (t, 2H, J=6Hz), 4.68-4.79 (m, 1H), 6.82-6.89 (m, 1H), 6.95-7.18 (m, 4H), 7.13-7.18 (m, 2H), 7.26-7.31 (m, 1H), 8.02 (dd, 1H, J=2Hz, 4Hz), 8.48-8.53 (m, 2H).

Example 19: Obtaining 2-(3-bromophenoxy)-3-[3-(3,5-dimethoxypyridine-4-aimere 1, and triphenylphosphine (1.18 g, 4.5 mmol) dissolved in THF (30 ml) and the resulting mixture under stirring consistently add diisopropylethylamine (0,78 g, 3.9 mmol) and 2-(3-bromophenoxy)-3-pyridinol (1.04 g, 3.9 mmol) obtained in comparative example 11, while cooling on ice. The mixture is then stirred at room temperature for 30 minutes and the reaction solution was concentrated under reduced pressure. To the residue is added ethyl acetate (50 ml) and the mixture extracted with 10% aqueous hydrochloric acid (50 ml of 2). The pH value of the aqueous layer was adjusted to 12 with potassium carbonate and the mixture extracted with ethyl acetate (100 ml of 2). The organic layer was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol) to give the result 2-(3-bromophenoxy)-3-[3-(3,5-dimethoxypyridine-4-yl)-propoxy]-pyridine, which is then treated with fumaric acid to deliver specified in the header of the example compound (1.26 g) with a melting point of 106-S.

Example 20: Obtaining 2-(3-bromobenzyl)-3-[3-(3,5-dimethoxypyridine-4-yl)-propoxy]pyridine 1.2-oxalate

2-(NY in example 1, treated in the same manner as in example 19, receiving the 2-(3-bromobenzyl)-3-[3-(3,5-dimethoxypyridine-4-yl)propoxy]pyridine, which is then treated with oxalic acid, to deliver specified in the header of the example compound (1.27 g) with a melting point 153-C (recrystallized from ethanol).

Example 21: Getting 2-phenoxy-3-[3-(3,5-dichloropyridine-4-yl)propoxy]-pyridine

2 Phenoxy-3-pyridinol obtained in comparative example 12, and 3-(3,5-dichloropyridine-4-yl)-1-propanol obtained in comparative example 23, is treated in the same manner as in example 19, to deliver specified in the header of the example compound as a colourless oil.

1H-NMR (200 MHz, CDCl3, ppm): 2.05-2.21 (m, 2H), 3.11 (t, 2H, J=7Hz), 4.15 (t, 2H, J=7Hz), 6.97 (dd, 1H, J=5Hz, 8Hz), 7.07-7.27 (m, 4H), 7.33-7.43 (m, 2H) 7.77 (dd, 1H, J=2Hz, 5Hz), 8.41 (s, 2H).

Example 22: Obtain 2-(3-chlorophenoxy)-3-[3-(3-cyano-4-yl)propoxy]-pyridine

2-(3-Chlorophenoxy)-3-pyridinol obtained in comparative example 14, and 3-(3-cyano-4-yl)-1-propanol obtained in comparative example 34, is treated in the same manner as in example 19, to deliver specified in the header of the example compound with a melting point of 146-150C.

2-(3-Chlorophenoxy)-3-pyridinol obtained in comparative example 14, and 3-(3-ethoxycarbonylmethyl-4-yl)-1-propanol obtained in comparative example 35, is treated in the same manner as in example 19, receiving the 2-(3-chlorophenoxy)-3-[3-(3-ethoxycarbonylmethyl-4-yl)propoxy]-pyridine, which is then treated with fumaric acid, receiving the result specified in the header of the example compound with a melting point of 140-164 ° C. (recrystallized from isopropyl ether).

Example 24: Getting 2-(3-chlorophenoxy)-3-[3-(3-carboxypropyl-4-yl)-propoxy]pyridine

2-(3-Chlorophenoxy)-3-[3-(3-ethoxycarbonylmethyl-4-yl)-propoxy]pyridine (1.0 g, 2.4 mmol) obtained in example 23, was dissolved in methanol (50 ml), the mixture was added 1 M aqueous sodium hydroxide solution (3.0 ml) and the mixture is heated in a flask under reflux for 2 hours. The methanol is distilled off under reduced pressure, the pH value of the residue was adjusted to 4 using 1 M aqueous solution of hydrochloric acid and the mixture extracted with chloroform/tetrahydrofuran (1:1) (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is recrystallized from ethanol/diethyl ether, obtaining the result indicated the ptx2">

Example 25: Obtain 2-(3-chlorophenoxy)-3-[3-(3-aminopyridine-4-yl)propoxy]-pyridine

2-(3-Chlorophenoxy)-3-[3-(3-carboxypropyl-4-yl)propoxy]-pyridine (0.50 g, 1.3 mmol) obtained in example 24 was dissolved in tert-butanol (20 ml), add to it diphenylphosphinite (0,42 ml, 2.0 mmol) and triethylamine (with 0.27 ml, 2.0 mmol) and the mixture is heated in a flask under reflux for 8 hours. The reaction is quenched with a saturated saline solution (50 ml) and the reaction solution is extracted with ethyl acetate (50 ml of 2). The organic layer was washed with saturated saline solution (30 ml 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in methylene chloride (10 ml), add to it triperoxonane acid (5 ml) and the mixture was stirred at 25C for 30 minutes. The reaction solution is concentrated under reduced pressure, to the residue is added saturated aqueous sodium hydrogen carbonate solution (50 ml) and the mixture extracted with ethyl acetate (50 ml of 2). The organic layer was washed with saturated saline solution (30 ml 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol), and then paracrystal the colored crystals with a melting point of 140-S.

Example 26: Obtaining 2-(3-pampanito)-3-[3-(3-hydroxypyridine-4-yl)-propoxy]pyridine

3-(3-Methoxypiperidine-4-yl)-1-propanol (1,59 g, 9.2 mmol) obtained in example 2, and triphenylphosphine (2,78 g, 10.6 mmol) dissolved in THF (40 ml) and the resulting mixture under stirring consistently add diisopropylethylamine (1.85 g, 9.2 mmol) and 2-(3-pampanito)-3-pyridinol (2.00 g, 7.1 mmol) obtained in comparative example 1, while cooling on ice. The mixture is then stirred at room temperature for 30 minutes and the reaction solution was concentrated under reduced pressure. To the residue is added ethyl acetate (50 ml) and the mixture extracted with 10% aqueous hydrochloric acid (50 ml of 2). The pH value of the aqueous layer was adjusted to 12 with potassium carbonate, the mixture is then extracted with ethyl acetate (100 ml of 2). The organic layer was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue is added ethanol (200 ml) and 15% aqueous hydrochloric acid solution (10 ml), the mixture is heated in a flask under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, neutralized with a saturated aqueous solution hydrocarbonate), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/ethyl acetate) and then recrystallized from diethyl ether, to deliver specified in the header of the example compound (1.98 g) as colorless crystals with a melting point of 169-S.

Example 27: Obtaining 2-(3-acetylphenol)-3-[3-(3-hydroxypyridine-4-yl)-propoxy]pyridine

2-(3-Acetylphenol)-3-pyridinol obtained in comparative example 17, are treated the same way as described in example 26, to deliver specified in the header of the example compound as colorless crystals with a melting point of 101 1 0 2.

Example 28: Obtaining 2-(3-cianfrocca)-3-[3-(3-hydroxypyridine-4-yl)-propoxy]pyridine

2-(3-Cianfrocca)-3-pyridinol obtained in comparative example 16, are treated the same way as described in example 26, to deliver specified in the header of the example compound as colorless crystals with a melting point of 84-S.

Example 29: Obtain 2-(3-ethoxycarbonylphenyl)-3-[3-(3-hydroxypyridine-4-yl)propoxy]pyridine 0.5-fumarata

2-(3-Ethoxycarbonylphenyl)-3-pyridine is the head of the sample compound in the form of colorless crystals with a melting point of 76 S.

Example 30: Obtaining 2-phenoxy-3-[3-(3-hydroxypyridine-4-yl)propoxy]-pyridine

2 Phenoxy-3-pyridinol obtained in comparative example 12, are treated the same way as described in example 26, to deliver specified in the header of the example compound as colorless crystals with a melting point 163-S.

Example 31: Obtain 2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridine-4-yl)-propoxy]pyridine

3-(3-Methoxypiperidine-4-yl)-1-propanol (9,11 g, for 52.6 mmol) obtained in example 2, and triphenylphosphine (14.8 g, of 56.5 mmol) dissolved in THF (100 ml) and with stirring to them consistently add diisopropylethylamine (10.6 g, for 52.6 mmol) and a solution of 2-(3-chlorophenoxy)-3-pyridinol (9,65 g of 43.5 mmol) obtained in comparative example 14, in THF while cooling on ice. The mixture is then stirred at 50C for 30 minutes and the reaction solution was concentrated under reduced pressure. To the residue is added ethyl acetate (150 ml) and the mixture extracted with 10% aqueous hydrochloric acid (150 ml 2). The pH value of the aqueous layer was adjusted to 12 with potassium carbonate, the mixture is then extracted with ethyl acetate (200 ml of 2). The organic layer was washed with saturated saline solution (50 ml of 2), dried over anhydrous color hydrochloric acid (100 ml) and the mixture is heated in a flask under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, the residue is neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (300 ml 2). The organic layer was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate) and then recrystallized from diethyl ether/isopropyl ether, to deliver specified in the header of the example compound (8.90 g) as colorless crystals with a melting point of 109-110S.

Example 32: Obtain 2-(3-bromophenoxy)-3-[3-(3-hydroxypyridine-4-yl)-propoxy]pyridine

3-(3-Methoxypiperidine-4-yl)-1-propanol (2.50 g, 12.7 mmol) obtained in example 2, and triphenylphosphine (4,50 g of 17.0 mmol) dissolved in THF (40 ml) and with stirring to them consistently add diisopropylethylamine (3.00 g, 15.0 mmol) and 2-(3-bromophenoxy)-3-pyridinol (2.50 g, 9.4 mmol) obtained in comparative example 11, while cooling on ice. The mixture is stirred at a temperature of 40C for 30 minutes and the reaction solution was concentrated under reduced pressure. To the residue add utilized to 12 with potassium carbonate, the mixture is then extracted with ethyl acetate (100 ml of 2). The organic layer was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue is added ethanol (200 ml) and 47% aqueous solution of Hydrobromic acid (20 ml) and the mixture is heated in a flask under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (100 ml of 2). The organic layer was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate/ethanol), and then recrystallized from ethanol/diethyl ether, to deliver specified in the header of the example compound (3,10 g) as colorless crystals with a melting point of 116-S.

Example 33: Obtain 2-(3-bromophenoxy)-3-[3-(3-methoxypyridine-4-yl)-propoxy]pyridine

Sodium hydride (60% in mineral oil, 0.26 g, 6.5 mmol) suspended in DMF (30 ml), add 2-(3-bromophenoxy)-3-[3-(3-hydroxypyridine-4-yl)propoxy]Piranesi add methyliodide (0,78 g, 0, 34 mmol) while cooling on ice and the mixture is stirred for another 30 minutes. To the reaction solution was added ethyl acetate (250 ml), the organic layer was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified using the main method chromatography on a column of silica gel (eluent: chloroform/ethyl acetate) and then recrystallized from diethyl ether, to deliver specified in the header of the example compound (0.75 g) as colorless crystals with a melting point 134-S.

Example 34: Obtain 2-(3-tetrasulfane)-3-[3-(3-hydroxypyridine-4-yl)-propoxy]pyridine

2-(3-Cianfrocca)-3-[3-(3-hydroxypyridine-4-yl)propoxy]-pyridine of 0.85 g, 2.5 mmol) obtained in example 28, was dissolved in DMF (10 ml) and add sodium azide (0.20 g, 3.0 mmol) and ammonium chloride (0.16 g, 3.0 mmol). The mixture was stirred at 130C for one hour and the reaction solution was concentrated under reduced pressure. Thus obtained residue is purified by chromatography on a column of silica gel (eluent: acetic acid/ethanol), and then recrystallized from ethanol, to deliver specified in the header of the example se 35: Obtain 2-(3-bromophenoxy)-3-[3-(pyridin-4-yl)propoxy]-pyridine

2-Bromo-3-[3-(pyridin-4-yl)propoxy]pyridine (1.0 g, 3.4 mmol) obtained in comparative example 27, and 3-bromophenol (0.87 g, 5.0 mmol) dissolved in DMF (10 ml) and add to them the potassium carbonate (1.4 g, 10 mmol) and copper bromide (monovalent) (0,72 g, 5.0 mmol). The mixture is heated in a flask under reflux at 140 C for 1.5 hours. After the reaction solution has cooled, added ethyl acetate (100 ml) and the organic layer was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified using the method of chromatography on a column of silica gel (eluent: ethyl acetate/hexane) and then recrystallized from diethyl ether, to deliver specified in the header of the example compound (0,80 g) as colorless crystals with a melting point of 111-S.

Examples 36 to 42

The corresponding starting compound is treated in the same way as in example 3, resulting in the compounds of examples 36 to 42, are listed in table 5.

Example 43: Obtain 2-(3,5-dichlorophenoxy)-3-[3-(3-hydroxypyridine-4-yl)-propoxy]pyridine

2-Bromo-3-[3-(3-methoxypiperidine-4-yl)propoxy]pyridine (2.0 g, 5.7 mmol), half the keys potassium carbonate (1.4 g, 10 mol) and copper bromide (monovalent) (0,86 g, 6.0 mmol), the mixture was heated in a flask under reflux at 140 C for 1.5 hours. After the reaction solution has cooled, added ethyl acetate (200 ml), the organic layer was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue is added ethanol (200 ml) and 15% aqueous hydrochloric acid solution (20 ml), the mixture is heated in a flask under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (150 ml 2). The organic layer was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol) and then recrystallized from diethyl ether, to deliver specified in the header of the example compound (1.19 g) as colorless crystals with a melting point of 99-S.

Example 44: Obtain 2-(3-pertenece)-3-[3-(3-hydroxypyridine-4-yl)-propoxy]pyridine

2-CHL is anywayt so, as described in example 43, to deliver specified in the header of the example compound as colorless crystals with a melting point of 68-70C.

Example 45: Obtain 2-(3,5-dimethoxyphenoxy)-3-[3-(3-hydroxypyridine-4-yl)propoxy]pyridine

2-Bromo-3-[3-(3-methoxypiperidine-4-yl)propoxy]pyridine obtained in comparative example 29, and 3.5-dimethoxyphenol treated as described in example 43, to deliver specified in the header of the example compound as colorless crystals with a melting point of 172-S.

Example 46: Obtaining 2-(3-bromoaniline)-3-[3-(3-hydroxypyridine-4-yl)-propoxy]pyridine

2-Bromo-3-[3-(3-methoxypiperidine-4-yl)propoxy]pyridine obtained in comparative example 29, 3-bromaniline treated as described in example 43, to deliver specified in the header of the example compound as pale brown crystals with a melting point 138-S.

Example 47: Obtaining 2-phenoxy-3-[3-(3-methoxyethoxymethyl-4-yl)-propoxy]pyridine of monopolarity

2-Methoxyethanol (0.08 g, of 0.93 mmol) and triphenylphosphine (0.32 g, 1.2 mmol) dissolved in THF (20 ml) and the resulting mixture under stirring consistently add diisopropylate example 30, while cooling on ice. The mixture is then stirred at a temperature of 60C for one hour and the reaction solution was concentrated under reduced pressure. To the residue is added ethyl acetate (50 ml) and the mixture extracted with 10% aqueous hydrochloric acid (50 ml of 2). The pH value of the aqueous layer was adjusted to 12 with potassium carbonate, the mixture is then extracted with ethyl acetate (50 ml of 2). The organic layer was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/methanol), to obtain 2-phenoxy-3-[3-(3-methoxyethoxymethyl-4-yl)-propoxy]pyridine, which is then treated with fumaric acid to deliver specified in the title compound (0.12 g) with a melting point of 120 C (recrystallized from diethyl ether).

Example 48: Obtaining 2-phenoxy-3-[3-(3-(2-hydroxyethoxy)pyridine-4-yl)-propoxy]pyridine of monopolarity

Sodium hydride (60% in mineral oil, 0.08 g, 2.0 mmol) suspended in DMF (5 ml) to the resulting mixture add 2 phenoxy-3-[3-(3-hydroxypyridine-4-yl)propoxy]pyridine (0.20 g, of 0.62 mmol) obtained in example 30, in room temperorary on ice and the mixture was stirred at 50C for 30 minutes. To the reaction solution was added chloroform (100 ml), the mixture was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue is added ethanol (20 ml) and 35% aqueous hydrochloric acid solution (2 ml) and the resulting mixture was stirred at 60C for 30 minutes. The pH value of the reaction solution is adjusted to 10 with saturated aqueous sodium hydrogen carbonate solution, the mixture is then extracted with chloroform (50 ml of 2), washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol) to give 2-phenoxy-3-[3-(3-(2-hydroxyethoxy)pyridine-4-yl)propoxy]pyridine, which is then treated with fumaric acid to deliver specified in the header of the example compound (0.17 g) with a melting point 129-C (recrystallized from ethanol/isopropyl ether).

Example 49: Obtaining 2-phenoxy-3-[3-(3-ethoxycarbonylmethoxy)pyridine-4-yl)-propoxy]pyridine of difumarat

Sodium hydride (60% in mineral oil, of 0.13 g, 3.1 mmol) suspended in DMF (20 ml), the resulting mixture dobavlyayte and stirred for 30 minutes. To the mixture add ethylbromoacetate (0.34 g, 3.1 mmol) under cooling on ice and the mixture is stirred at room temperature for 20 minutes. To the reaction solution was added ethyl acetate (100 ml), the mixture was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane) to give 2-phenoxy-3-[3-(3-ethoxycarbonylmethoxy)pyridine-4-yl)propoxy]pyridine, which is then treated with fumaric acid to deliver specified in the header of the example compound (0,22 g) with a melting point of 130-140 C (recrystallized from ethanol/diethyl ether).

Example 50: Obtaining 2-phenoxy-3-[3-(3-carboxymethoxy)pyridine-4-yl)-propoxy]pyridine of monopolarity

2 Phenoxy-3-[3-(3-carboxymethoxy)pyridine-4-yl)propoxy]-pyridine (0,30 g of 0.74 mmol) obtained in example 49, dissolved in ethanol (10 ml), the mixture was added 1 M aqueous sodium hydroxide solution (3 ml) and heated in a flask under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, add acetic acid (3 ml) and the mixture extracted with epitom magnesium and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol) to give 2-phenoxy-3-[3-(3-carboxymethoxy)pyridine-4-yl)propoxy]-pyridine, which is then treated with fumaric acid, and receive specified in the header of the example compound (0.17 g) with a melting point of 167-C (recrystallized from ethanol/water).

Example 51: Obtaining 2-phenoxy-3-[3-(3-methoxypyridine-4-yl)propoxy]-pyridine

Sodium hydride (60% in mineral oil, 0.04 g, 1.0 mmol) suspended in DMF (10 ml) to the resulting mixture add 2 phenoxy-3-[3-(3-hydroxypyridine-4-yl)propoxy]pyridine (0.20 g, of 0.62 mmol) obtained in example 30, at room temperature and stirred for 30 minutes. To the mixture add methyliodide (0.06 ml, 1.0 mmol) while cooling on ice and stirred for 10 minutes. To the reaction solution was added ethyl acetate (50 ml), the mixture was washed with saturated saline solution (30 ml 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol) and recrystallized from isopropyl ether, to deliver specified in the header of the example compound (0.09 g) in the-[3-(pyridin-4-yl)propoxy]-pyridine

2-(3-Cianfrocca)-3-[3-(pyridin-4-yl)propoxy]pyridine (1,15 g, 3.5 mmol) obtained in example 41, was dissolved in methanol (50 ml) and to the resulting mixture is added 30% aqueous sodium hydroxide solution (30 ml), after which the mixture is heated in a flask under reflux for 20 hours. The reaction solution is concentrated under reduced pressure, the pH value of the mixture was adjusted to 3 using 15% aqueous solution of hydrochloric acid, and the mixture is then extracted with chloroform/THF (2:1) (50 ml 3). The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol) and subjected to crystallization from diethyl ether, to deliver specified in the header of the example compound (0,86 g) as colorless crystals with a melting point 208-S.

Example 53: Obtain 2-(3-methoxycarbonylbenzyl)-3-[3-(pyridin-4-yl)-propoxy]pyridine

2-(3-Carboxyphenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine (0.20 g, or 0.57 mmol) obtained in example 52, dissolved in methylene chloride (10 ml), the mixture was added 1-ethyl-3-(3’-dimethylaminopropyl) carbodiimide hydrochloride (0,13 g of 0.68 mmol) and methanol (0.10 ml) and obtained the (100 ml), the mixture was washed with saturated saline solution (30 ml 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol), to deliver specified in the header of the example compound (0.17 g) as a colourless oil.

1H-NMR (200 MHz, CDCl3, ppm): 2.07-2.24 (m, 2H), 2.59 (t, 2H, J=8Hz), 3.89 (s, 3H), 4.06 (t, 2H, J=6Hz), 6.99 (dd, 1H, J=5Hz, 8Hz), 7.10-7.14 (m, 2H), 7.20 (dd, 1H, J=2Hz, 8Hz), 7.35 (ddd, 1H, J=1Hz, 2Hz, 8Hz), 7.47 (t, 1H, J=8Hz), 7.76 (dd, 1H, J=2Hz, 5Hz), 7.77-7.80 (m, 1H, J=2Hz), 7.86 (dt, 1H, J=1Hz, 8Hz), 8.47-8.51 (m, 2H).

Example 54: Obtain 2-(3-chlorophenoxy)-3-[3-(3-acetoxyphenyl-4-yl)-propoxy]pyridine of monopolarity

2-(3-Chlorophenoxy)-3-[3-(3-hydroxypyridine-4-yl)propoxy]-pyridine (1.0 g, 2.8 mmol) obtained in example 31, was dissolved in pyridine (3 ml) and to the resulting mixture is added acetic anhydride (1.3 ml, 14 mmol), the mixture is then stirred at room temperature for 5 hours. To the reaction solution was added ethyl acetate (100 ml), the mixture was washed with saturated saline solution (30 ml 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane) to give 2-(3-chla the result is specified in the header of the example compound (1.07 g) with a melting point of 107-C (recrystallized from diethyl ether).

Example 55: Obtain 2-(3-bromophenoxy)-3-[3-(3-acetoxyphenyl-4-yl)- propoxy]pyridine 1.5 oxalate

2-(3-Bromophenoxy)-3-[3-(3-hydroxypyridine-4-yl)propoxy]-pyridine obtained in example 32, are treated the same way as described in example 54, obtaining specified in the header of the example compounds with a melting point of 110-S.

Example 56: Obtaining 2-phenoxy-3-[3-(3-acetoxyphenyl-4-yl)propoxy]-pyridine

2 Phenoxy-3-[3-(3-hydroxypyridine-4-yl)propoxy]pyridine obtained in example 30, are treated the same way as described in example 54, obtaining specified in the header of the example compounds with a melting point of 79-80C.

Example 57: Obtain 2-(3-bromobenzyl)-3-[3-(3-acetoxyphenyl-4-yl)-propoxy]pyridine 1.5 fumarata

2-(3-Bromobenzyl)-3-pyridinol obtained in comparative example 20, are treated the same way as described in example 26, to obtain 2-(3-bromobenzyl)-3-[3-(3-hydroxypyridine-4-yl)-propoxy]pyridine (melting point 138-S), which is then treated in this way, as described in example 54, obtaining specified in the header of the example compounds with a melting point 122-S.

Example 58: Obtain 2-(3-bromophenoxy)-3-[3-(3-hydroxy-5-methoxypyridine-4-yl)propoxy]pyridine rata

A mixture of 2-(3-bromophenoxy)-3-[3-(3,5-dimethoxypyridine-4-yl)-propoxy]pyridine (3.15 g, 7.1 mmol) obtained in example 19, and pyridinecarboxamide (8.0 g) was stirred at 180C for 1.5 hours. After the mixture has cooled, and to it was added a saturated aqueous solution of sodium bicarbonate (100 ml) and extracted with ethyl acetate (100 ml 3). The organic layer was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol) to give 2-(3-bromophenoxy)-3-[3-(3-hydroxy-5-methoxypyridine-4-yl)propoxy]-pyridine and 2-(3-bromophenoxy)-3-[3-(3,5-dihydropyridines-4-yl) -propoxy]pyridine, which are separately treated with fumaric acid to obtain 2-(3-bromophenoxy)-3-[3-(3-hydroxy-5-methoxypyridine-4-yl)propoxy]pyridine 0.5 fumarata (1,00 g) [melting point 157-C (recrystallized from ethanol/diethyl ether)] and 2-(3-bromophenoxy)-3-[3-(3,5-dihydroxypyridine-4-yl)propoxy]pyridine 0.5 fumarata (1,36 g) [melting point 184-C (recrystallized from ethanol)], respectively.

Example 60: Obtain 2-(3-acetylphenol)-3-[3-(pyridin-4-yl)propoxy]-pyridine 0.5 fumarata

Example 61: Obtain 2-[3-(1-hydroxyethyl)phenoxy]-3-[3-(pyridin-4-yl)propoxy]pyridine 1.0 fumarata

2-(3-Acetylphenol)-3-[3-(pyridin-4-yl)propoxy]pyridine (0.20 g, 0.3 mmol) obtained in example 60, was dissolved in methanol (10 ml) to the mixture is added sodium borohydride (0.50 g, 13 mmol) and stirred at room temperature for 10 minutes. To the reaction solution was added saturated lanim solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol) to give 2-[3-(1-hydroxyethyl)phenoxy]-3-[3-(pyridin-4-yl)propoxy]-pyridine, which is then treated with fumaric acid to obtain specified in the header of the example compound (0.06 g) with a melting point of 93-C (recrystallized from ethanol/diethyl ether).

Example 62: Obtain 3-(3-hydroxypyridine-4-yl)-1-propanol

3-(3-Methoxypiperidine-4-yl)-1-propanol (3,67 g of 18.6 mmol) obtained in example 2 was dissolved in ethanol (100 ml) and add 15% aqueous solution of hydrochloric acid (20 ml), then the mixture is heated in a flask under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, the residue is purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate) and then recrystallized from diethyl ether to obtain specified in the header of the example compounds (2,08 g) as colorless crystals with a melting point of 123-S.

Example 63: Obtain 3-[3-(2,6-dimethoxybenzoyl)pyridine-4-yl]-1-propanol

(i) 3-(3-Hydro is dihydropyran (5.0 ml, 55 mmol), D,L-Campero-10-sulfonic acid and 1.00 g, 4.30 mmol) and the resulting mixture is heated in a flask under reflux for 20 minutes. The reaction solution was poured into aqueous sodium hydrogen carbonate solution, the mixture Astrovirus with ethyl acetate (200 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate) to obtain 3-hydroxy-4 -(3-tetrahydropyranyloxy)pyridine as a colourless oil.

(ii) the Oily product obtained as described above was dissolved in pyridine (12 ml) to the resulting mixture is added 2,6-dimethoxybenzonitrile (4.6 g, 7.4 mmol) and stirred at room temperature for 10 minutes. To the reaction solution was added ethyl acetate (300 ml) and the mixture is successively washed with saturated aqueous sodium bicarbonate (50 ml of 2), saturated aqueous copper sulfate (monovalent) (50 ml of 2) and saturated saline (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate), obtaining as a result of 3-(2,6-dimethoxybenzyl, obtained in (ii) is added to methanol (100 ml) and 10% aqueous solution of hydrochloric acid (5 ml) and the resulting mixture stirred at 40C for 30 minutes. After cooling, the reaction solution is neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate (400 ml) and washed with saturated saline solution (50 ml of 2). The mixture is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is recrystallized from diethyl ether, to deliver specified in the header of the example compound (0,80 g) as colorless crystals with a melting point 117-S.

Example 64: Obtain 3-(5-benzyloxypyridine-3-yl)propanol

Ethyl ester of 3-(5-benzyloxypyridine-3-yl)propanolol acid (2.65 g, 9.4 mmol) obtained in comparative example 36, was dissolved in ethanol (150 ml) and to the resulting mixture is added sodium borohydride (3,54 g, 94 mmol) and then heated in a flask under reflux for 3 hours. The reaction solution is evaporated under reduced pressure, to the residue water is added (100 ml) and the mixture extracted with ethyl acetate (100 ml of 2). The extract was washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under ponan), receiving the result specified in the header of the example compound (1.8 g) as a pale yellow oil.

1H-NMR (300 MHz, CDCl3, ppm): 1.80-2.10 (m, 3H), 2.71 (t, 2H, J=8Hz), 3.66 (t, 2H, J=6Hz), 5.10 (s, 2H), 7.11 (t, 1H, J=2Hz), 7.30-7.48 (m, 5H), 8.09 (d, 1H, J=2Hz), 8.21 (d, 1H, J=2Hz).

Example 65: Obtain 2-(3-chlorophenoxy)-3-[3-(5-hydroxypyridine-3-yl)-propoxy]pyridine

2-(3-Chlorophenoxy)-3-pyridinol obtained in comparative example 14, and 3-(5-benzyloxypyridine-3-yl)-1-propanol obtained in example 64, treated as described in example 3 to obtain 2-(3-chlorophenoxy)-3-[3-(5-benzyloxypyridine-3-yl)propoxy]pyridine.

Thus obtained 2-(3-chlorophenoxy)-3-[3-(5-benzyloxypyridine-3-yl)propoxy]pyridine (2.5 g, 5.6 mmol) was dissolved in ethanol (100 ml) to the resulting mixture is added concentrated hydrochloric acid (100 ml) and then this mixture is heated in a flask with reflux condenser. After 5 hours and 10 hours to the mixture is added concentrated hydrochloric acid (50 ml of 2), after which the mixture is heated in a flask under reflux for 20 hours and allowed to cool. The mixture is neutralized with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate (100 ml of 2). The extract was washed with saturated saline solution (50 ml of 2), dried over anhydrous CX silica gel (eluent: ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane, receiving the result specified in the header of the example compound (1.3 g) as colorless crystals with a melting point 148-S.

Example 66: Obtain 3-(3-etoxycarbonyl-5-methoxypyridine-4-yl)-1-propanol

1-(3-Cyano-5-methoxypyridine-4-yl)-3-benzyloxypropionic (2.3 g, 8 mmol) obtained in comparative example 41, was dissolved in ethanol (35 ml) and add 10% aqueous sodium hydroxide solution (15 ml), and then the mixture was stirred at 70 C for 1.5 hours. The mixture is neutralized with concentrated hydrochloric acid and the reaction solution was concentrated under reduced pressure. Thus obtained residue is dissolved in 30% solution of hydrochloric acid in ethanol (50 ml) and the resulting mixture is heated in a flask under reflux for 14 hours. The mixture is neutralized with sodium bicarbonate and the reaction solution was again concentrated under reduced pressure. Thus obtained residue is extracted with ethyl acetate (200 ml), washed with saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane) and recrystallized from ether, proclivity 85-89S.

Example 67: Getting 2-(3-chlorophenoxy)-3-[3-(3-etoxycarbonyl-5-methoxypyridine-4-yl)propoxy]pyridine

2-(3-Chlorophenoxy)-3-pyridinol obtained in comparative example 14, and 3-(3-etoxycarbonyl-5-methoxypyridine-4-yl)-1-propanol obtained in example 66, treated as described in example 3, to obtain specified in the header of the example compounds with a melting point of 82-83 C get.

Example 68: Obtain 2-(3-chlorophenoxy)-3-[3-(3-carboxyl-5-methoxypyridine-4-yl)propoxy]pyridine

2-(3-Chlorophenoxy)-3-[3-(3-etoxycarbonyl-5-methoxypyridine-4-yl)propoxy]pyridine (4.4 g, 10 mmol) obtained in example 67, was dissolved in ethanol (40 ml) to the resulting mixture add a solution of sodium hydroxide (0,80 g, 20 mmol) in water (5 ml) and then stirred at 70C for 30 minutes. The mixture is concentrated under reduced pressure, add water (50 ml), and then this mixture is added dropwise acetic acid (3 ml) under stirring. The precipitated crystals are collected by filtration, washed with water and dried to obtain specified in the header of the example compound (3.6 g) as colorless crystals with a melting point 166-168S.

Example 69: Obtain 2(3 chlorophenoxy)-3-[3-(3-amino-5-hydroxypyridine-4-yl)-propoxy]PL), obtained in example 68, suspended in toluene (40 ml) to the resulting mixture add triethylamine (3.5 g, 35 mmol), and then diphenylphosphinic (4.1 g, 15 mmol) at 70 C for 30 minutes. Then, to the obtained mixture is added n-methoxybenzyloxy alcohol (3.5 g, 25 mmol), and 30 minutes thereafter, to the reaction solution was added ethyl acetate (300 ml). The mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated saline solution (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane) to give the result 2-(3-chlorophenoxy)-3-{3-[3-(4-methoxybenzenesulfonyl)amino-5-hydroxypyridine-4-yl]propoxy}pyridine (3.5 g) as a pale yellow oil.

Thus obtained oily product is mixed with pyridinecarboxamide (30 g) and the mixture is stirred to melt it at 150 for 1.5 hours. After the mixture has cooled, add water (100 ml), neutralizing the resulting mixture with sodium bicarbonate and extracted with chloroform (100 ml 4). The chloroform layers are combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The remainder of the XI)-3-[3-(3-amino-5-hydroxypyridine-4-yl)propoxy]-pyridine (0.85 grams) as a pale brown oil, which is then treated with fumaric acid to deliver specified in the header of the example compound (0,53 g) with a melting point of 75 to 90 ° C (recrystallized from ethyl acetate).

Example 70: Obtain 2-(3-chlorophenoxy)-3-[3-(3-methylsulfonylamino-4-yl)propoxy]pyridine

2-(3-Chlorophenoxy)-3-[3-(3-aminopyridine-4-yl)propoxy]-pyridine (0.15 g, 0.42 mmol) obtained in example 25, dissolved in methylene chloride (5 ml) and pyridine (0,34 ml), add to it ethylsulfonyl (0.04 ml, 0.50 mmol) under cooling on ice and the mixture is stirred for 3 hours. Then add a mixture of ice water (20 ml) and extracted with the mixture with ethyl acetate (50 ml of 2). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (20 ml of 2) and saturated saline solution (20 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: chloroform/methanol) and then recrystallized from diethyl ether, to deliver specified in the header of the example compound (0.07 g) as colorless crystals with a melting point 131-S.

Example 71: Obtain 3-(3-chloro-5-methoxypyridine-4-yl) is the first in comparative example 38, dissolved in ethanol (100 ml), the mixture is added 15% aqueous solution of hydrochloric acid (3 ml) and stirred at 60C for 20 minutes. The reaction solution is concentrated under reduced pressure, the residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate), to deliver specified in the header of the example compound (2.2 g) as a pale yellow oil.

1H-NMR (300 MHz, CDCl3, ppm): 1.77 (t, 1H, J=6Hz), 1.80-1.89 (m, 2H), 2.89 (t, 2H, J=7Hz), 3.63 (q, 2H, J=7Hz), 3.95 (s, 3H), 8.12 (s, 1H), 8.23 (s, 1H).

Example 72: Obtain 2-(3-chlorophenoxy)-3-[3-(3-chloro-5-methoxypyridine-4-yl)-propoxy]pyridine

2-(3-Chlorophenoxy)-3-pyridinol obtained in comparative example 14, and 3-(3-chloro-5-methoxypyridine-4-yl)-1-propanol obtained in example 71, treated as described in example 3, to obtain specified in the header of the example compound (2.7 g) as a colourless oil.

1H-NMR (300 MHz, Dl3, ppm): 2.03-2.15 (m, 2H), 2.95 (t, 2H, J=7Hz), 3.87 (s, 3H), 4.08 (t, 2H, J=7Hz), 6.97-7.06 (m, 2H), 7.11-7.17 (m, 2H), 7.20 (dd, 1H, J=2Hz, 8Hz), 7.26-7.33 (m, 1H), 7.76 (dd, 1H, J=2Hz, 5Hz), 8.09 (s, 1H), 8.21 (s, 1H).

Example 73: Obtain 2-(3-chlorophenoxy)-3-[3-(3-chloro-5-hydroxypyridine-4-yl)propoxy]pyridine

2-(3-Chlorophenoxy)-3-[3-(3-chloro-5-methoxypyridine-4-yl)-propoxy]pyridine (8.5 g, 21 who and melted, at 150 for one hour. Then to this mixture is added a mixture of ice water (300 ml), the mixture is neutralized with sodium bicarbonate and extracted with ethyl acetate (100 ml 3). The organic layer was washed with saturated aqueous sodium bicarbonate (50 ml of 2) and saturated saline (50 ml of 2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethanol/ethyl acetate) and then recrystallized from diethyl ether/diisopropyl ether, to deliver specified in the header of the example compound (5.6 g) as colorless crystals with a melting point of 95 S.

Receiving: Making pill

The following components are mixed and mix in the usual way, and the resulting mixture granularit. Then from this mixture stamp tablets with output 1000 tablets (100 mg each).

2-(3-chlorophenoxy)-3-[(3-hydroxypyridine-4-yl)propoxy]-pyridine (compound of example 31) (5 g), corn starch (25 g), lactose (54 g), crystalline cellulose (11 g), hydroxypropylcellulose (3 g), light anhydrous silicic acid (1 g) and magnesium stearate (1 g).

Practical application

1. The compound of formula (I)

in which a represents an oxygen atom, a sulfur atom, CH2or NH;

X1and X2- same or different and each represents a hydrogen atom, halogen atom, cyano, hydroxyl group, replacement of the lower alkyl group, halogen-substituted lower alkyl group, lower CNS group, lower cycloalkyl group, carboxyl group, lower alkoxycarbonyl group, a lower acyl group, a 5-tetrazolyl group;

Y1represents a hydrogen atom;

Z1and Z2- same or different and each represents a hydrogen atom, halogen atom, cyano, hydroxyl group, lower CNS group, replacement of the lower CNS group, substituted lower CNS group, n is at school by a group of low CNS group, carboxyl group, a lower alkoxycarbonyl group, lower Allexinno group, amino group, lower alkylsulfonamides;

n = 2, 3, 4,

or its pharmaceutically acceptable salt.

2. Connection on p. 1, in which Z1and Z2- same or different and each represents a hydrogen atom, halogen atom, hydroxyl group, lower CNS group, replacement of the lower CNS group, substituted lower CNS group lower CNS group, carboxyterminal lower CNS group, substituted lower alkoxycarbonyl group lower CNS group, lower Allexinno group, amino group, lower alkylsulfonyl, or its pharmaceutically acceptable salt.

3. Connection on p. 1, which is selected from the group consisting of compounds of the formula (Ia)

in which AND1represents an oxygen atom, a sulfur atom, CH2or NH;

X11represents a hydrogen atom, halogen atom, cyano, hydroxyl group, replacement of the lower alkyl group, halogen-substituted lower alkyl group, lower CNS group, the lower is made by a hydrogen atom, halogen atom, a lower CNS group;

Y1represents a hydrogen atom;

Z11and Z21- same or different and each represents a hydrogen atom, halogen atom, hydroxyl group, lower CNS group, replacement of the lower CNS group, substituted lower CNS group lower CNS group, carboxyterminal lower CNS group, substituted lower alkoxycarbonyl group lower CNS group, lower Allexinno group, an amino group or a lower alkylsulfonyl, or their pharmaceutically acceptable salts.

4. Connection on p. 3, which is chosen from the group consisting of the following compounds:

2 phenoxy-3-[3-(pyridin-4-yl)propoxy]pyridine;

2-(3-bromophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine;

2-(3-pertenece)-3-[3-(pyridin-4-yl)propoxy]pyridine;

2-(3-pertenece)-3-[3-(3-hydroxypyridine-4-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridine-4-yl)propoxy]pyridine;

2-(3-bromophenoxy)-3-[3-(3-hydroxypyridine-4-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-aminopyridine-4-yl)propoxy]pyridine

2-pheno is;

2-(3-chlorophenoxy)-3-[3-(3-acetoxyphenyl-4-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-chloro-5-hydroxypyridine-4-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridine-5-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-amino-5-hydroxypyridine-4-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-methylsulfonylamino-4-yl)propoxy]pyridine and

2-(3-pampanito)-3-[3-(pyridin-4-yl)propoxy]pyridine,

or their pharmaceutically acceptable salts.

5. Connection on p. 1 representing 2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridine-4-yl)propoxy]pyridine or its pharmaceutically acceptable salt.

6. The method of obtaining the compounds of formula (I)

in which a represents an oxygen atom, a sulfur atom, CH2;

X1and X2- same or different and each represents a hydrogen atom, halogen atom, cyano, hydroxyl group, halogen-substituted lower alkyl group, lower CNS group, lower cycloalkyl group, lower alkoxycarbonyl group, a lower acyl group or a 5-tetrazolyl group;

Y1represents a hydrogen atom;

Z

n = 2, 3, 4,

or its pharmaceutically acceptable salt, comprising the condensation of the compounds of formula (III)

in which AND2represents an oxygen atom, a sulfur atom or CH2;

X12and X22- same or different and each of themrepresents a hydrogen atom, halogen atom, cyano, getagentname lower alkyl group, lower CNS group, lower cycloalkyl group, lower alkoxycarbonyl group, a lower acyl group;

Y1has the values defined above,

with the compound of the formula (IV)

in which Z12and Z22- same or different and each represents a hydrogen atom, a halogen atom, C is CNS group, lower alkoxycarbonyl group, lower Allexinno group, amino group, lower alkylsulfonamides;

n = 2, 3, 4,

converting, if necessary, the substituents X12X22, Z12and Z22in other deputies.

7. The method of obtaining the compounds of formula (I)

in which a represents an oxygen atom or NH;

X1and X2- same or different and each represents a hydrogen atom, halogen atom, cyano, replacement lower alkyl group, halogen-substituted lower alkyl group, lower CNS group, carboxyl group, lower alkoxycarbonyl group or lower acyl group;

Y1represents a hydrogen atom;

Z1and Z2- same or different and each represents a hydrogen atom, a hydroxyl group;

n = 2, 3, 4,

or its pharmaceutically acceptable salt, comprising the reaction of compounds of formula (V)

in which L represents a halogen atom;

Z13and Z23- same or different and each represents an atom is P>1
and n are as defined above values

with the compound of the formula (VI)

in which AND3represents an oxygen atom or NH;

X12and X22- same or different and each of themrepresents a hydrogen atom, halogen atom, cyano, getagentname lower alkyl group, lower CNS group, carboxyl group, lower alkoxycarbonyl group and the lower acyl group, with subsequent conversion if necessary deputies 12X22, Z13and Z23in other deputies.

8. The phosphodiesterase IV inhibitor, which as the active component includes a compound described in any of paragraphs.1-5, or its pharmaceutically acceptable salt.

9. The pharmaceutical composition exhibiting inhibitory activity against phosphodiesterase IV, which as the active component includes a compound described in any of paragraphs.1-5, or its pharmaceutically acceptable salt.

10. The compound of formula (II)

in which Z3represents a hydrogen atom, a lower alkyl group, a substituted lower CNS group, a lower alkyl group, benzyl Afleet a hydrogen atom, halogen atom, a lower alkoxycarbonyl group or lower CNS group.

11. Connection on p. 10, which in the 4th position of the pyridine ring is n-propanamine group, and in the 5th position of the pyridine ring is a group of the Z4.

 

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The invention relates to new and nitrate salts of heterocyclic compounds of formulas (a) and (b), where R is hydrogen, alkoxyl, R1- alkyl, alkoxyl, R2is hydrogen, alkyl, R3- alkyl, alkoxyl, X denotes N-R11or oxygen, R11means the free valence, Y represents N-R16, sulfur or alkyl, R16means hydrogen; other values radicals presented in the description of the invention

The invention relates to new indole derivative of the formula I

where two of R1a, Rlb, Rlc, Rldindependently from each other denote H, F, I, Cl, Br, (C1-C4)alkyl, phenyl, phenyl-(C1-WITH4)alkyl, (C1-C4)alkoxy, phenyl-(C1-C4)alkoxy, phenyloxy, HE, -NR5aR5b, -SOn-R6c, n is 1-2, and are the same or different, and two other mean N; where all residues R5a, R5b, R6cif present in the molecule more than once, are independent from each other and may be each the same or different; one of R2and R3means -(CH2)p-CO-R8and the other denotes H, F, Cl, Br, or -(CH2)p-CO-R8; p is 0, 1 or 2; R8means-NR9R10, -OR10; A represents the bivalent residue of(C1-C4)alkyl, which is saturated or which contains a triple bond, or -(C1-C4)alkyl-CO-NH-, where the nitrogen is associated with R4; R4means phenyl, which is substituted by one residue R15bor pyridyl, which is unsubstituted or substituted14on the nitrogen atom; all their stereozoom

The invention relates to new compounds of the formula (I) and their pharmaceutically acceptable salts and esters possessing inhibitory ability against endothelioma receptors, the Compounds can be used to treat diseases associated with abnormal vascular tone and endothelial dysfunction

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

The invention relates to compounds of General formula (I)

in which R1means a hydrogen atom, a radical, CH3or the radical (CH2HE; R2means the radical (CH2HE; X-Y represents a relationshiporZ indicates cycle selected among the cycles of the following formulas:

; R3means alkyl chain with 4 to 8 carbon atoms, substituted by one or more hydroxyl groups and, in addition, possibly substituted by one or more lower alkyl groups and/or substituted by one or more halogen atoms and/or substituted by one or more groups of CF3and/or in which one or a few simple links of the chain may be substituted with one or more double bonds, and R3is a cycle in the para - or meta-position relative to the link X-Y, as well as optical and geometrical isomers of the above compounds of formula (I)
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