Derivative azole, the pharmaceutical composition on the basis thereof, the intermediate

 

(57) Abstract:

The invention relates to new derivatives of asola General formula I, where R1and R2the same or different, each represents hydrogen, cycloalkyl and so forth, or R1and R2forming (a) a condensed ring, (b) or (C), which may be optionally substituted substituted lower alkyl, amino group and the like; R3, R6, R7, R8the same or different, each represents a hydrogen atom, and so on; R4represents a cyano, tetrazolyl, -COOR9and so on; R5represents a hydrogen atom or lower alkyl; D represents optionally substituted lower alkylene; X and Z are the same or different, each represents oxygen or sulfur, Y is-N= or-CH=; A is-B is-O-, -S-B-, -B-S - or-In-; represents the lowest alkylene or lower albaniles; n = 2. Derivative azole General formula I or their pharmaceutically acceptable salts with pharmaceutically acceptable carrier to form farbkomposition with the action of leukotriene antagonist and antagonist of the thromboxane A2useful for the prevention or treatment of allergic diseases, ischemic heart disease and brain. Prolie relates to a medicinal product, namely the new derivative azole or its salt, which is an antagonist of leukotriene (LTs) and thromboxane (TX) A2and useful as a drug for the prevention and treatment of diseases, where these compounds serve as mediators, as well as pharmaceutical compositions comprising the above derivative, and intermediate products, used in obtaining the specified derived.

There are different types of asthma - dyspeptic asthma, allergic asthma, atopic asthma, bronchial asthma, infectious-allergic asthma, cardiac asthma, and others. In particular, a large number of patients suffer from bronchial asthma, therefore, this study was conducted on the means or methods suitable for the prevention and treatment of this disease. The mechanism of action of drugs against asthma is considered from two points of view, i.e. bronchiectasis and protivopostavlenie, and developed many drugs for the treatment and prevention of disease. Examples of the above-mentioned bronchodilators are B2stimulants, methylxanthines and anticholinergic agents, and steroids and mediator inhibitors can be examples of protivovospalitiona give strong side effects, and anti-inflammatory drugs are ineffective for the treatment and prevention of disease compared with other means, most efforts have focused on developing better tools for prevention and treatment of asthma, which are devoid of these shortcomings.

In recent years, among these anti-inflammatory agents and mediator inhibitors, such as PAF antagonists, antagonists or inhibitors of the synthesis of thromboxane A2(TXA2and antagonists of leukotriene (LTs) has been used to treat asthma, and their effectiveness was recognized. However, it was noted that therapeutic effect of these agents in the treatment of asthma (agents average or high efficiency) is about 50% when using it one (Iqakuno Ayumi 168 (4), 295 (1994) and Iqakuno Ayumi 164 (4), 225 (1993)), assuming that the efficiency is not sufficient due to the difference in the group of mediators, which play a major role in the treatment of patients with asthma.

Recently it was reported that some compounds are able to inhibit many of the mediators (e.g., a non-examination of the published patent application Japan (Kokai) N 4-154766). However, their effectiveness is insufficient from the point of view of oral suction, so balanced inhibitors of a variety of mediators, and well absorbed after oral administration.

The purpose of this invention to provide a connection which gives a well-balanced suppression of two or more mediators (hereinafter called "multiple mediator inhibitor") and the creation of a pharmaceutical preparation containing this compound. The authors of the present invention have conducted extensive studies based on the assumption that multiple neurotransmitter inhibitor can be used as effective against a wide spectrum of allergic diseases such as asthma and similar diseases and, in particular, as a very good anti-asthmatic agent, in the case of the inhibitor, which is an antagonist as TXA2and LTs. In the result it was found that derivative represented by the below General formula (I) or its salt, which is characterized in that it has a monocyclic or condensed core of the azole ring, and which differs in structure from known compounds, has two above-mentioned functions well balanced inhibitor and is very well absorbed when administered orally, and that it may even be anti-asthmatic agent, shii.

Accordingly, the present invention relates to a derivative azole presented to the following General formula (I), its salts and pharmaceutical composition containing these compounds as active ingredients, mainly antagonists leukotriene and thromboxane A2.

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R1and R2can be the same or different from each other, and each represents a hydrogen atom, cycloalkyl group, a lower alkyl group which may be substituted, or aryl group which may be substituted, or R1and R2can be connected to the ring with the formation of a condensed ring represented by the formula: or of the formula: and these condensed rings may be substituted by a lower alkyl group which may be substituted by amino, a cyano, a nitro-group, a hydroxyl group, a halogen atom or a lower alkyl group,

R3, R6, R7and R8can be the same or different from each other, and each represents a hydrogen atom, an amino group, a cyano, a nitro-group, hydroxyl group, halogen atom, lower alkoxygroup or a lower alkyl group, which is my: -COOR9or a group represented by the formula: -E-NH-F-R10,

R9represents a hydrogen atom or the residue of ester,

E represents a single bond or carbonyl group,

F represents a single bond or lower alkylenes group

R10represents a hydrogen atom; karbamoilnuyu group; mono - or di(lower alkyl) karbamoilnuyu group; carboxyl group; lower alkoxycarbonyl group; arylcarbamoyl group which may be substituted by a lower alkyl group; a lower alkanoyloxy group; lower alkylsulfonyl group; or arylsulfonyl group which may be substituted by a lower alkyl group,

R5represents a hydrogen atom or a lower alkyl group,

D represents the lower alkylenes group which may be substituted,

X and Z can be the same or different from each other, and each represents an oxygen atom (O) or sulfur atom (S),

Y represents a nitrogen atom (-N=) or methine group (-CH=),

A is a group represented by the formula:

-O-B-, -B-O-, -S-B-, -B-S - or-B-,

B is the lowest Allenova group or lower alkenylamine group, and

n is 0, 1 or 2; the same notation will be prisoedineniyem is

a) derived asola, its pharmaceutically acceptable salt, hydrate or MES, in which R4represents a

1) tetrazolyl group

2) a group represented by the formula-COOR9(R9is a hydrogen atom or an ester residue), or

3) a group represented by the formula: -E-NH-F-R10(where E is a simple bond or a carbonyl group, F is a simple bond or lower Allenova group, and R10is a hydrogen atom, carnemolla group, a carboxyl group or a lower alkoxycarbonyl group, lower alcoolica group, lower alkylsulfonyl group or arylsulfonyl group which may be substituted by a lower alkyl group),

b) derived asola, its pharmaceutically acceptable salt, hydrate or MES, in which X is a sulfur atom,

c) a derivative azole, its pharmaceutically acceptable salt, hydrate or MES, in which Y is retinovoy group (-CH=), or

d) a derivative azole, its pharmaceutically acceptable salt, hydrate or MES, in which R1and R2can be the same or different from each other, and each represents a hydrogen atom, cycloalkyl group, a lower alkyl group, phenyl group, which is my condensed ring, represented by the formula: or of the formula: and these condensed rings may be substituted by a lower alkyl group which may be substituted by 1-3 halogen atoms, or amino group, cyano, a nitro-group, a hydroxyl group, a halogen atom, a lower alkoxygroup; D - lower Allenova group which may be substituted by a halogen atom, and A group represented by the formula; -B-O-, the formula: -S-B-, the formula: -B-S -, or the formula: -B (where B is the lowest Allenova or lower alkenylamine group).

The most preferred compound is derived asola, its pharmaceutically acceptable salt, hydrate or MES, in which R1and R2can be the same or different from each other, and each represents a hydrogen atom, cycloalkyl group, a lower alkyl group or phenyl group which may be substituted by a lower alkyl group, each of R3, R6and R7represents a hydrogen atom, R8is a halogen atom, R5is a hydrogen atom, D is a methylene group, X is a sulfur atom, Y is a methine group (-CH= ), Z is an oxygen atom, A group represented by the formula: -CH2O-, and n = 2.

The present invention relates also to farmatsevticheskii acceptable salt, hydrate or MES as an active ingredient, in particular, to the antagonist of leukotriene and thromboxane A2.

The present invention relates also to the derived 2-hydroxyanisole below General formula (IVc), or its pharmaceutically acceptable salt and a derivative of benzoic acid represented by the following formula (IIIa), or its pharmaceutically acceptable salts, which are useful as intermediates for the compounds represented by the aforementioned formula (I) or their pharmaceutically acceptable salts.

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In the above formula, R6aand R7acan be the same or different from each other, and each represents a hydrogen atom or a halogen atom.

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In this formula, R1aand R2acan be the same or different from each other, and each represents a hydrogen atom, cycloalkyl group, a lower alkyl group or phenyl group which may be substituted by a lower alkyl group, or R1aand R2acan be combined with the ring with the formation of a condensed ring represented by the formula: or of the formula: and these condensed rings may be substituted by lower ALK is, a halogen atom or a lower alkoxygroup,

R3represents a hydrogen atom, an amino group, a cyano, a nitro-group, hydroxyl group, halogen atom, lower alkoxygroup or a lower alkyl group,

Rarepresents a hydrogen atom or a lower alkyl group.

The following is a detailed description of the present invention.

In the General formulas of the present invention, the term "lower" means a straight or branched carbon chain having from 1 to 6 carbon atoms, unless otherwise specified.

In the illustrative examples of the term "lower alkyl group are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and similar groups. The preferred alkyl group having from 1 to 4 carbon atoms, and more preferred methyl and ethyl groups.

may represent even a regular Deputy, which can be substituted by lower alkyl groups, and illustrate its examples include a halogen atom (e.g. chlorine, bromine, fluorine, etc.,), hydroxyl group, lower CNS group (e.g. a methoxy group, ethoxypropan, p-propoxylate, out-propoxylate and similar groups), alloctype (for example, naphthyloxy, fenoxaprop and similar groups), aralkylated (for example, benzyloxy, penetrometry and similar groups), mercaptopropyl, lower allylthiourea (for example, methylthiourea, ethylthiourea or similar groups), killigrew (for example, phenylthiourea, naphthylthiourea or similar groups), arkitip (for example, menzilcioglu, penitentiary or similar group), amino group, mono - or disubstituted by an amino group, a substituted lower alkyl group (for example, methylaminopropyl, ethylamino, dimethylaminopropyl, diethylaminopropyl or similar groups), lower alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl or similar group), a lower acyl group (for example, formyl, acetyl, propionyl, benzoyl or similar groups), alloctype (for example, acetoxy, propionyloxy or similar groups), karboksilnuyu 3 hydrogen atoms of the lower alkyl group, optional, can be substituted for these groups.

Examples of "cycloalkyl group are saturated hydrocarbon cyclic group having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and similar groups, of which preferred is cycloalkyl group containing from 3 to 7 carbon atoms.

"Aryl group" means a cyclic hydrocarbon aryl group, and illustrating its examples include phenyl, naphthyl and the like groups.

Examples of the substituent in the "aryl group which may be substituted" include an amino group, a cyano, a nitro-group, hydroxyl group, halogen atom, lower CNS group and the above-mentioned lower alkyl group which may be substituted.

Examples of the "halogen atom" include fluorine, chlorine, bromine, etc.

Examples of "lower CNS group are methoxy group, ethoxypropan, propoxylate, isopropoxide, butoxypropan, isobutoxy, second-butoxypropan, tert-butoxypropan, pentyloxy (lilacchrome), isopentylamine, tert-pentyloxy, neopentadactyla, 2-="ptx2">

The examples of the ester residue are essential residues, such as lower alkyl, aralkyl (benzyl, phenethyl, 1-naphthylmethyl or similar) and similar groups, or ether residues, hydrolyzed by metabolism in a living organism, such as (lower alkanoyloxy-)a lower alkyl group (acetoacetyl, acetoacetyl, tert-butanonoxime or similar group), (lower alkanoyl-)a lower alkyl group (vinylcarbazole, vinylcarbazole or similar group), (cycloalkylcarbonyl-)a lower alkyl group (cyclopropanecarboxylate, cyclobutanecarbonitrile, cyclopentanecarboxylate or similar groups), (lower alkanoyloxy-)a lower alkyl group (vinylcarbazole, vinylcaprolactam or similar group), (lower alkoxy)lower alkyl group (methoxymethyl, methoxyethyl, ethoxymethyl or similar group), (lower alkoxy)lower alkyl group (methoxyethoxymethyl or similar group), (lower alkoxycarbonyl-)a lower alkyl group (methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl or similar groups), benzoyloxy-lower alkyl group (benzoyloxymethyl, benzoyloxymethyl or similar group), 2-oxoalkyl group" in this formula, preferably represents methyl, ethyl, propyl, isopropyl, butyl or the like group), tetrahydroprotoberberine group, felicilda group and similar groups.

Preferred among these groups are lower alkyl, kalkilya, (lower alkanoyloxy-)lower alkyl, felicilda, 2-oxo-5-(lower alkyl)-1,3-dioxolan-4-ylmethylene and (lower alkoxycarbonyl-)lower alkyl groups. The most preferred lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl and the like groups.

"Lower alkalinous group is Allenova group having from 1 to 6 carbon atoms, and illustrating its examples include methylene, ethylene, METROTILE trimethylene, propylene dimethylmethylene tetramethylene, 1-metallisation, 2-metallisation, 3-metallisation, pentamethylene, 1-methyltyramine, 2-methyltyramine, 3-methyltyramine, 4-methyltyramine, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, 1,3-dimethyltrimethylene, 2,3-dimethyltrimethylene, 1,2-dimethyltrimethylene, 1,1,2-trimethylethylene, diethylethylene, hexamethylene, 1-methylpentylamino, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene and similar groups. Predpochtitaemye and a methylene group is preferable.

"Mono - or di-(lower alkyl)carbonilla group" in R10means a group in which 1 or 2 hydrogen atom carbamoyl group substituted by the above lower alkyl group, and preferred examples are mono - or di-C1-4-alkylcarboxylic group, for example, methylcarbamoyl, ethylcarbitol, propellerblades, isopropylcarbamate, dimethylcarbamoyl and diethylcarbamoyl.

"Lower alkoxycarbonyl group" means a group in which the above-mentioned lower CNS group is connected to the carbonyl group, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, pentyloxybenzoyl, isopentylamine, neopentylglycol, tert-pentyloxybenzoyl and hexyloxybenzoyl.

Arylcarbamoyl group "arylcarbamoyl group which may be substituted by lower alkyl group" means a cyclic hydrocarbon arylcarbamoyl group, and its examples are benzoyl and naphtol.

These arylcarbamoyl groups can be substituted by the above lower alkyl group, and in this case they can be replaced, pre the 3-methylbenzoyl, 4-methylbenzoyl, 2-ethylbenzoyl, 3-ethylbenzoyl, 4-ethylbenzyl, 1-naftol, 2-naftol and similar groups.

Examples of "lower alkanoyloxy group" include formyl, acetyl, propionyl, butisol, isobutyryl, valeryl, isovaleryl, pivaloyl and the like groups. Preferred are formyl, acetyl and propylaniline group.

"Lower alkylsulfonyl group" means a group in which sulfonylurea group connected with the above-mentioned lower alkyl group, and illustrating its examples include methylsulphonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl, butylsulfonyl, peterculter, hexylsilane and similar groups. It is preferable alkylsulfonyl group having from 1 to 3 carbon atoms.

Arylsulfonyl group "arylsulfonyl group which may be substituted by lower alkyl group" means a cyclic hydrocarbon arylsulfonyl group, and its examples are phenylsulfonyl and naphthylmethyl. These arylsulfonyl groups can be substituted by the above lower alkyl group. In this case they can be, preferably, a substituted alkyl group having from 1 to 3 carbon atoms, which intenlational, 3-ethylphenethylamine, 4-ethylphenethylamine, 2-propylaniline, 3-propylenecarbonate and 4-propylaniline.

Lower Allenova group "lower alkalinous group which may be substituted" in D is a group as defined above. Examples of substituents are halogen atom, a hydroxyl group, and the lowest alkoxygroup.

"Lower Allenova group" B is as defined above, and examples of "lower alkalinous group" in B are vinile, propylen (-CH2-CH= CH-, -CH=CH-CH2-), butylen (-CH2-CH2-CH=CH-, -CH2-CH=CH-CH2, -CH= CH-CH2-CH2- and similar groups. Preferred of them is venelinova group.

Compounds of the present invention represented by the General formula (I) form salts. Salts of compounds (I) are included in this invention, and examples of these salts are salts of joining acids, formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid, phosphoric acid and similar acids, and with organic acids such as formic acid, expalained acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, etc. and also with acidic amino acids such as aspartic acid, glutamic acid and the like acid.

Examples of basic salts of these compounds are their salts with inorganic bases, such as salts of sodium, potassium, magnesium, calcium, aluminum, etc., and organic bases such as methylamine, ethylamine, ethanolamine, and basic amino acids (e.g. lysine, arginine, ornithine, etc.,), and ammonium salt.

The compound (I) of the present invention may also have an asymmetric carbon atom, the double bond and so on, in some cases, depending on the type of substituent, so that the connection can be in the form of stereoisomers such as optical isomers, geometrical isomers, etc.

As a result, these stereoisomers are included in the invention or in the form of single stereoisomers or as mixtures.

In addition, this invention also includes hydrates, various solvate and crystalline polymorphs of compound (I).

The compounds of this invention can be synthesized, for example, with PR1the halogen atom or the residue of an organic sulfonate, P2- hydroxyl group, halogen atom or the residue of an organic sulfonate, R3ais a hydrogen atom, halogen atom, lower CNS group, a lower alkyl group which may be substituted, cyano, a nitro-group, a protected hydroxyl group or a protected amino group, and R9a- the remainder of ester. The same notation will be used in the future.

In the first stage of the method 1 of carboxylic acid represented by the General formula (III) or its reactive derivative and the amine represented by the formula (IV) or its salt is subjected to amidation in the usual way of obtaining the compound represented by the General formula (V).

In this regard, examples of protective groups for amino group, denoted by R3aare p-nitrobenzyl, benzyl, benzhydryl, p-nitrobenzenesulfonyl and similar groups. Examples of protective groups for hydroxyl groups are killtokiga, such as benzyloxy etc., alloctype, for example, benzoyloxy lowest alkanoyloxy or similar groups, and trialkylsilyl group.

Examples of reactive derivatives of the esters of 1-hydroxybenzotriazole, N-hydroxysuccinimide and like ethers; symmetric acid anhydride; and mixed anhydrides with alkalicarbonate acid, p-toluensulfonate acid and anhydrides such.

When the compound (III) is introduced into the reaction in the form of free carboxylic acid, it is convenient to perform the reaction in the presence of a condensing agent, for example, dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide, 1,1'-carbonyldiimidazole or similar compounds.

The reaction is performed using a compound (III) or its reactive derivative and the compound (IV) at an approximately equimolar ratio of the reactants or an excess of one of them, in an organic solvent, which is inert in the reaction, for example, pyridine, tetrahydrofuran, dioxane, ether, benzene, toluene, xylene, dichloromethane, dichloroethane, chloroform, dimethylformamide (DMF), ethyl acetate, acetonitrile, or other similar solvent.

Depending on the type of the reactive derivative, in some cases it is advantageous to add a base, such as triethylamine, pyridine, picoline, lutidine, N, N-dimethylaniline, potassium carbonate, sodium hydroxide or a similar basis, with the purpose of smoothly proteous the solvent, for example, when used silaprany solvent, such as DMF, smoothly flowing reaction can be performed by adding, in advance, the reaction mixture is equal to or larger quantities of N-hydroxysuccinimide or N-hydroxybenzotriazole.

The reaction temperature varies depending on the type of the reactive derivative and is selected arbitrarily.

In the second stage receive the compound (Ia) of the present invention, subjecting the amide compound (V) obtained in the first stage, halogenated alkyl compound or similar compound represented by the General formula (VI).

The etherification perform, exposing substitution reaction of the compound (V) and the halide (or sulfonate) (VI) in the presence of a base.

In this regard, examples of the halogen atom denoted by R1or R2are iodine, bromine, chlorine, fluorine, etc., and examples of the residue of the organic sulfonate is alkylsulfonates (for example, methanesulfonamido, econsultancy and similar groups) and arylsulfonate (for example, benzolsulfonate, toluene (especially p-toluene)sulfonyloxy and similar groups).

When quality is out (VI) at an approximately equimolar ratio or excess of one of them, at a temperature of from room temperature to the heating temperature or at the boiling point under reflux in an organic solvent inert to this reaction, for example, N, N-dimethylformamide, dimethyl sulfoxide, acetone, methylethylketone, methanol, ethanol, isopropanol, dichloromethane, dichloroethane, chloroform, ether, tetrahydrofuran, dioxane or other similar solvent, or in water, or in mixtures of these solvents.

In some cases the reaction can be performed smoothly by adding secondary or tertiary base, e.g. pyridine, picoline, N,N-dimethylaniline, N-methylmorpholine, trimethylamine, triethylamine, dimethylamine or the like, or inorganic bases, such as sodium hydride, sodium hydroxide, potassium hydroxide, n-utility, trebuchet potassium, potassium carbonate, sodium carbonate, sodium bicarbonate or similar grounds.

When the compounds (VI) sulfonate is used, the reaction is preferably performed in a solvent inert in the reaction, as described above, in the amounts described above, and cooled to room temperature.

In the third stage, the compound (Ib) of this invention obtained by hydrolysis loneferret used conventional method, when the hydrolysis is performed in the presence of a base, for example sodium carbonate, sodium hydroxide or similar reasons, or in the presence of acid, for example, triperoxonane acid, hydrochloric acid or similar acids. It is desirable to carry out the reaction at a temperature of from room temperature to 100oC.

At the fourth stage, the compound (Ia) of this invention are obtained by esterification of the compound (Ib) of the present invention, which is a carboxylic acid. This stage is performed using a conventional method of esterification using such agents of esterification as alcohol or halide, sulfate, vatsayana, or similar agents, which are well known in the art, including necessary protection, deprotection, hydrolysis, recovery, etc.

In addition, sulfinyl or sulfonylurea connection, as representatives of the compounds of this invention can be obtained by oxidation of the corresponding sulfide or sulfinyl compounds in the usual way.

Method of obtaining 2 (see the end of the description).

In the formula method 2: P1lower alkyl group or aryl group. The same notation will be used in the care, represented by the General formula (V), i) with cenocoeliinae represented by the formula (VIII), and then ii) azide triamcinolone, azide triarylamine or sodium azide represented by the General formula (IX).

When using cyanocobalamine i) can be applied inert in this reaction the solvent described in the first stage of the method of obtaining 1, under the same reaction conditions.

The reaction of compound (ii) synthesis can be carried out by conducting the reaction at a temperature from room temperature up to the boiling temperature under reflux for from several days to several hours, in an inert solvent, for example benzene, toluene or a similar solvent, in the presence of azide triamcinolone or azide tiarella. The synthesis can also be done within a few hours to several days under stirring at a temperature of from room temperature up to the boiling point under reflux in dimethylformamide, in the presence of sodium azide and ammonium chloride.

Method for the preparation of 3 (see end of description).

In a method for the preparation of 3 compound (Ie) of the present invention are obtained by reaction of compound (Id) of the present invention with ammonia (X).

The connection is imolarot ratio or excess of one of them, while cooling with ice or at room temperature before cooling with ice or boiling under reflux, in an inert organic solvent, for example, methanol, ethanol, tetrahydrofuran, ether, dioxane, 2-propanol, benzene, toluene, xylene, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, pyridine or other similar solvent, or in water, or in mixtures of these solvents.

On the other hand, the compound (Ie) of the present invention are synthesized from compound (Ib) by conventional amidation reaction described in the first stage of the method of getting 1, or from compound (V) and compounds of formula: P1-D-CONH2(where P1a halogen atom (chlorine, bromine or iodine) or a residue of an organic sulfonate) in the same way as in the case of the second stage of the method of obtaining 1.

Method 4 (see end of description).

In the formula method 4: R12group, which may occur amino group. The same notation will be used hereafter.

In the method of obtaining 4 connections (If) and (Ig) of the present invention receives, exposing the amine or its salt (IVb), which are obtained by esterification of phenol derivative represented by the General formula (IVa), and further the N-acetylation and N-alkylsulfonamides.

In the first stage receive amine derivatives represented by General formula (IVb), (i) subjecting the esterification of phenol derivative represented by the formula (IVa), compound (XI), and (ii) restoring, then, the nitro group.

In this regard, talimena group and this group can serve as examples of the group denoted by R12from which you can get the amino group.

Etherification i) can be performed in the same manner as in the second stage of the method of obtaining 1, if P2the halogen atom or the residue of an organic sulfonate.

When P2- hydroxyl group, the reaction can be performed at temperatures from cooling with ice to the boiling point under reflux in a solvent such as tetrahydrofuran (THF), diethyl ether, dioxane, benzene, toluene, xylene, N,N-dimethylformamide, acetonitrile, ethyl acetate, or other similar solvent, in the presence of phosphorus compounds represented by the formula, R3P, and compounds represented by the formula: R13OCO-N= N-COOR13(where R is lower alkyl or aryl group, and R13lower alkyl group).

Recovery nitro ii) may be made in the usual way.

In the third stage, the compound (If) of the present invention are obtained by reaction of compound (XII) with hydrazine, phenylhydrazine, lower alkylamino or similar connection whereby the amino group derived from the group, able to give the amino group. This reaction can be carried out using the compound (XII) and hydrazine, phenylhydrazine, lower alkylamine or similar connection at equimolar ratio or by using an excess of one of them, at a temperature from a temperature under cooling with ice to the boiling point under reflux in an inert organic solvent, for example methanol, ethanol, 2-propanol, tetrahydrofuran (THF), dioxane, ether, N,N-dimethylformamide, benzene, toluene, xylene, or similar solvent.

At the fourth stage, the compound (Ig) of the present invention receives, subjecting the compound (If) the normal reaction N-alkylation, acylation or sulfonylurea. This stage can be applied to the above-mentioned compound (Ie).

Method of obtaining 5 (see the end of the description).

In the method of obtaining 5 compound (Ih) this is possible can be performed in the same way, as in the case of the second stage of the method of obtaining 1.

On the other hand, the compound (Ih) of the present invention can be synthesized from compound (Ib) of this invention by conventional amidation reaction, as in the first stage of the method of obtaining 1.

Method of obtaining 6 (see the end of the description).

In the formula method 6: R10ais the group R10other than a hydrogen atom. The same notation will be used hereafter.

In the method of obtaining 6 the compound (Ii) of this invention are obtained by reaction of compound (Ib) of this invention or its reactive derivative with aminoguanidinium (XIV).

The reaction can be performed in the same manner as in the case of the first stage of the method of obtaining 1.

Method of obtaining 7 (see the end of the description).

In the method of obtaining 7 compound (Ij) of this invention are obtained by reaction of compound (Ib) of this invention or its reactive derivative with sulfonamidnuyu derivative represented by the formula (XV), or similar connection.

The reaction is performed using the compound (Ib) or its reactive derivative of the compound (XV) in equimolar ratio or in a small ISBs reflux, in the presence of an organic base such as 4-(dimethylamino)pyridine or similar reasons, or in the presence of inorganic bases, e.g. sodium hydroxide, potassium hydride or the like grounds and, in certain cases, with the addition of an appropriate dehydrating agent (for example, disclocated or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or its hydrochloride or hydrobromide).

As inert in the reaction of an organic solvent can be used, for example, pyridine, THF, dioxane, diethyl ether, benzene, toluene, xylene, dichloromethane, dichloroethane, chloroform, DMF, ethyl acetate, acetonitrile or a similar solvent.

Method of obtaining 8 (see end of description).

In the method of obtaining 8 connection (Im), having a thiocarbonyl group, produced from compound (Il) having a carbonyl group. This reaction is performed by allowing to react the compound (Il) with a phosphorus compound (for example, dephosphorylation or [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide] , in quantities corresponding to this reaction, at a temperature from room temperature up to the boiling point under reflux in an inert solvent, NAPAT inorganic base, for example, sodium bicarbonate or similar base to the reaction proceeded smoothly.

Method of obtaining 9 (see at the end of the description).

In the formulas of the method 9 R5a- lower alkyl group.

In the method of obtaining 9 connection (Io) receive, by subjecting compound (In) reactions of N-alkylation.

The reaction is carried out by stirring lidocaine (In) and alkylating agent (for example, halogenoalkane) in amounts corresponding to this reaction, in an inert solvent, for example DMF, dimethyl sulfoxide, benzene or other similar solvent at room temperature or by heating, in the presence of an organic base such as 4-(dimethylamino)pyridine or the like bases, or inorganic bases, e.g. sodium hydroxide, potassium hydride or similar grounds.

Method of obtaining 10

In addition to the above-described methods of producing compounds of the present invention, it is possible to use a modification of the methods well known in the art. For example, other interest compounds of this invention can be obtained by using a modified method of obtaining 1, wherein the source compound (IV) allow to implement the second stage of the method of obtaining 1, and then subjecting the obtained derivative compounds IV of the amidation reaction with a derivative of the compound (III) and, if necessary, then remove the protective group by hydrolysis, recovery, or in a manner similar to the above.

The removal of the protective group

When R3acompounds (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) and (Ij) of this invention obtained by each of the above methods, is a protected hydroxyl group or a protected amino group, the protective group is removed as soon as it is no longer needed.

Deleting a group protecting the hydroxyl group may be accomplished 1) by hydrolysis in the presence of acid or base, 2) recovery of liquid ammonia, 3) catalytic recovery using palladium-on-coal or palladium hydroxide-on-coal or 4) disilylgermane using organofluorine compounds, for example, Tetra-n-butylammonium or similar connection, or by using a fluorine-containing inorganic compounds such as sodium fluoride, potassium fluoride, hydrofluoric acid.

Hydrolysis of 1) may be a conventional method in which the hydrolysis is performed in the presence of a base, nepriyatnoi acid, hydrochloric acid or similar acids. Preferably, the reaction is carried out at a temperature from temperature under ice cooling to 100oC.

Recovery method 2) can be performed by adding a compound having a group protecting the hydroxyl group, to liquid ammonia, with the addition of metallic sodium and stirring, then the mixture.

Recovery method 3) can be performed at a temperature under ice cooling to the temperature when heated in the presence of a catalyst, e.g. palladium-on-coal or palladium hydroxide-on-charcoal grill.

Method desirelove 4) can be accomplished by reaction of the compounds having a group protecting the hydroxyl group with an organofluorine compound, such as Tetra-n-butylammonium or similar compound or inorganic compound fluoride such as sodium fluoride, potassium fluoride, hydrofluoric acid or similar compound, in an inert reaction solvent, for example tetrahydrofuran, dichloromethane, DMF, benzene or similar solvents.

Deleting a group protecting the amino group may be accomplished 1) by restoring using zinc or ASS="ptx2">

Recovery method 1) can be performed by adding a compound having a group protecting the amino group, to the buffer (if necessary, is added to an inert solvent), then adding zinc in an amount corresponding to this reaction or in excess, followed by stirring the mixture at a temperature of from cooling with ice and the temperature when heated.

Recovery method 2) can be performed by adding a compound having a group protecting the amino group, to liquid ammonia, adding metallic sodium and the subsequent stirring of the mixture.

Recovery method 3) can be performed while cooling with ice, and when heated in the presence of a catalyst, e.g. palladium-on-coal or palladium hydroxide-on-charcoal grill.

The reaction time is chosen arbitrarily, depending on the reaction conditions for starting compounds, reagents and so on, but it usually ranges from several tens minutes to several tens hours, preferably from several tens minutes to several hours.

Starting materials for preparing compounds of this invention can be easily obtained with the use of a Method of obtaining compound (IV) (see at the end of the description).

Symbols used in the formulas of the method for obtaining compounds IV are installed above values.

Alcohol compound (d) receive, subjecting the esterification of the compound (a) in the usual way to protect the phenolic hydroxyl group methoxymethyl group, and then restoring the ether. The usual way it turned into the ether methanesulfonate acid, which is then injected into the reaction bentolila, and get through this connection (f). After the oxidation of the sulfide group, when necessary, methoxymethyl group is removed in the usual way, after which the nitrogroup is restored to the amino group, and the result is the compound (IV) (R5= H in this case).

A method of obtaining compound III (see the end of the description).

In formulas the method of obtaining the compound III: B, R1and R2denote the same as before, Rb- lower alkyl group.

The compound (j) allow to react with compound (i) and then with diethyl ether dithiophosphoric acid (m) that gives compound (n), which then reacts with bromoethanol (p), and by this means obtain the compound (IIIb). This compound is then in the normal way functions esterification or diatrypaceae. Connection in which A has the formula: -CH=CH-, can be obtained using a method not described in the examined published patent application Japan (Kokai) N 63-258854. By restoring this connection, you can get a connection in which A is an ethylene group.

The compound of the present invention, thus obtained, is isolated and purified as a free compound, its salt, hydrate, different solvate, for example, in the form of MES with ethanol, etc. or in the form of a polymorphic material. Pharmaceutically acceptable salt of the compound (I) can also be obtained by subjecting compound conventional salt formation reaction.

Isolation and purification performed using conventional methods of chemical treatment, such as extraction, fractional crystallization, various types of fractional chromatography and the like methods.

Various isomers can be separated using differences in physico-chemical properties of the isomers.

In addition, the optical isomers can be obtained in pure stereochemical form by selecting the appropriate starting compounds or by racemic splitting of racemic mixtures of compounds (e.g., using a method prestem it is subjected to optical splitting).

Below are examples of compounds that can be synthesized using the above methods of obtaining, production techniques, which will be described later in the examples, and various modifications of these methods, known to experts in this field that do not require special experiments.

A1) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[2-[2-(4-methyl-2 - thiazolyl)vinyl]benzoylamine]venexiana acid.

A2) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[2-[2-(5-ethyl-2 - thiazolyl)vinyl]benzoylamine]venexiana acid.

A3) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[2-[(5-phenyl-2 - thiazolyl)methoxy]benzoylamine]venexiana acid.

A4) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[2-[(4-phenyl-2 - thiazolyl)thiomethyl]benzoylamine]venexiana acid.

A5) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[2-[(5-phenyl-2 - thiazolyl)methylthio]benzoylamine]venexiana acid.

A6) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[2-(5-methyl-2 - thiazolyl)vinyl]benzoylamine]venexiana acid.

A7) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[2-(4-propyl-2 - thiazolyl)vinyl]benzoylamine]venexiana acid.

A8) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[2-(5-phenyl-2 - thiazolyl)vinyl]benzoylphenyl)propyl]venexiana acid.

A10) 4-[3-(4-chlorophenylsulfonyl)propyl]-2-[3-[2-(5-cyclohexyl-2 - thiazolyl)vinyl]benzoylamine]venexiana acid.

A11) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[(4-cyclopentyl-2 - thiazolyl)oxymethyl]benzoylamine]venexiana acid.

A12) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[(5-methyl-2 - thiazolyl)oxymethyl]benzoylamine]venexiana acid.

A13) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[2-(4-phenyl-2 - thiazolyl)oxymethyl]benzoylamine]venexiana acid.

A14) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[(5-phenyl-2 - thiazolyl)methoxy]benzoylamine]venexiana acid.

A15) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[(5-ethyl-2 - thiazolyl)methoxy]benzoylamine)venexiana acid.

A16) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[(5-methyl-2 - thiazolyl)methoxy]benzoylamine]venexiana acid.

A17) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[(4-propyl-2 - thiazolyl)methoxy]benzoylamine]venexiana acid.

A18) 4-[3-(4-chlorophenylsulfonyl)propyl]-2-[3-[[4-(4-were)-2 - thiazolyl]methoxy]benzoylamine]venexiana acid.

A19) 2-[3-[(5-tert-butyl-2-thiazolyl)methoxy]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

is.

A21) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[(5-phenyl-2 - thiazolyl)thiomethyl]benzoylamine]venexiana acid.

A22) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[(5-isopropyl-2 - thiazolyl)methylthio]benzoylamine]venexiana acid.

A23) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[(5-phenyl-2 - thiazolyl)methylthio]benzoylamine]venexiana acid.

A24) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[4-[2-(4-phenyl-2 - thiazolyl)vinyl]benzoylamine]venexiana acid.

A25) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[4-[2-(5-phenyl-2 - thiazolyl)vinyl]benzoylamine]venexiana acid.

A26) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[4-[2-(4-isopropyl-2 - thiazolyl)vinyl]benzoylamine]venexiana acid.

A27) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[4-[2-(5-methyl-2 - thiazolyl)vinyl]benzoylamine]venexiana acid.

A28) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[4-[(5-phenyl-2 - thiazolyl)oxymethyl]benzoylamine]venexiana acid.

A29) 2-[4-[(4-tert-butyl-2-thiazolyl)oxymethyl] benzoylamine]- 4-[3-(4-chlorophenylsulfonyl)propyl]venexiana acid.

A30) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[4-[(4-phenyl-2 - thiazolyl)methoxy]benzoylamine]venexiana acid.

A31) 4-[3-(4-glorp-(4-chlorophenylsulfonyl)propyl] -2-[4-[(4-isopropyl-2 - thiazolyl)methoxy]benzoylamine]venexiana acid.

A33) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[4-[(5-methyl-2 - thiazolyl)methoxy]benzoylamine]venexiana acid.

A34) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[4-[(5-isopropyl-2 - thiazolyl)thiomethyl]benzoylamine]venexiana acid.

A35) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[4-[(5-phenyl-2 - thiazolyl)methylthio]benzoylamine]venexiana acid.

A36) 4-[3-(4-chlorophenylsulfonyl)propyl]-2-[3-[2-(2- thiazolyl)vinyl]benzoylamine]venexiana acid.

A37) 4-[3-(4-chlorophenylsulfonyl)propyl]-2-[3-[(2- thiazolyl)methoxy]benzoylamine]venexiana acid.

A38) 3-[(4-cyclobutyl-2-thiazolyl)methylthio] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A39) 2-[3-[2-(4-cyclobutyl-2-thiazolyl)ethyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A40) 2-[3-[(4-cyclobutyl-2-thiazolyl)methylthio] benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A41) 2-[3-[2-(4-tert-butyl-2-thiazolyl)ethyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]PHENOXYACETIC.

A42) 2-[3-[(4-tert-butyl-2-thiazolyl)methylthio] benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]PHENOXYACETIC.

A43) 2-[3-[(4-cyclobutyl-2-thiazolyl)methods is)ethyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]PHENOXYACETIC.

A45) 2-[3-[(4-cyclobutyl-2-thiazolyl)methylthio] benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]PHENOXYACETIC.

A46) 2-[2-[2-(5-chloro-2-benzothiazolyl)vinyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A47) 2-[2-[2-(2-benzothiazolyl)vinyl] benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A48) 2-[2-[(5-chloro-2-benzothiazolyl)methoxy]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A49) 2-[2-[(2-benzothiazolyl)thiomethyl] benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A50) 2-[2-[(5-bromo-2-benzothiazolyl)methylthio]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A51) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[2-(5-fluoro-2 - benzothiazolyl)vinyl]benzoylamine]venexiana acid.

A52) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[2-(7-fluoro-2 - benzothiazolyl)vinyl]benzoylamine]venexiana acid.

A53) 2-[3-[2-(4-chloro-2-benzothiazolyl)vinyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A54) 2-[3-[2-(6-chloro-2-benzothiazolyl)vinyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A55) 4-[3-(4-CHL is ASS="ptx2">

A56) 2-[3-[(2-benzothiazolyl)oxymethyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A57) 2-[3-[(5-chloro-2-benzothiazolyl)oxymethyl] benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A58) 2-[3-[(6-chloro-2-benzothiazolyl)oxymethyl] benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A59) 2-[3-[(4-chloro-2-benzothiazolyl)methoxy] benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A60) 2-[3-[(6-chloro-2-benzothiazolyl)methoxy] benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A61) 2-[3-[(5-bromo-2-benzothiazolyl)thiomethyl] benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A62) 2-[3-[(5-chloro-2-benzothiazolyl)methylthio] benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A63) 2-[3-[(2-benzothiazolyl)methylthio] benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A64) 2-[3-[(2-benzoxazolyl)oxymethyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A65) 2-[3-[(2-benzoxazolyl)thiomethyl] benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A67) 2-[3-[(5-chloro-2-benzoxazolyl)oxymethyl] benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A68) 2-[3-[2-(5-chloro-2-benzoxazolyl)vinyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A69) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[4-[2-(4-fluoro-2 - benzothiazolyl)vinyl]benzoylamine]venexiana acid.

A70) 2-[4-[2-(5-bromo-2-benzothiazolyl)vinyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A71) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[4-[2-(7-fluoro-2 - benzothiazolyl)vinyl]benzoylamine]venexiana acid.

A72) 4-[3-(4-chlorophenylsulfonyl)propyl]-2-[4-[2-(5-trifluoromethyl-2 - benzothiazolyl)vinyl]benzoylamine]venexiana acid.

A73) 2-[4-[(5-chloro-2-benzothiazolyl)oxymethyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A74) 2-[4-[(6-chloro-2-benzothiazolyl)oxymethyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A75) 2-[4-[(4-chloro-2-benzothiazolyl)methoxy]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A76) 4-[3-(4-chlorophenylsulfonyl)propyl]-2-[4-[(6-trifluoromethyl-2 - benzothiazolyl)methoxy]benzoylamine]phenoxyl]venexiana acid.

A78) 2-[4-[(5-chloro-2-benzothiazolyl)methylthio]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A79) 2-[4-[(2-benzoxazolyl)oxymethyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A80) 2-[4-[(2-benzoxazolyl)thiomethyl] benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A81) 2-[4-[2-(2-benzoxazolyl)vinyl] benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A82) 2-[4-[(5-chloro-2-benzoxazolyl)oxymethyl] benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A83) 2-[4-[2-(5-bromo-2-benzoxazolyl)vinyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A84) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[2-[2-(4-fluoro-2 - benzothiazolyl)vinyl]benzoylamine]venexiana acid.

A85) 4-[3-(4-chlorophenylsulfonyl)propyl]-2-[2-[(5-methoxy-2 - benzoxazolyl)oxymethyl]benzoylamine]venexiana acid.

A86) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[2-[(6-the nitro-2 - benzothiazolyl)methylthio]benzoylamine]venexiana acid.

A87) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[2-[(7-methyl-2 - benzoxazolyl)thiomethyl]benzoylamine]venexiana acid.

A89) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[(5-cyano-2 - benzoxazolyl)oxymethyl]benzoylamine]venexiana acid.

A90) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[(6-hydroxy-2 - benzothiazolyl)methylthio]benzoylamine]venexiana acid.

A91) 2-[3-[(7-chloro-2-benzoxazolyl)thiomethyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A92) 2-[3-(5-bromo-2-benzothiazolylazo)benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

A93) 4-[3-(4-chlorophenylsulfonyl)propyl]-2-[4-[(6-trifluoromethyl-2 - benzothiazolyl)methylthio]benzoylamine]venexiana acid.

A94) 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[4-[(7-hydroxy-2 - benzoxazolyl)thiomethyl]benzoylamine]venexiana acid.

A95) 5'-[3-(4-brompheniramine)propyl] -3-[(4-tert-butyl-2 - thiazolyl)methoxy]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A96) 3-[(4-tert-butyl-2-thiazolyl)methoxy] -5'-[3-(4- perpenicular)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A97) 3-[(4-tert-butyl-2-thiazolyl)methoxy] -5'-[3-(4- iodinesulphur)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A98 motorway) 3-[(4-tert-butyl-2-thiazolyl)methoxy] -5'-[3-(4- methylphenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylmethoxycarbonyl)propyl]benzanilide.

A100) 5'-[3-(4-chlorophenylsulfonyl)propyl] -3-[(2-propyl)-2 - thiazoleacetate]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A101) 5'-[3-(4-chlorophenylsulfonyl)propyl]-3-[4-(2-methylpropyl)-2 - thiazoleacetate]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A102) 3-[4-cyclopropyl-2-thiazoleacetate] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A103) 3-[4-cyclopentyl-2-thiazoleacetate] -5'-[3-(4- chlorophenylsulfonyl)propyl-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A104) 5'-[3-(4-chlorophenylsulfonyl)propyl]-3-[4-(2-propyl)-2 - triazolylmethyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A105) 5'-[3-(4-chlorophenylsulfonyl)propyl]-3-[4-(2-methylpropyl)-2 - triazolylmethyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A106) 3-[4-cyclopropyl-2-triazolylmethyl] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A107) 3-[4-cyclopentyl-2-triazolylmethyl] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A108) 3-[4-cyclobutyl-2-triazolylmethyl] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A109) 5'-[3-(4-chlorophenylsulfonyl)propyl] -3-[2-[4-(2-propyl)-2 - thiazolyl]ethyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A110) 5'-[3-(4

A111) 3-[2-[4-cyclopropyl-2-thiazolyl] ethyl] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A112) 3-[2-[4-cyclopentyl-2-thiazolyl] ethyl] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A113) 5'-[3-(4-chlorophenylsulfonyl)propyl] -3-[2-[4-(2-propyl)-2 - thiazolyl]vinyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A114) 5'-[3-(4-chlorophenylsulfonyl)propyl] -3-[2-[4-(2- methylpropyl)-2-thiazolyl]vinyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A115) 3-[2-[4-cyclopropyl-2-thiazolyl] vinyl]-5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A116) 3-[2-[4-cyclopentyl-2-thiazolyl] vinyl]-5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A117) 3-[2-[4-cyclobutyl-2-thiazolyl] vinyl] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A118) 3-[2-[4-tert-butyl-2-thiazolyl] vinyl] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A119) 5'-[3-(4-chlorophenylsulfonyl)propyl]-3-[4-(2-propyl)-2 - thiazoleacetic]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A120) 5'-[3-(4-chlorophenylsulfonyl)propyl]-3-[4-(2-methylpropyl)-2 - thiazoleacetic]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A121) 3-[4-is="ptx2">

A122) 3-[4-cyclopentyl-2-thiazoleacetic] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A123) 3-[4-cyclobutyl-2-thiazoleacetic] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A124) 3-[4-tert-butyl-2-thiazoleacetic] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A125) 5'-[3-(4-chlorophenylsulfonyl)propyl]-3-[4-(2-propyl)-2 - triazolylmethyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A126) 5'-[3-(4-chlorophenylsulfonyl)propyl]-3-[4-(2-methylpropyl)-2 - triazolylmethyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A127) 3-[4-cyclopropyl-2-triazolylmethyl] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A128) 3-[4-cyclopentyl-2-triazolylmethyl] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A129) 3-[4-cyclobutyl-2-triazolylmethyl] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

A130) 3-[4-tert-butyl-2-triazolylmethyl] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy)benzanilide.

Industrial application

The compounds of this invention are substances that serve as the antagonists in Thanany of this invention are useful as tools for the prevention and treatment of diseases, associated with TXA2and related diseases LTsfor example, as pharmaceuticals for the prevention and treatment of allergic diseases (e.g. bronchial asthma, allergic rhinitis, urticaria, etc.,), ischemic heart disease and cerebral thrombosis, angina pectoris, inflammatory and petchesky ulcers and hepatitis. They are particularly suitable for the prevention and treatment of allergic diseases (e.g. bronchial asthma, allergic rhinitis, urticaria, etc.,), ischemic heart disease and brain and thrombosis, which are relevant both mediator.

The suitability of the compounds of the present invention is confirmed by the following examples of tests on their activity as antagonists TXA2and LTsand their actions when administered orally.

Examples test

(1) test Method of suppressing platelet aggregation induced by U-46619:

Using a plastic syringe containing 1 volume of 3.8% aqueous sodium citrate, select 9 volumes of blood from the abdominal aorta of male Guinea-pig line Hartley weight of about 800, platelet-rich plasma (CCP) is obtained by centrifugation of blood for 10 min the United platelets (SWEAT). OTP diluted fraction SWEAT to obtain controlled platelet count 500000/µl, and platelet aggregation under the influence of a stable analogue of TXA2, U-46619 (chemical name: 9,11-dideoxy-9 , 11 - mechanoactivation F2measure method Beaune and Cross (Journal of discrimination, vol. 168, pp. 178-195, 1963). Namely, using hemacytometer NBS (Hematracer) measure the change in light transmission of drug OTP caused by U-46619 (10-6or 510-7M). 2 minutes before the addition of U-46619 add the connection and the value of the IC50(concentration inhibiting 50%) calculated from the degree of inhibition based on the maximum light transmittance U-46619. The results are shown in table 1.

(2) the test Method for inhibition of ileal contractions induced LTD4, in Guinea-pig.

Male Guinea-pig line Hartley weighing 500-700 g score a stun. The terminal ileum is placed in a flask Magnus containing 10 ml of the solution Tirade, aerated with a gas mixture of 95% O2+ 5% CO2at a voltage of 1.0 g Tissue balance within 60 minutes during this period, the solution Tyrode replace at intervals of 15 min, and the voltage is set each time 1.0 was Developed cloth napryazhyeniya ileum under the action LTD4(10-8M) measured in the absence of a connection and then in the presence of test compounds at various concentrations. The time of incubation with the compound is 20 minutes. The results are shown in table 1.

(3) test Method of inhibiting the increase of airway resistance in Guinea pigs caused by U-46619, by oral administration of the compounds.

Male Guinea-pig line Hartley (500-800 g) anaesthetize with urethane (1.2 g/kg, I. p.) and fixed on the back for the introduction of the tracheal cannula. Spontaneous breathing stopped by gallamine (1 mg/kg, centuries), and artificial respiration is carried out with a frequency of 60 times/min, volume of 1 ml/100 g body weight/cycle. After the introduction in eremochloa Vienna U-46619 (3 mg/kg) measured an increase of airway resistance using the device for measuring respiratory function (Model 6, Buxco Electronics Inc.). In this case the test compound is administered orally 1 hour prior to the introduction of U-46619 in the form of a solution in dimethyl sulfoxide or in suspension in methylcellulose.

The result is calculated as the degree of suppression of airway resistance with the introduction of 10 mg/kg of the compound. Results for typical compounds are shown in table 2.

(4) the Method is unity.

The male Guinea-pig line Hartley, who on the eve of the trials were removed dorsal hair, intravenous 1% aqueous solution of Evans blue (1 ml/animal). Two minutes after that animals injected intradermally into the dorsal area LTD4(5 ng/site), and after 30 minutes the animals slaughtered by decapitation. The skin, which was introduced LTD4collect, and penetrated into the skin pigment extracted. The number of infiltrated pigment calculated by measuring its absorption at 620 nm, and is used as an indicator of vascular permeability. The test compound is administered orally in the form of a solution in dimethyl sulfoxide for 1 hour before intradermal introduction of LTD4. The results are calculated as the degree of suppression with the introduction of 10 mg/kg of the compound. Results for typical compounds are shown in table 2.

(5) test Method for suppressing the increase of the airway resistance induced by antigen in actively sensitized Guinea pigs.

As antigen male Guinea-pig line Hartley injected intraperitoneally three times at two-week intervals ovalbumin (OA) with Al(OH)3to obtain active sensitization. Under anesthesia writingin (OA) 1-2 weeks after the last sensitization, and through different periods of time after that, measure the resistance of the respiratory tract. In this case, 10 minutes before injection of the antigen, by intravenous injection administered Gallatin (1 mg/kg) and indomethacin (2 mg/kg) for 3 minutes, and mepyramine (2 mg/kg) and propranolol (0.3 mg/kg) for 2 minutes prior to the introduction of antigen. The test compound administered orally 1 hour before injection of antigen. By calculating the change in the degree of resistance of the respiratory tract after administration of the antigen, the effect of the test compounds test, using its effect by inhibition of increased airway resistance as an indicator. In this test, the compound of the present invention detects a superb action as an inhibitor of increasing airway resistance.

Compare compound: 4-[3-(4-chlorophenylsulfonyl)propyl]- 2-[3-(2-chinaillon)benzoylamine] venexiana acid (compound of example 2 not in the examined published patent application (Kokai) N 4-154766).

DMSO: enter in the form of a solution in dimethyl sulfoxide.

MC: introducing a suspension in methylcellulose.

Pharmaceutical composition, which contains as active Ingram is introduced orally or parenterally in the form of such dosage forms, as tablets, powders, fine granules, capsules, pills, solutions, injections, suppositories, ointments, adhesive preparations, etc., using carriers, excipients and other additives usually used in the production of pharmaceutical preparations.

Clinical dose of the compounds of the present invention for a person selected by the request, taking into account symptoms, body weight, age, sex, and similar individual characteristics of each patient, which are treated, but they usually range from 0.1 to 500 mg for oral administration and from 0.01 to 100 mg for parenteral administration per day for an adult and the daily dose is given once a day or divided into several doses per day. Since the dose varies depending on various conditions, in some cases, a sufficient effect can be obtained at doses smaller than those indicated above.

Tablets, powders, granules, etc. are used as the solid composition of the present invention for oral administration. In such a solid composition, one or more active substances are mixed with at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, poly is the composition may contain additives, such as lubricants (for example, the glycolate, calorically or similar substance), stabilizers (for example, lactose, or similar substance) and solubilizers or contribute to solubilize the substance (for example, glutamic acid, aspartic acid or a similar substance). If necessary, tablets or pills may be coated with films of substances soluble in the stomach and small intestine, for example, sucrose, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose etc.

A liquid composition for use in oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. that usually contain

used inert diluents, for example, purified water or ethyl alcohol. Besides inert diluents, these compositions may also contain auxiliary substances, such as solubilization or promote solubilization agents, moisturizing agents, suspendresume agents, etc., podslushivala, coregency, aromatics and antiseptics.

Injections for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions and emulsion is Zoologicheskii solution. Examples of the solvent for non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols, e.g. ethanol, and Polysorbate 80 (trade name). Such compositions may also contain additives, such as toning agents, antiseptics, moistening agents, emulsifiers, dispersing agents, stabilizing agents (e.g., lactose) and solubilizing or contribute to solubilize substances. These compositions are sterilized by filtration through filters, inhibiting bacteria, mixing with antimicrobial agents or irradiation. They can be made in advance in the form of an aseptic solid compositions and then, before use, dissolved in sterile water or aseptic solvent for injection.

If the connection of the present invention has a low solubility, it is possible to apply processing to increase solubility. Such processing can be accomplished using known methods that can be used for pharmaceutical preparations, for example, by a method in which added surfactants (for example, polyoxyethylenated hydrogenated is sucrose esters of fatty acids, etc. ), as well as a method by which such substances are prepared in the form of a solid dispersion with solubilizers substance, such as a polymer (for example, water-soluble polymers, such as hypromellose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) or similar polymers, or enteric polymers, for example, karboksimetiltselljuloza (CMAC), the phthalate of hydroxypropylmethylcellulose (HPMCP), a copolymer of methyl methacrylate with methacrylic acid (Eudraqit L, S, trade name; manufacture of Rohm & Haas Co.,), etc.). If you want, you can also use a method in which the substance is prepared in the form of soluble salts, and a method in which the injected substance is formed using a cyclodextrin or a similar substance. Methods of solubilization can vary depending on the substance used ["Saikin no seizaigijyutu sonooyo I", I. Utsumi et al., Iyaku Juornal, 157-159 (1983) and "Iyaku Monoqraph N 1, Seibutuqakuteki riyono", K. Naqai et al. Soft Science, 78-82 (1981)].

It is preferable to use a method in which the increase in solubility is achieved by formation of solid dispersions with solubilization agent (not passed examination published patent application Japan (Kokai) N 56-49314, FR 2460667).

Experience toxicity.

Soy is 200 mg/100 ml/kg once a day for two weeks. The amount of feeding and the results clinicopathological experience has not changed with the introduction of the connection.

An example of pharmastaff.

Sodium bicarbonate (280 mg) is added to the compound of example 39 (120 mg) and the resulting mixture (400 mg) is placed in a capsule, receiving the drug in the form of capsules.

The best way of carrying out the invention

Interest compounds of this invention and methods for their preparation will be described in detail in the following examples, which should not limit the present invention.

Reference example 1

(1) Phenolic hydroxyl group of 3-(4-hydroxy-3-nitrophenyl)propionic acid (J. Heterocycl. Chem., 9 (3), 681, (1972)) protect methoxymethyl group, and a carboxylic acid group atrificial the corresponding alcohol. The resulting ether is reduced to the alcohol, and then the hydroxyl group is subjected to methanesulfonamido, receiving, as a result, 3-(4-methoxyethoxy-3-nitrophenyl)propyl-methylsulfonate.

(2) 60% sodium hydride (4,47 g of 0.11 mol) is suspended in tetrahydrofuran (100 ml), dropwise with stirring, while cooling with ice, add 4-chlorothiophenol (15,85 g of 0.11 mol).

After additional paramelaconite-3-nitrophenyl)propylmalonate (35,00 g, of 0.11 mol) dissolved in tetrahydrofuran (100 ml). After that the reaction mixture is stirred for 1 hour under ice cooling and for 1 hour at room temperature, and then concentrated under reduced pressure. To the resulting residue, water is added, and the resulting product is extracted twice with chloroform. The organic layer was washed with 5% aqueous potassium carbonate solution and brine in sequence, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent chloroform:hexane = 1: 4-7: 3). Get 4-chlorophenyl= 3-(4-methoxyethoxy-3-nitrofen)propyl=sulfide 40,30 g, 100%) as an oily product.

Data mass spectroscopy (m/z): 367 (M+)

Spectrum of nuclear magnetic resonance (CDCl3, TMS (tetramethylsilane was) - internal standard)

: 1,95 for 2.01 (2H, m), and 2.79 (2H, ush-t, J = 7.9 Hz), to 2.94 (2H, ush-t, J = 7,3 Hz), 3,52 (3H, s), of 5.26 (2H, s), 7,26-7,44 (6H, m), 7,68 (1H, ush-d, J = 2.4 Hz)

(3) 4-Chlorophenyl-3-(4-methoxyethoxy-3-nitrophenyl)propyl= sulfide (40,00 g, 108,87 mmol) dissolved in dichloromethane (800 ml). To the resulting solution, maintained at 0oC or below, in small portions, add 80% 3-charnie 1 hour and then at room temperature for 1 hour, add ice and 5% aqueous potassium carbonate solution. The organic layer is separated, washed with 5% aqueous potassium carbonate solution and brine in sequence, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue is crystallized from a mixture of chloroform with hexane, and receive a 4-chlorophenyl=3-(4-methoxyethoxy-3-nitrophenyl)propylsulfonyl (42,60 g, 98%).

Data mass spectroscopy (m/z): 399 (M-)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 2,02-of 2.08 (2H, m), is 2.74 (2H, t, J = 7,3 Hz), is 3.08 (2H, ush-t, J = 7,3 Hz), 3,52 (3H, s), of 5.26 (2H, s), 7,24 (1H, ush-d, J = 8.5 Hz), 7,29 (1H, DD, J = 8,5, 1.8 Hz), 7,55 (2H, d, J = 7.8 Hz), 7,56 (1H, ush-C), at 7.55 (2H, d, J = 7,8 Hz).

(4) 4-Chlorophenyl-3-(4-methoxyethoxy-3-nitrophenyl)propylsulfonyl (42,40 g, 106,29 mmol) suspended in tetrahydrofuran (200 ml), added 6N hydrochloric acid, and the mixture is stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, and the resulting product is extracted twice with chloroform. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue is crystallized from a mixture of chloroform, with ether, and receive 4-[3-(4-HART nuclear magnetic resonance (CDCl3, TMS internal standard).

: 2,02-of 2.09 (2H, m), is 2.74 (2H, ush-t, J = 7,3 Hz) to 3.09 (2H, ush-t, J = 7,3 Hz), to 7.09 (1H, d, J = 8.5 Hz), 7,38 (1H, DD, J = 8,5, 2.4 Hz), 7,55 (2H, d, J = 8.5 Hz), 7,82-7,86 (3H, m), 10,44 (1H, s).

(5) 4-[3-(4-Chlorophenylsulfonyl)propyl]-2-nitrophenyl (10,00 g, 28,11 mmol) dissolved in 1,4-dioxane, added 4N hydrochloric acid in 1,4-dioxane (8,43 ml, 33,73 mmol) and 10% palladium-on-charcoal, and stirred for 4 hours in an atmosphere of hydrogen gas at a pressure of 1 atmosphere. Crystals precipitated from the reaction solution, is dissolved by adding methanol, the reaction mixture is filtered and then the filtrate concentrated under reduced pressure. By crystallization of the resulting residue from a mixture of acetonitrile-ether to obtain the hydrochloride of 2-amino-4-[3-(4-chlorophenylsulfonyl)propyl] phenol (9,71 g, 95%).

Data mass spectroscopy (m/z): 326 (M-HCl + 1)+< / BR>
Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,74-of 1.80 (2H, m), 2.57 m (2H, ush-t, J = 7,3 Hz) to 3.33 (2H, ush-t, J = 7,3 Hz), 6,99 (2H, s), 7,17 (1H, ush-C) of 7.75 (2H, d, J = 8.5 Hz), of 7.75 (2H, d, J = 8.5 Hz), was 9.33 (2H, ush), or 10.60 (1H, ush -)

Reference example 2

Thionyl chloride (2 ml) are added to 3-[2-(4-phenyl-2-thiazolyl) vinyl]benzoic acid (0.45 g, of 1.46 mmol), the mixture was stirred at the boiling treatment is obtained residue add toluene, the mixture is concentrated under reduced pressure, and after repeating this stage, dried in vacuum. The obtained residue is added to a mixture of the hydrochloride of 2-amino-4-[3-(4-chlorophenylsulfonyl)propyl]phenol (0.50 g, 1.38 mmol), pyridine (3 ml) and dichloromethane (2 ml) with stirring under ice cooling, and the reaction continued for 12 hours at room temperature. The reaction solution was poured into ice and 1N hydrochloric acid and the solid precipitate collected by filtration. After washing the solid residue with ethanol 5'-[3-(4-chlorophenylsulfonyl)propyl] -2'- hydroxy-3-[2-(4-phenyl-2-thiazolyl)vinyl] benzanilide (0,79 g, 1.28 mmol, 93%) as a solid.

Compounds of reference examples 3-17 synthesized in the same manner as described in reference example 2. Names and physical properties of these compounds are shown in tables 3-6.

Reference example 18

3-[2-(4-tert-Butyl-2-thiazolyl)ethyl]-5'-[3-(4- chlorophenylsulfonyl)propyl] -2'-hydroxybenzamide (0,60 g, 1.0 mmol) dissolved in DMF (6.0 ml) to the solution under cooling with ice add potassium carbonate (0.21 g, 1.5 mmol), a catalytically effective amount of tetrabutylammonium and bromoacetonitrile (0,080 ml, 1.2 mmol) in sequence, and then stirred for 12 Airout mixture of benzene with ethyl acetate (1: 1). The obtained organic layer was washed with 5% aqueous potassium carbonate solution and brine in order, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (eluent-chloroform) and crystallized from acetonitrile, receiving, as a result, 3-[2-(4-tert-butyl-2-thiazolyl)ethyl] -5'-3-(4 - chlorophenylsulfonyl)propyl-2'-cinemadocumentalist (0,60 g of 0.94 mmol, 94%) as colorless crystals.

Compounds of reference examples 19 to 21 are synthesized in the same manner as described in reference example 18. Names and physical properties of these compounds are shown in tables 7 and 8.

Reference example 22

N-(2-Hydroxyethyl)phthalimide (970 mg, 5.1 mmol) and triphenylphosphine (1.3 g, 5.1 mmol) are added in sequence to a solution of 4-[3-(4-chlorophenylsulfonyl)propyl]-2-NITROPHENOL (1.5 g, 4.2 mmol) in anhydrous tetrahydrofuran (30 ml) under ice cooling, and the mixture added dropwise diethylazodicarboxylate (800 μl, 5.1 mmol). The reaction solution is stirred overnight while cooling with ice and then concentrated. The resulting residue is purified column chromatography on silica gel (eluent = chloroform:ethyl acetate is l)propyl]-2-nitrophenoxy] ethyl]phthalimide (2.1 g, 4.1 mmol, 96%) as white crystals.

Data mass spectroscopy (m/z): 529 (M+)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,99-to 2.06 (2H, m), 2,71 (2H, ush-t, J = 7,6 Hz), 3.04 from (2H, ush-t, J = 7,6 Hz) to 4.15 (2H, t, J = 6,1 Hz), 4,37 (2H, t, J = 6,1 Hz), 7,02 (1H, d, J = 8.5 Hz), 7,29 (1H, d, J = 8.6 Hz), 7,54 (1H, s), 7,54 (2H, d, J = 8.5 Hz), 7,72 to 7.75 (2H, m), 7,81 (2H, d, J = 8.5 Hz), 7,86-of 7.90 (2H, m).

Reference example 23

4N solution of hydrogen chloride in dioxane (1.2 ml) and 10% Pd-C is added in sequence to the mixture 2-[4-[3-(4-chlorophenylsulfonyl)propyl] -2-nitrophenoxy] ethelfleda (2.1 g, 3.9 mmol), ethanol (20 ml) and dioxane (20 ml) and the resulting mixture was stirred at room temperature in hydrogen atmosphere. After 4 hours stirring the reaction solution is filtered through celite, and the obtained filtrate is concentrated and the resulting residue is crystallized from a mixture of chloroform with ethanol. Receive hydrochloride N-[2-[2-amino-4-[3-(4-chlorophenylsulfonyl)propyl] phenoxy]ethyl]phthalimide (1.4 g, 2.6 mmol, 66%) as white crystals.

Data mass spectroscopy (m/z): 499 (M+)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: 1,98-of 2.05 (2H, m), 2,61-by 2.73 (2H, m), 3,03 (2H, t, J = 7.8 Hz), 4,15-4,17 (2H, m), 4,23-4,24 (2H, m), 6,74-described in reference example 2, synthesize the following compound.

Reference example 24

N-[2-[2-[3-[(4-tert-Butyl-2-thiazolyl)methoxy] benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]phenoxy]ethyl]phthalimide

Data mass spectroscopy (m/z): 772 (M+)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: to 1.35 (9H, s), 1,98-2,03 (2H, m) to 2.65 (2H, t, J = 7,3 Hz), 3,03-of 3.07 (2H, m), 4,19-4,24 (4H, m), of 5.50 (2H, s), 6.73 x-6,79 (2H, m), 6,93 (1H, s), 7,49-rate of 7.54 (3H, m), 7,63-7,71 (7H, m), 7,80 (2H, d, J = 8,8 Hz), of 8.27 (1H, s), 8,58 (1H, s).

Reference example 25

(1) Under cooling at -30oC or below to methanol (150 ml) is added dropwise thionyl chloride (75 ml). To this solution at a temperature of -30oC add 3-(4-hydroxy-3-nitrophenyl)propionic acid (26,20 g to 0.12 mol). The reaction solution was stirred at room temperature for 1 hour and then at 40-50oC for 3 hours. The reaction solution is concentrated under reduced pressure. Then twice repeating a procedure of adding toluene (100 ml) to the residue and concentrating the mixture under reduced pressure. The resulting residue is crystallized from a mixture of ether and hexane and obtain methyl 3-(4-hydroxy-3-nitrophenyl)propionate (26,20 g, 94%).

(2) Methyl 3-(4-hydroxy-3-nitrophenyl)propionate (26,10 g. the ATEM at the same temperature to the reaction solution was added dropwise chloromethylation ether (9,68 ml of 0.13 mol). The reaction continued for 4 hours at room temperature. Then add water (200 ml) and the mixture is intensively stirred. Separate the organic layer, washed with 5% aqueous potassium carbonate solution and brine in order, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Get so oily substance (31,20 g). This compound is used without purification in subsequent reactions.

Maintaining the temperature within 50-60oC, to a solution of the mixture just obtained oily substance (30,00 g of 0.11 mol), sodium borohydride (8,83 g and 0.22 mol) and tetrahydrofuran (446 ml) is added dropwise within 1 hour, methanol (89,14 ml). The reaction solution was stirred at the same temperature for 30 minutes and then concentrated under reduced pressure. To the obtained residue, add a mixture of ice water and the product extracted three times with chloroform. The organic layer was washed with 5% aqueous potassium carbonate solution and brine in order, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure is taximeters-3-nitrophenyl)propanol (26,8 g, of 0.11 mol) dissolved in dichloromethane (270 ml) and to this solution with stirring under cooling with ice add triethylamine (18,58 ml of 0.13 mol). To this solution is added dropwise, while cooling with ice with stirring, added dropwise within 2 hours methanesulfonanilide (9,03 ml of 0.12 mol), dissolved in dichloromethane (27 ml). The reaction solution was stirred at room temperature for 30 minutes and add ice and 10% aqueous citric acid solution. After that, the organic layer is separated, washed with saturated aqueous sodium bicarbonate and brine in sequence, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Get 3-(4-methoxyethoxy-3-nitrophenyl)propylmalonate (35,10 g, 99%).

Reference example 26

To a mixture of 4-[2-(2-benzothiazolyl)vinyl] benzoic acid (247 mg, 0.88 mmol), dimethylformamide (one drop) and dichloromethane (10 ml) is added at -78oC oxalicacid (135 mg, 1.06 mmol). The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. Under ice cooling, the obtained compound is gradually added to the mixture of the hydrochloride of 2-amino-4-[3-(4-chlorophenylsulfonyl)propyl]genre within 12 hours. The reaction solution is concentrated under reduced pressure, to the residue water is added, and the mixture is heated to boiling under reflux and then cooled, the formed solid is collected by filtration and dried under reduced pressure. To the obtained solid substance added ethanol (10 ml) and the mixture heated to boiling under reflux and then cooled. The resulting crystals are collected by filtration and dried under reduced pressure. Receive 4-[2-(2-benzothiazolyl)vinyl] -5'- [3-(4-chlorophenylsulfonyl)propyl]-2'-hydroxybenzamide (335 mg, or 0.57 mmol, 65%) as colorless crystals.

The following compounds of reference examples 27 to 36 are synthesized in the same manner described in reference example 26. Names and physico-chemical properties of these compounds are shown in tables 9-11.

Reference example 37

A mixture of 4-tert-butyl-2-(hydroxymethyl)thiazole (441 mg, 2.57 mmol), of potassium tert-butylate (580 mg, 5.17 mmol), tricaprylmethyl ammonium chloride (100 mg) and methyl-6-chloropyridin-2-carboxylate (660 mg, of 3.85 mmol) was stirred at 120oC for 2 hours. To this reaction solution was added water and the product extracted with ethyl acetate. Extract premium pressure. The resulting residue is purified column chromatography on silica gel (eluent=hexane:ethyl acetate = 20:1 to 10:1). Get methyl-6-(4-tert-butyl-2-thiazoleacetate)pyridine-2-carboxylate (198 mg, of 0.65 mmol, 25%).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,36 (N, (C), of 3.96 (3H, s), of 5.75 (2H, s), 6.89 in (1H, s), 6,98-to 7.09 (1H, m), 7,71 for 7.78 (2H, m).

Reference example 38

Hydrochloride 4-[3-(4-chlorobenzenesulfonyl)propyl] -2-aminophenol (2.0 g, 5,52 mmol) suspended in dichloromethane (20 ml) and added dropwise pyridine (1,79 ml, 22,08 mmol) and acetic anhydride (1,00 ml, 13,80 mmol) in sequence with stirring and cooling with ice. The reaction solution was stirred at room temperature for 12 hours, and then add ice and 5% aqueous solution of sodium bisulfate. The organic layer is separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 5% aqueous solution of sodium bisulfate, 5% aqueous potassium carbonate solution and brine in sequence, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (20 ml) and methanol (20 ml), to the solution was added 1N aqueous process is nnow mixture is acidified, adding ice and 5% solution of sodium bisulfate, and the mixture is then extracted with chloroform. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After crystallization of the resulting residue from a mixture of chloroform with diethyl ether to obtain 5-[3-(4-chlorobenzenesulfonyl)propyl]-2-hydroxyacetanilide (1,69 g, 83%) as colorless crystals.

Spectrum of nuclear magnetic resonance (CDCl3,TMS internal standard)

: 1,67-and 2.14 (2H, m), and 2.14 (3H, s), 2,48-of 2.64 (2H, m), 3,07-3,30 (2H, m), 6,60-of 6.90 (2H, m), 7,40 (1H, ush-C), to 7.61 (2H, ush-d, J=8.5 Hz), 7,86 (2H, ush-d, J=8.5 Hz), 9,20-9,40 (1H, ush), of 9.30-9,60 (1H, ush).

Reference example 39

Dimethylformamide (10 ml) is added to a mixture of 5-[3-(4-chlorobenzenesulfonyl) propyl] -2-hydroxyacetanilide (1,00 g of 2.72 mmol) and N-chlorosuccinimide (0,44 g, 3,26 mmol), and the solution is allowed to react at 50oC for 1 hour and then at 80oC for 2 hours. To the reaction mixture add ice and water and the mixture extracted with ethyl acetate. The obtained organic layer was washed with water and brine in sequence, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the obtained residue is added 2-propanol (10 ml) is laidout and then concentrated under reduced pressure. After crystallization of the residue from acetonitrile receive hydrochloride 6-chloro-4-[3-(4-chlorobenzenesulfonyl)propyl] -2-aminophenol (0,47 g, 44%) as a white solid.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 1,60-1,90 (2H, m), 2.40 a is 2.80 (2H, m), 3,15-3,50 (2H, m), 6.90 to-7,30 (2H, m), 7,72 (2H, ush-d, J=8,8 Hz), to $ 7.91 (2H, ush-d, J =8,8 Hz)

Reference example 40

Dimethylformamide (25 ml) is added to a mixture of 5-[3-(4-chlorobenzenesulfonyl)propyl] -2-hydroxyacetanilide (1,65 g of 4.49 mmol) and N-chlorosuccinimide (1,32 g, 9,88 mmol), and the solution is allowed to react at 50oC for 1 hour and then at 80oC for 1 hour. To the reaction solution was added ice water and the mixture extracted with ethyl acetate. The obtained organic layer was washed with water and brine in sequence, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue is crystallized from chloroform, and receive a white solid (0.95 g). Then to this substance (0,90 g) is added 2-propanol (30 ml) and 3N hydrochloric acid (30 ml) and the resulting mixture is refluxed for 3 hours. The reaction solution is cooled and then concentrated under reduced pressure. After kichler-2-aminophenol (0.75 g, 38%) as a white solid.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 1,60-1,90 (2H, m), 2.40 a is 2.80 (2H, m), 3,15-3,50 (2H, m), 6.90 to-7,30 (2H, m), 7,72 (2H, ush-d, J =8,8 Hz), to $ 7.91 (2H, ush-d, J =8,8 Hz).

Reference example 41

A mixture of 2-bromocyclohexane (865 mg, 4.9 mmol), methyl 3-(thiocarbamoylation)benzoate (1,00 g, 4.4 mmol) and 1,4-dioxane (10 ml) is stirred for 5 hours at room temperature, then for 12 hours at 80oC, after which it is cooled and concentrated under reduced pressure. To the obtained residue is added saturated aqueous sodium bicarbonate solution and the product extracted with ethyl acetate. The extract is washed with water and brine in sequence, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (eluent= hexane: ethyl acetate = 4:1). Get 3-(4,5,6,7-tetrahydroindazole-2-ylethoxy)benzoate (369 mg, 1.2 mmol, 27%).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,84-1,89 (4H, m), 2,73 is 2.80 (4H, m), 3,91 (3H, s), USD 5.76 (2H, s), 7.18 in-7,20 (1H, m), of 7.36 (1H, t, J=8.0 Hz), 7,66-to 7.68 (2H, m)

Reference example is canola (2 ml) and 1N sodium hydroxide (2 ml) was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The resulting residue is dissolved in water, and the pH of the solution was adjusted to 3 by adding 10% aqueous citric acid solution. After that, the formed solid is collected by filtration, washed with water and then dried under reduced pressure. Get 3-(4,5,6,7-tetrahydroindazole-2-ylethoxy)benzoic acid (257 mg, 0.89 mmol, 75%).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard)

: 1,74-to 1.82 (4H, m), 2,67-2,78 (4H, m), of 5.39 (2H, s), 7,29 (1H, d, J= 8.0 Hz), 7,44 (1H, t, J =8.0 Hz), 7,53-7,58 (2H, m), 13,0 (1H, s).

In the same way described in reference example 42, are provided the following compounds of reference examples 43-50.

Reference example 43

6-(4-tert-Butyl-2-thiazoleacetate)pyridine-2-carboxylic acid.

Spectrum of nuclear magnetic resonance (CDCl3TMS internal standard)

: 1,35 (N, C) of 5.68 (2H, s), 6,93 (1H, s), 7,08-to 7.18 (1H, m), 7,82-7,88 (2H, m)

Reference example 44

3-[(4-tert-Butyl-2-thiazolyl)methoxy]-5-chlorbenzene acid.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,37 (N, C), 5,42 (2H, s), to 6.95 (1H, s), 7,29 (1H, ush-t, J=2.0 Hz), of 7.64-7,74 (2H, m), 9,10-9,60 (1H, ush)

Reference example 45

5-[(4-tert-Butyl-2-thiazolyl)methoxy] the ANSA (DMSO-d6, TMS internal standard).

: 1,30 (N, (C), the 5.45 (2H, s), 7.23 percent (1H, DD, J=8,8 Hz, 3.4 Hz), 7,31 (1H, s), 7,45 - of 7.48 (2H, m), 13,43 (1H, s)

Reference example 46

3-[(4-tert-Butyl-2-thiazolyl)methoxy]-4-methoxybenzoic acid.

The data of mass spectrometry (m/z): 322 (M+)

Spectrum of nuclear magnetic resonance (DMSO-D6, TMS internal standard).

: 1,30 (N, C), 3,86 (3H, s) 5,41 (2H, s), to 7.09 (1H, d, J =8,3 Hz), 7,29 (1H, s), to 7.61 (1H, J=8,3 Hz), a 7.62 (1H, s), 12,64 (1H, s).

Reference example 47

3-[4-tert-Butyl-2-thiazolyl)methoxy]-4-chlorbenzene acid.

The data of mass spectrometry (m/z): 326 (M+H+)

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,30 (N, C) 5,59 (2H, s), 7,32 (1H, s), 7,55-to 7.61 (2H, m), 7,81 (1H, d, J=1.5 Hz), of 13.18 (1H, s).

Reference example 48

3-[(4-tert-Butyl-2-thiazolyl)methoxy]-4-methylbenzoic acid.

The data of mass spectrometry (m/z): 306 (M+)

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,30 (N, C) of 2.28 (3H, s), of 5.48 (2H, s), 7,29 (1H, s), 7,30 (1H, d, J =8,3 Hz) to 7.50 (1H, d, J =8,3 Hz), 7,60 (1H, s), 12,80 (1H, s).

Reference example 49

3-[(4-tert-Butyl-2-thiazolyl)methoxy]-4-nitrobenzoic acid.

Danni standard).

: 1,29 (N, C) 5,69 (2H, s), 7,33 (1H, s), to 7.68 (1H, DD, J=8,3, 1.5 Hz), to 7.99 (1H, ush-d, J=8,3 Hz), 8,00 (1H, s), 13,62 (1H, s).

Reference example 50

3-[(4-tert-Butyl-5-methyl-2-thiazolyl)methoxy]benzoic acid.

The data of mass spectrometry (m/z): 306 (M+N)+< / BR>
Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,35 (N, C), 2,47 (3H, s), of 5.34 (2H, s), 7,28 (1H, ush-d, J=8,3 Hz), the 7.43 (1H, t, J= 8,3 Hz), 7,56 (1H, ush-d, J=8,3 Hz), EUR 7.57 (1H, ush-C) 13,0 (1H, s).

In the same way described in reference example 41, are provided the following compounds of reference examples 51-58.

Reference example 51

Methyl-3-[(4-tert-butyl-2-thiazolyl)methoxy]-5-chlorobenzoate.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,36 (N, C), 3,91 (3H, s), lower than the 5.37 (2H, s), 6,93 (1H, s), 7.23 percent (1H, ush-t, J =2.0 Hz), 7,56-to 7.67 (2H, m).

Reference example 52

Methyl 5-[(4-tert-butyl-2-thiazolyl)methoxy]-2-chlorobenzoate.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,35 (N, C) to 3.92 (3H, s), to 5.35 (2H, s), 6,93 (1H, s), was 7.08 (1H, DD, J=8,8, 2,9 Hz), 7,35 (1H, d, J=8,8 Hz), 7,51 (1H, d, J =2,9 Hz).

Reference example 53

Methyl 3-[(4-tert-butyl-2-thiazolyl)methoxy]-4-methoxybenzoate.

Spectrum,44 (2H, C) 6,91 (1H, d, J =8,3 Hz), 7,71 (1H, d, J=2.0 Hz), 7,72 (1H, ush-d, J =8,3 Hz).

Reference example 54

Methyl 3-[(4-tert-butyl-2-thiazolyl)methoxy]-4-chlorobenzoate.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: of 1.36 (9H, s), 3,90 (3H, s), vs. 5.47 (2H, s) 6,94 (1H, s), 7,45 (1H, d, J =8,3 Hz), 7,63 (1H, DD, J=8,3, 2.0 Hz), to 7.77 (1H, d, J=2.0 Hz).

Reference example 55

Methyl-3-[(4-tert-butyl-2-thiazolyl)methoxy]-4-methylbenzoate.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: of 1.36 (9H, s) to 2.35 (3H, s) to 3.89 (3H, s), of 5.40 (2H, s) 6,91 (1H, s), 7,22 (1H, d, J=7,3 Hz), 7,60 to 7.62 (2H, m).

Reference example 56

Methyl-3-[(4-tert-butyl-2-thiazolyl)methoxy]-4-nitrobenzoate.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: to 1.35 (9H, s), of 3.95 (3H, s) 5,54 (2H, s), of 6.96 (1H, s), 7,74 (1H, DD, J=8,3, 1.5 Hz), 7,86 (1H, d, J=8,3 Hz), to 7.99 (1H, d, J=1.5 Hz).

Reference example 57

Methyl 3-[(4-tert-butyl-5-methyl-2-thiazolyl)methoxy] benzoate.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,38 (N, C) of 2.50 (3H, s), 3,91 (3H, s), at 5.27 (2H, s), 7.23 percent was 7.45 (2H, m), 7,63-7,72 (2H, m)

Reference example 58

The hydrobromide of methyl 3-[2-(4-tert-butyl-2-thiazolyl)this is="ptx2">

: 1,28 (N, C), 3,39 is 3.57 (2H, m), and 4.40 (2H, t, J =6.3 Hz), 7,18 (1H, s), 7.23 percent to 7.62 (4H, m).

Reference example 59

A mixture of hydrogen bromide methyl 3-[2-(4-tert-butyl-2-tietzel) ethoxy]benzoate (102 mg, 0.25 mmol), methanol (1 ml) and 6N hydrochloric acid (0.5 ml) was stirred at 60oC for 2 hours, added 6N hydrochloric acid (1 ml) and the mixture stirred at 110oC for 2 hours. The reaction solution is cooled and concentrated under reduced pressure. The obtained solid is collected by filtration and washed with acetonitrile and diethyl ether in this order. Receive hydrochloride 3-[2-(4-tert-butyl-2-thiazolyl)ethoxy]benzoic acid (0.20 mmol, 80%, 69 mg).

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,30 (N, C) of 3.53 (2H, t, J=5.8 Hz), and 4.40 (2H, t, J=5.8 Hz), 7,21 - of 7.25 (2H, m), 7,40-7,46 (2H, m), 7,55 (1H, d, J =8.0 Hz).

In the same way described in reference example 2, to obtain the following compounds of reference examples 60-73.

Reference example 60

5'-[3-(4-Chlorophenylsulfonyl)propyl] -2'-hydroxy-3- (6-methoxy-2-benzothiazolylazo)benzanilide.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,76-to 1.82 (2H, m), of 2.56 (2H, t,J=7.5 Hz), 7,68-7,74 (4H, m), 7,88-a 7.92 (3H, m), of 9.51 (1H, s), at 9.53 (1H, s).

Reference example 61

5'-[3-(4-Chlorophenylsulfonyl)propyl] -2'-hydroxy-3- (4,5,6,7-tetrahydro-2-benzothiazolylazo)benzanilide.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,73-1,83 (6N, m) of 2.56 (2H, t, J=7.5 Hz), 2.63 in-2,78 (4H, m), 3,31-of 3.42 (2H, m), 5,42 (2H, s), PC 6.82 (2H, s), 7.23 percent-to 7.32 (1H, m), 7,42-to 7.50 (2H, m), 7,54-7,63 (2H, m), 7,73 (2H, d, J=8.0 Hz), 7,89 (2H, d, J =8.0 Hz), 9,49 (1H, s), 9,54 (1H, s).

Reference example 62

3-[(4-tert-Butyl-2-thiazolyl)methoxy] -5'-chloro-5'- [3-(4-chlorophenylsulfonyl)propyl]-2'-hydroxybenzamide.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,30 (N, C), 1,73-of 1.85 (2H, m), of 2.56 (2H, ush-t, J=7,6 Hz), 3,30-to 3.36 (2H, m), of 5.53 (2H, s), 6,83 (2H, s), 7,32 (1H, ush-C), 7,33 (1H, s), 7,44 (1H, ush-C), a 7.62 (2H, ush-C), 7,73 (2H, ush-d, J =8,8 Hz), 7,89 (2H, ush-d, J = 8,8 Hz), 9,46 (1H, ush-C), 9,65 (1H, ush-C).

Reference example 63

5-[(4-tert-Butyl-2-thiazolyl)methoxy] -2-chloro-5'-[3- (4-chlorophenylsulfonyl)propyl]-2'-hydroxybenzamide.

The data of mass spectrometry (m/z): 633 (M+N)+< / BR>
Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,35 (N, C), 1,99-2,04 (2H, m) of 2.64 (2H, ush-t, J=7,3 Hz), 3,03-of 3.07 (2H, m), to 5.35 (2H, s), to 6.88 (1H, ush-d, J=8,3 Hz), 6.8 Hz), 8,32 (1H, ush-C), 8,49 (1H, s).

Reference example 64

3-[(4-tert-Butyl-2-thiazolyl)methoxy]-5'-[3-(4-chlorophenylsulfonyl)propyl] - 2'-hydroxy-4-methoxybenzanilide.

The data of mass spectrometry (m/z), 629 (M+)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

equivalent : 1.33 (9H, s), 1,95-2,04 (2H, m), 2,62 (2H, ush-t, J=7,3 Hz), 3,01-to 3.09 (2H, m), of 3.96 (3H, s), 5,46 (2H, s), 6,85 (1H, DD, J=8,3, 2.0 Hz), 6,88-6,98 (3H, m), 7,00 (1H, d, J=2.0 Hz), 7,52 (2H, ush-d, J=8,8 Hz), to 7.59 (1H, DD, J= 8,3, 2.0 Hz), the 7.65 (1H, d, J=2.0 Hz), 7,79 (2H, ush-d, J =8,3 Hz), compared to 8.26 (1H, s), is 8.75 (1H, ush-C).

Reference example 65

3-[(4-tert-Butyl-2-thiazolyl)methoxy] -4-chloro-5'-[3- (4-chlorophenylsulfonyl)propyl]-2'-hydroxybenzamide.

The data of mass spectrometry (m/z): 633 (M+H+)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: to 1.35 (9H, s), 1,98 is 2.01 (2H, m), 2.63 in (2N, ush-t, J=7,3 Hz), 3,01 was 3.05 (2H, m), vs. 5.47 (2H, s), 6.87 in (1H, ush-d, J=8,3 Hz), to 6.95 (1H, d, J=8,3 Hz), of 6.96 (1H, s), 7,10 (1H, d, J=2.0 Hz), 7,47 (1H, ush-d, J=8,3 Hz), 7,51 (1H, d, J=8,3 Hz), 7,52 (2H, ush-d, J =8,8 Hz), to 7.68 (1H, d, J=2.0 Hz), 7,79 (2H, ush-d, J=8,8 Hz), a 8.34 (1H, s), 8,35 (1H, s).

Reference example 66

3-[(4-tert-Butyl-2-thiazolyl)methoxy] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-hydroxy-4-methylbenzamide.

Data range spectrometry (m/z): 613 (M+

Reference example 68

3-[(4-tert-Butyl-5-methyl-2-thiazolyl)methoxy] -5'-[3- (4-chlorophenylsulfonyl)propyl]-2'-hydroxybenzamide.

The data of mass spectrometry (m/z): 613 (M+N)+< / BR>
Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,36 (N, C), 1,77-of 1.81 (2H, m), 2.49 USD (3H, s), of 2.56 (2H, ush-t, J=7,3 Hz), 3,32-to 3.35 (2H, m), lower than the 5.37 (2H, s), PC 6.82 (2H, ush-C), 7,27 (1H, DD, J=7,8, 2.0 Hz), 7,42 (1H, ush-C), 7,46 (1H, t, J=7.8 Hz), EUR 7.57 (1H, d, J=7.8 Hz), to 7.64 (1H, ush-C), 7,74 (2H, ush-d, J=8,8 Hz), 7,89 (2H, ush-d, J=8,8 Hz), of 9.51 (1H, s), at 9.53 (1H, s).

Reference example 69

6-(4-tert-Butyl-triazolylmethyl)-N-[5-[3-(4-chlorophenylsulfonyl) propyl] -2-hydroxyphenyl]pyridine-2-carboxamide.

Spectrum of nuclear magnetic resonance (DMSO-d6TM - internal standard).

: of 1.30 (9H, s), 2,01-of 2.08 (2H, m) to 2.67 (2H, t, J=7.2 Hz), 3.04 from-to 3.09 (2H, m), USD 5.76 (2H, s), 6,88-6,98 (3H, m),? 7.04 baby mortality (1H, s), 7,12 (1H, d, J=8.0 Hz), 7,52 (2H, d, J=8,4 Hz), 7,80-7,88 (3H, m), 7,94 (1H, d, J=7,2 Hz), 9,06 (1H, ush), to 9.91 (1H, s).

Reference example 70

3-[2-(4-tert-Butyl-2-thiazolyl)ethoxy] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-hydroxybenzo: of 1.28 (9H, C) 1,70 of-1.83 (2H, m), of 2.56 (2H, t, J =7,3 J Hz), 3,31-to 3.35 (2H, m), 3,44 (2H, t, J=5,9 Hz), to 4.41 (2H, t, J=5,9 Hz), PC 6.82 (2H, s), 7,12 (1H, s), 7,18 (1H, d, J=8.0 Hz), 7,42-7,46 (2H, m), 7,53-of 7.55 (2H, m), 7,73 (2H, d, J=8,8 Hz), of 7.90 (2H, d, J=8,8 Hz), of 9.51 (1H, s) 9,52 (1H, s).

Reference example 71

3-(4-tert-Butyl-2-thiazoleacetate)-2'-hydroxy-5'- (3-phenylsulfonyl)benzanilide.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: to 1.31 (9H, s), a 1.75 of-1.83 (2H, m), of 2.56 (2H, t, J =7.2 Hz), 3.27 to of 3.32 (2H, m), of 5.50 (2H, s), PC 6.82 (2H, s), 7,28-to 7.32 (2H, m), 7,42 (1H, s), 7,47 (1H, t, J=8,4 Hz), to 7.59 (1H, d, J=7,6 Hz), of 7.64-to 7.67 (3H, m), 7,45

1H, t, J=6.8 Hz), 7,89 (2H, d, J =8.0 Hz), 9,52 (2H, ush).

Reference example 72

3-[(4-tert-Butyl-2-thiazolyl)methoxy] -5'-[3-(4- chlorophenylsulfonyl)propyl]-3',4'-dichloro-2'-hydroxybenzene.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,31 (N, C), 1,76 is 1.86 (2H, m), 2,72-2,77 (2H, m), 3,39-3,44 (2H, m), of 5.50 (2H, s), 7,32-7,33 (2H, m), 7,38 (1H, s), 7,49 (1H, ush-t, J=7.8 Hz), 7,63 (1H, ush-d, J=7.8 Hz), 7,71-7,74 (3H, m), to $ 7.91 (2H, d J=8,8 Hz), becomes 9.97 (1H, ush-C), 10,08 (1H, ush-C).

Reference example 73

3-[(4-tert-Butyl-2-thiazolyl)methoxy] -3'-chloro-5'- [3-(4-chlorophenylsulfonyl)propyl]-2'-hydroxybenzamide.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,, =7,8 Hz), 7,70-7,74 (1H, m), 7,73 (2H, d, J=8,8 Hz), of 7.90 (2H, d, J=8,8 Hz), 9,58 (1H, ush-C), 9,96 (1H, ush-C).

Reference example 74

5'-[3-(4-Chlorobenzenesulfonyl)propyl] -2'-hydroxy-3-[(4 - tert-butyl-2-thiazolyl)methoxy an benzanilide (1.60 g, to 2.67 mmol) dissolved in dimethylformamide (16 ml), in the specified order while cooling with ice add potassium carbonate (0.55 g, 4.00 mmol), a catalytically effective amount of tetrabutylammonium and bromoacetonitrile (0,22 ml, 3,20 mmol) and then stirred over night at room temperature. To the reaction mixture is added ice water and the mixture is extracted twice with a mixture of benzene with ethyl acetate (1: 1). The obtained organic layer was washed with 5% aqueous potassium carbonate solution and brine in sequence, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. By crystallization of the resulting residue from acetonitrile get 3-(4 - tert-butyl-2-thiazolyl)methoxy-5'-3-(4-chlorophenylsulfonyl)propyl -2'-cinemadocumentalist in the form of colorless crystals (1,34 g, 79%).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,36 (N, C) 2,02 - of 2.08 (2H, m), of 2.72 (2H, ush-t, J=7,3 Hz), 3,07-3,11 (2H, m), to 4.87 (2H, s) 5,41 (2H, s), 6,88-6,94 (3H, m), 7,22 (2H, dt, J= 6,8, 2.4 Gbom, what is described in reference example 74, are provided the following compounds of reference examples 75 and 76.

Reference example 75

3-[(4-tert-Butyl-2-thiazolyl)methoxy]-2'-(cyanoethoxy) 5'-[3-(4-phenylsulfonyl)propyl]benzanilide.

The data of mass spectrometry (m/z): 604 (M+N)+< / BR>
Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,36 (N, C) 2,02 is 2.10 (2H, m), a 2.71 (2H, t, J=7,3 Hz), 3,07-of 3.12 (2H, m), of 4.67 (2H, s) 5,41 (2H, s), 6,88-6,94 (3H, m), 7,20-of 7.23 (1H, m), 7,41 was 7.45 (2H, m), 7,54-to 7.59 (3H, m), 7,62-to 7.67 (1H, m), of 7.90 (2H, d, J=8.0 Hz), of 8.27 (1H, s), 8,32 (1H, s).

Reference example 76

5'-[3-(4-Chlorophenylsulfonyl)propyl] -2'- (cyanoethoxy)-3-[(4-cyclobutyl-2-thiazolyl)methoxy] benzanilide.

The data of mass spectrometry (m/z): 636 (M+N)+< / BR>
Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,89-of 1.95 (1H, m), 2,00-2,09 (3H, m), 2.23 to-2,31 (2H, m), 2,34-to 2.41 (2H, m), 2,70-by 2.73 (2H, m), 2,88-3,10 (2H, m), 3,65-and 3.72 (1H, m), to 4.87 (2H, s) 5,41 (2H, s), 6.89 in (1H, DD, J=8,6, 1.8 Hz), 6,93 (1H, d, J=8.6 Hz), to 6.95 (1H, s), 7,21 (1H, DD, J=7,3 Hz, 1.8 Hz), the 7.43 (1H, t, J=7,3 Hz), 7,46 (1H, ush-d, J= 7,3 Hz), 7,53 (2H, d, J=8,3 Hz), 7,54 (1H, s), 7,83 (2H, d, J=8,3 Hz), of 8.28 (1H, s), 8,32 (1H, d, J=1,8 Hz).

Reference example 77

Methyl-3-hydroxybenzoate (10,00 g, 65,72 mmol) dissolved in dimethylformamide (100 ml). When paramasivan acetonitril (4,99 ml, 78,86 mmol). The mixture is stirred at room temperature for 12 hours. The reaction solution was poured into water with ice, and the precipitated crystals are collected by filtration. The resulting crystals are dissolved in chloroform and the solution washed with 5% aqueous potassium carbonate solution, 10% aqueous citric acid solution and brine in sequence, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. By crystallization of the resulting residue from a mixture of diethyl ether and hexane get methyl-3-cyanometallates (811,80 g, 94%).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 3,93 (3H, s), 4,82 (2H, s), 7,11-of 7.25 (1H, m), the 7.43 (1H, ush-t, J=7.5 Hz), to 7.61-7,66 (1H, m), 7,79 (1H, dt, J =7,5, 1.3 Hz).

Reference example 78

Solution (4N) of hydrogen chloride in ethyl acetate (50 ml) and the dithiophosphate =O, O-diethyl (4,47 ml, 26,67 mmol) are added in sequence to methyl-3-cinematografo (5,00 g, 26,15 mmol). The resulting solution was stirred at room temperature for 12 hours. Precipitated from the reaction solution, the crystals are collected by filtration and washed with diethyl ether. Get methyl-3-thiocarbamoylation (4,60 g, 78%).<, ,83 (2H, s), 7,27 (1H, DD, J=7,9, 2.4 Hz), 7,46 (1H, ush-t, J=7.9 Hz), 7,54 (1H, ush-C), to 7.59 (1H, ush-d, J=7.9 Hz), 9,43 (1H, ush-C), of 10.01 (1H, ush -)

The following compound of reference example 79 receive the same manner described in reference example 78.

Reference example 79

Methyl 3-(2-thiocarbamoylation)benzoate

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: of 2.92 (2H, t, J=6.2 Hz), 3,85 (3H, s), 4,39 (2H, t, J=6.2 Hz), 7,14-of 7.60 (4H, m), 9,20-to 9.70 (2H, ush).

Reference example 80

Cyclopentylmethyl (0.20 g, 1.78 mmol) was dissolved in methanol (5 ml). With stirring under ice cooling to the solution add a catalytically effective amount of a 33% hydrogen bromide in acetic acid, and then added dropwise bromine (0.34 g, 2.14 mmol). To the reaction solution was added potassium carbonate (0.15 g, 1.07 mmol) and the mixture was stirred at room temperature for 10 minutes. Then to the reaction solution was added methyl 3-thiocarbamoylation (0.40 g, 1.78 mmol) and the mixture refluxed for 1 hour. After cooling, the reaction solution was concentrated under reduced pressure, to the obtained residue, add the ice water and 5% aqueous potassium carbonate solution, and then the resulting product is Anna sequence, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the obtained residue, add tetrahydrofuran (5 ml), methanol (5 ml) and 1 N aqueous sodium hydroxide solution (2 ml). The mixture is stirred at room temperature for 12 hours. The reaction solution is concentrated under reduced pressure, to the obtained residue, add 10% aqueous citric acid solution, and then the resulting product is extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. By crystallization from a mixture of diethyl ether and hexane get 3-(4-cyclopentyl-2-thiazolyl)methoxybenzoic acid (0.15 g, 28%).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,66-1,81 (6N, m), 2.06 to of 2.16 (2H, m), 3,22-of 3.31 (1H, m), 5,43 (2H, s), 6,93 (1H, s), 7.23 percent-7,26 (1H, m), 7,40 (1H, ush-t, J=8,3 Hz), 7,75 for 7.78 (2H, m), is 8.5-9.5 (1H, ush).

In the same way as described in reference example 80, you receive the following compounds of reference examples 81-85.

Reference example 81

3-(4-Cyclohexyl-2-thiazolyl)methoxybenzoic acid.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)m), 7,38 - 7,41 (1H, m), 7,75-7,80 (2H, m), a 10.6 to 11.2 (1H, ush).

Reference example 82

3-(4-Cyclobutyl-2-thiazolyl)methoxybenzoic acid.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,8-2,2 (6N, m), 3,54-3,91 (1H, m), 5,43 (2H, s) 6,94 (1H, d,J=0.8 Hz), 7,16-7,42 (2H, m), 7,70-to 7.84 (2H, m).

Reference example 83

3-(4-Phenyl-2-thiazolyl)methoxybenzoic acid.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 5,49 (2H, s), 7,20-EUR 7.57 (6N, m), 7,72-of 7.97 (4H, m)

Reference example 84

3-(4-Cyclopropyl-2-thiazolyl)methoxybenzoic acid.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 0,87-1,02 (4H, m), 1,95-of 2.26 (1H, m), 5,38 (2H, s) 6,86 (1H, s), 7,16-7,49 (2H, m), 7,72-7,81 (2H, m), of 8.8 and 9.3 (1H, ush).

Reference example 85

3-(4-tert-Butyl-2-thiazolyl) methoxybenzoic acid.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,03 (N, C), 5,46 (2H, s), 7,30 (1H, s), 7,31-7,34 (1H, m), 7,44 (1H, ush-t, J=8,3 Hz), EUR 7.57-to 7.59 (2H, m), 13,01 (1H, ush-C).

Reference example 86

3-[2-(4-tert-Butyl-2-thiazolyl)vinyl]benzoic acid

(1.20 g, 4,18 mmol) dissolved in tetrahydrofuran (24 ml), the solution we use is re hydrogen. The reaction solution is filtered and the resulting filtrate concentrated under reduced pressure. By crystallization from a mixture of diethyl ether and hexane receive 3-[2-(4-tert-butyl-thiazolyl)ethyl]benzoic acid (1.12 g, 93%).

Spectrum of nuclear magnetic resonance (CDCl3), TMS internal standard).

: 1,34 (N, C), 3,05-of 3.48 (4H, m), 6,74 (1H, s), 7,32-7,40 (2H, m), a 7.85-8,01 (2H, m).

In the same way, which is described in the reference example 86, receive the following compound of reference example 87.

Reference example 87

3-[2-(4-Cyclobutyl-2-thiazolyl)ethyl]benzoic acid.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,85-of 1.94 (1H, m), 1,98-of 2.08 (1H, m), 2,18-of 2.27 (2H, m), 2,33-to 2.41 (2H, m), and 3.16 (2H, t, J=8,5 Hz) to 3.36 (2H, t, J=8.5 Hz), 3,67 of 3.75 (1H, m), 6,78 (1H, s), 7,34-7,39 (2H, m), 7,95-of 7.97 (1H, m), 8,03 (1H, ush-C).

Reference example 88

Methyl-3-mercaptobenzoic (0.50 g, of 2.97 mmol) and 2-methyl bromide-4 - tert-butylthiazole (0.50 g, with 3.27 mmol) dissolved in 2-butanone (10 ml). To the solution was added potassium carbonate (0,41 g of 4.46 mmol) with stirring under ice cooling, and the mixture is stirred at room temperature for 12 hours. Add ice and 5% aqueous potassium carbonate solution and the product extracted with gloty and brine in sequence, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the obtained residue, add tetrahydrofuran (10 ml), methanol (5 ml) and 1N aqueous sodium hydroxide solution (4,46 ml). The mixture is stirred at room temperature for 7 hours. The reaction solution is concentrated under reduced pressure, to the obtained residue, add 10% aqueous citric acid solution, and then the resulting product is extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. By crystallization of the resulting residue from a mixture of chloroform with diethyl ether to obtain 3-(4-tert-butyl-2-thiazolyl) methyldibenzo acid (0,81 g, 83%).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,29 (N, C) 5,41 (2H, s), to 6.80 (1H, s), 7,33 (1H, ush-t, J=7.8 Hz), 7,56 (1H, dt, J=7,8, and 1.6 Hz), to 7.93 (1H, dt, J=7,8, and 1.6 Hz), 8,14 (1H, ush-t, J=l,6 Hz).

EXAMPLE 1

5'-[3-(4-chlorophenylsulfonyl)propyl] -2'-hydroxy-3- [2-(4-phenyl-2-thiazolyl)vinyl] benzanilide (0,60 g, 0.98 mmol) dissolved in dimethylformamide (6 ml), add potassium carbonate (0.20 g, 1,45 mmol), a catalytically effective amount of tetrabutylammonium and ativam is the temperature for 12 hours. To the reaction solution was added ice water, and the resulting product is extracted twice with a mixture of benzene with ethyl acetate (1: 1). The obtained organic layer was washed with 5% aqueous potassium carbonate solution and brine in sequence, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (eluent= acetone: chloroform= 1:100) and crystallized from acetonitrile. Obtain ethyl 4-[3-(4 - chlorophenylsulfonyl)propyl] -2-[3-2-(4-phenyl-2-thiazolyl)vinyl] benzoylamine phenoxyacetate (0.36 g, 0.51 mmol, 53%) as colorless crystals.

In the same way described in example 1, to synthesize the following compounds of examples 2 through 7. Structure and physico-chemical properties of these compounds are shown in tables 12 and 13.

In this regard, the term "binding position", shown in the tables indicates the position of the binding.

< / BR>
of the General formula (1), and the term "position of bonding with the thiazole ring" refers to the situation where R1associated with a thiazole ring. The same will be used next.

EXAMPLE 2

Ethyl 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[2-[4-(4- were)-2-teaseltail-2-thiazolyl)vinyl]benzoylamine]phenoxyacetate.

EXAMPLE 4

Ethyl 2-[3-[2-(4-tert-butyl-2-thiazolyl)vinyl]benzoylamine]-4-[3- (4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

EXAMPLE 5

Ethyl 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[(4- phenyl-2-thiazolyl)methoxy]benzoylamine] phenoxyacetate.

EXAMPLE 6

Ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy] benzoylamine]-4-[3-(4-chlorophenylsulfonyl)propyl] PHENOXYACETIC.

EXAMPLE 7

Ethyl 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[2-(4-cyclopropyl-2-thiazolyl) vinyl]benzoylamine]phenoxyacetate.

EXAMPLE 8

Ethyl 1-[3-(4-chlorophenylsulfonyl)propyl] -2 [3-[2-(4- phenyl-2-thiazolyl)vinyl] benzoylamine] phenoxyacetate (0,30 g, 0.43 mmol) was dissolved in a mixed solution of tetrahydrofuran (10 ml) and methanol (5 ml), to this solution was added 1N aqueous sodium hydroxide solution (1.0 ml), and the mixture is allowed to react for 12 hours. The reaction mixture is acidified by adding ice and 10% aqueous citric acid solution, and the resulting product is extracted three times with chloroform. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. By crystallization of the resulting residue from a mixture of chloroform with acetonitrile obtain 4-[3-(4 - chlorophenylsulfonyl what's crystals.

In the same way described in example 8, synthesize the following compounds of examples 9 through 14. Structure and physico-chemical properties of these compounds are shown in table 14.

EXAMPLE 9

4-[3-(4-Chlorophenylsulfonyl)propyl] -2 [3-[2-[4-(4- were)-2-thiazolyl]vinyl]benzoylamine]venexiana acid.

EXAMPLE 10

4-[3-(4-Chlorophenylsulfonyl)propyl] -2-[3-[2-(4- isopropyl-2-thiazolyl)vinyl]benzoylamine]venexiana acid.

EXAMPLE 11

2-[3-[2-(4-tert-Butyl-2-thiazolyl)vinyl] benzoylamine] -4-[3-(4-chlorophenylsulfonyl)propyl]venexiana acid.

EXAMPLE 12

4-[3-(4-Chlorophenylsulfonyl)propyl] -2-[3-[(4-phenyl-2 - thiazolyl)methoxy] benzoylamine]venexiana acid.

EXAMPLE 13

2-[3-[(4-tert-Butyl-2-thiazolyl)methoxy]benzoylamine]-4- [3-(4-chlorophenylsulfonyl)propyl] venexiana acid.

EXAMPLE 14

4-[3-(4-Chlorophenylsulfonyl)propyl] -2-[3-[2-(4- cyclopropyl-2-thiazolyl)vinyl]benzoylamine]venexiana acid.

In the same way described in example 1, to synthesize the following compounds of examples 15 to 21. Structure and physico-chemical properties of these compounds are shown in tables 15 and 16.

EXAMPLE 15

Ethyl 4-[3-(4-glorf is R>
Ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methylthio] benzoylamine]-4-[3-(4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

EXAMPLE 17

Ethyl 2-[3-[2-(4-tert-butyl-2-thiazolyl)ethyl]benzoylamine]-4- [3-(4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

EXAMPLE 18

Ethyl 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3- [(4-cyclohexyl-2-thiazolyl)methoxy]benzoylamine]phenoxyacetate.

EXAMPLE 19

Ethyl 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[(4- cyclopentyl-2-thiazolyl)methoxy]benzoylamine] phenoxyacetate.

EXAMPLE 20

Ethyl 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[(4- cyclobutyl-2-thiazolyl)methoxy]benzoylamine]phenoxyacetate.

EXAMPLE 21

Ethyl 2-[3-[1-(4-tert-butyl-2-thiazolyl)ethoxy] benzoylamine] -4-[3-(4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

EXAMPLE 22

1) According to the method of example 1 to synthesize the following compound.

Ethyl-2-[3-[(4-tert-butyl-2-thiazolyl)methoxy] -5- (4-nitrobenzenesulfonamide)benzoylamine]-4-[3- (4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

The data of mass spectrometry (m/z): 879 (M+)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: of 1.27 (3H, t, J=7,3 Hz), 1,34 (N, C), 1,98 e 2.06 (2H, m) to 2.67 (2H, ush-t, J= 7,3 Hz), 3,06-3,10 (2H, m), the 4.29 (2H, whom Hz), to 8.20 (2H, d, J=8,8 Hz), 8,24 (1H, ush-C) of 9.30 (1H, ush-C).

2) Ethyl-2-[3-[(4-tert-butyl-2-thiazolyl) methoxy] -5- (4-nitrobenzenesulfonamide)benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]phenoxyacetate (0.50 g of 0.57 mmol) dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), to the solution was added 10% palladium-on-coal (0.10 g) and the mixture is stirred at room temperature for 3 hours in hydrogen atmosphere. The reaction mixture is filtered and the resulting filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (eluent=acetone:chloroform=3:100) and crystallized from acetonitrile. Get ethyl-2-[3-amino-5-[(4-tert-butyl-2-thiazolyl) methoxy]benzoylamine]-4-[3-(4-chlorophenylsulfonyl) propyl]phenoxyacetate (0.17 g, 0.24 mmol, 43%) as light yellow crystals. Its structure is shown in table 30.

The data of mass spectrometry (m/z): 700 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: of 1.28 (3H, t, J =7,3 Hz), 1,34 (N, C), 1,99-2,07 (2H, m), 2,68 (2H, ush-t, J=7,3 Hz) to 3.89 (2H, ush-C), the 4.29 (2H, K, J=7,3 Hz), 4,70 (2H, s), of 5.39 (2H, s), of 6.52 (1H, ush-t, J=1.9 Hz), for 6.81 (2H, s), 6,91 (1H, s), of 6.99 (1H, ush-C), 7,07 (1H, ush-C), 7,53 (2H, d, J=8,8 Hz), 7,82 (2H, d, J=8,3 Hz), of 8.27 (1H, ush-C), 9,18 (1H, ush-C).

In the quiet of the compounds are given in table 17.

EXAMPLE 23

Ethyl 4-[2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamine]-4- [3-[4-chlorophenylsulfonyl)propyl]phenoxy]butyrate.

EXAMPLE 24

Ethyl 2-[2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamine]-4- [3-(4-chlorophenylsulfonyl)propyl]phenoxy]-2-methylpropionate.

EXAMPLE 25

Ethyl 2-[2-[3-[(4-tert-butyl-2-thiazolyl)methoxy benzoylamine] -4-[3-(4-chlorophenylsulfonyl)propyl]phenoxy] propionate

According to the method of example 8 synthesize the following compounds of examples 26 to 32. Structure and physico-chemical properties of these compounds are shown in Table 18.

EXAMPLE 26

4-[3-(4-Chlorophenylsulfonyl)propyl] -2-[3-[(4-cyclopropyl-2-thiazolyl) methoxy]benzoylamine]venexiana acid.

EXAMPLE 27

2-[3-[(4-tert-Butyl-2-thiazolyl)methylthio] benzoylamine] -4- [3-(4-chlorophenylsulfonyl)propyl]venexiana acid.

EXAMPLE 28

2-[3-[2-(4-tert-Butyl-2-thiazolyl)ethyl] benzoylamine] -4- [3-(4-chlorophenylsulfonyl)propyl]venexiana acid.

EXAMPLE 29

4-[3-(4-Chlorophenylsulfonyl)propyl] -2-[3-[(4-cyclohexyl - 2-thiazolyl)methoxy]benzoylamine]venexiana acid.

EXAMPLE 30

4-[3-(4-Chlorophenylsulfonyl)propyl] -2-[3-[(4-cyclopentyl-2-thiazolyl) methoxy]benzoylamine]PL) methoxy]benzoylamine]venexiana acid.

EXAMPLE 32

2-[3-[1-(4-tert-Butyl-2-thiazolyl)ethoxy] benzoylamine] - 4-[3-(4-chlorophenylsulfonyl)propyl]venexiana acid.

EXAMPLE 33

According to the method of example 8 synthesize the following compound. Its structure is shown in table 30.

2-[3-Amino-5-[(4-tert-butyl-2-thiazolyl)methoxy] benzoylamine]-4- [3-(4-chlorophenylsulfonyl)propyl]venexiana acid.

The pace. melting point: 133-135oC.

The data of mass spectrometry (m/z): 672 (M+)

Elemental analysis data (for C32H34N3O7S2Cl)

Calculated, %: C 55,68; H 5,26; N 6,09; S 9,29; Cl 5,14;

Found, %: C 55,47; H 5,02; N 6,06; S 9,10; Cl 4,92.

According to the method of example 8 synthesize the following compounds of examples 34 to 36. Structure and physico-chemical properties of these compounds are shown in table 19.

EXAMPLE 34

4-[2-[3-[(4-tert-Butyl-2-thiazolyl)methoxy] benzoylamine] -4-[3-(4-chlorophenylsulfonyl)propyl]phenoxy] butyric acid

EXAMPLE 35

2-[2-(3-[(4-tert-Butyl-2-thiazolyl)methoxy] benzoylamine] -4-[3-(4-chlorophenylsulfonyl)propyl]phenoxy]-2-methylpropionate acid, hemihydrate.

EXAMPLE 36

2-[2-[3-[(4-tert-Butyl-2-thiazolyl)methoxy] benzoylamine]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxy]about�] -4-[3- (4-chlorophenylsulfonyl)propyl] Phenoxyethanol acid (0,30 g, 0.44 mmol) is dissolved in methanol saturated with ammonia (10 ml) and this solution is allowed to react for 12 hours at room temperature. The reaction solution is concentrated under reduced pressure and the resulting residue is crystallized from acetonitrile. Get 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy] benzoylamine] -4-[3-(4-chlorophenylsulfonyl) propyl]phenoxyacetamide (0,22 g, 0.34 mmol, 77%) as colorless crystals. Its structure is shown in table 30.

The pace. melting point: 147-148oC.

The data of mass spectrometry (m/z): 656 (M+).

Elemental analysis data (for C32H34N3O6S2Cl)

Calculated, %: C 58,57; H 5,22; N 6,40; S 9,77; Cl 5,40;

Found, %: C 58,39; H 5,13; N 6,38; S 9,65; Cl 5,30.

EXAMPLE 38

Dimethylformamide (5.0 ml) are added to a mixture of 3-[2-(4-tert-butyl-2-thiazolyl)ethyl] -5'-[3-(4-chlorophenylsulfonyl) propyl] -2'-cinemacasinoenligne (0,57 g, 0.90 mmol), ammonium chloride (96 mg, 1.8 mmol) and sodium azide (0.12 g, 1.9 mmol) and the resulting mixture was stirred at 70oC for 12 hours. To the reaction solution was added ice and 10% aqueous citric acid solution. The resulting product is extracted with ethyl acetate. The obtained organic layer was washed with water and brine in the decree is. the received residue purified column chromatography on silica gel (eluent = methanol: chloroform = 3:100) and then crystallized from acetonitrile. Receive 3-[2-(4-tert-butyl-2-thiazolyl)ethyl] -5'-[3-(4- chlorophenylsulfonyl)propyl] -2'-(1H-tetrazol-5-ylethoxy)benzanilide (0.34 g, 0.50 mmol, 56%) as colorless crystals. Its structure is shown in table 30.

The pace. melting point: 152-153oC.

The data of mass spectrometry (m/z): 679 (M+)

According to the method of example 38 synthesize the following compounds of examples 39 to 41. Structure and physico-chemical properties of these compounds are shown in table 20.

EXAMPLE 39

3-[(4-tert-Butyl-2-thiazolyl)methoxy] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy) benzanilide.

EXAMPLE 40

3-[(4-tert-Butyl-2-thiazolyl)methylthio] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(1H-tetrazol-5-ylethoxy) benzanilide, 0.7 hydrate.

EXAMPLE 41

5'-[3-(4-Chlorophenylsulfonyl)propyl]-3-[2-(4- cyclobutyl-2-thiazolyl)ethyl] -2'-(1H-tetrazol-5-ylethoxy)benzanilide.

EXAMPLE 42

Ethanol (5.0 ml) are added to 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy] benzoylamine] -4-[3-(4-chlorophenylsulfonyl)propyl] phenoxyalkanoic acid (0,30 g, 0.46 mmol) and the mixture was stirred at room tionale (4.6 ml), and then concentrate under reduced pressure. The resulting residue is dried in vacuum and then dissolved in acetone (10 ml). The resulting solution was cooled with ice, and add 4-chloromethyl-5-methyl-1,3-dioxol-2-he (0.10 g, 0.67 mmol) and sodium iodide (0.21 g, 1.4 mmol) and the mixture was stirred at room temperature for 12 hours. To the reaction solution was added ice and saturated aqueous sodium bicarbonate solution, and the resulting product is extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium bicarbonate, 10% aqueous citric acid solution and brine in sequence, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (eluent = acetone : chloroform = 3:100) and crystallized from a mixture of chloroform with diethyl ether. Receive (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl=2-[3-[(4-tert-butyl-2-thiazolyl)methoxy] benzoylamine] -4-[3-(4-chlorophenylsulfonyl)propyl] Phenoxyethanol acid (0.15 g, 0,19 mmol, 43%) as colorless crystals. Its structure is shown in table 30.

The pace. melting point: 114-116oC.

The data of mass spectrometry (m/z): 769 (M+)

What's a 8.34; Cl br4.61;

Found, %: C 57,74; H 4,78; N 3,67; S To 8.41; Cl 4,67.

According to the method of example 42 synthesize the following compound.

EXAMPLE 43

Pivaloyloxymethyl= 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy] benzoylamine] -4-[3-(4-chlorophenylsulfonyl)propyl]venexiana acid.

The pace. melting point: 98-100oC.

The data of mass spectrometry (m/z): 177 (M+)

Elemental analysis data (for C38H43N2O9S2Cl)

Calculated, %: C 59,17; H 5,62; N 3,63; S A 8.34; Cl 4,60;

Found, %: C 59,42; H 5,62; N 3,56; S To 8.41; Cl With 4.64.

EXAMPLE 44

Under ice cooling hydrazine monohydrate (190 μl, 3.8 mmol) is added to a mixture of N-[2-[2-[3-[(4-tert-butyl-2-thiazolyl) methoxy]benzoylamine]-4-[3-(4-chlorophenylsulfonyl)propyl] phenoxy] ethyl] phthalimide (1.5 g, 1.9 mmol), ethanol (5 ml) and tetrahydrofuran (20 ml) and the resulting mixture is stirred over night at room temperature, and then refluxed for 3 hours. To the reaction solution was added ice water, and then the resulting product is extracted with chloroform. The obtained organic layer was washed with saturated aqueous sodium bicarbonate and distilled water in sequence, dried over betwedn the Le (eluent = chloroform:acetone=2:1), converted into hydrochloride by adding 4 N hydrochloric acid in ethyl acetate and then crystallized from diethyl ether. Receive 3-[(4-tert-butyl-2-thiazolyl) methoxy] -5'-[3-(4-chlorophenylsulfonyl)propyl]-2'-(2 - aminoethoxy] benzanilide, 1,4 hydrochloride,7 hydrate (160 mg, 0.23 mmol, 12%), as white crystals.

Melting point: 93-96oC.

The data of mass spectrometry (m/z): 642 (M+)

Elemental analysis data (for C32H36N3O5S2Cl HCl 1,4 0,7 H2O)

Calculated, %: C 54,45; H 5,54; N 5,95; S A 9.09; Cl 12,05;

Found, %: C 54,23; H 5,42; N By 5.87; S 8,95; Cl 11,90.

EXAMPLE 45

While cooling with ice, add acetic anhydride (30 μl, 0.3 mmol) to a mixture of 3-[(4-tert-butyl-2-thiazolyl)methoxy] -5'-[3- (4-chlorophenylsulfonyl)propyl] -2'-(2-aminoethoxy)benzanilide, 1,4 hydrochloride 0.7 hydrate (170 mg, 0.24 mmol), dichloromethane (2 ml) and pyridine (32 μl, 0.4 mmol). The resulting mixture was stirred at room temperature for 3 hours. To the reaction mixture with ice water, and the mixture is stirred for 1 hour. The resulting product is extracted with chloroform, and the organic layer washed with 20% aqueous solution of potassium hydrosulfate, saturated aqueous bicarbonate soda the center. The resulting residue is crystallized from a mixture of chloroform and ether. Receive 3-[(4-tert-butyl-2-thiazolyl)methoxy] -5'-[3-(4- chlorophenylsulfonyl)propyl]-2'-(2-acetylbenzoate)benzanilide hemihydrate (97 mg, 0.14 mmol, 58%) as white crystals.

The pace.melting point: 110,5-111,5oC.

The data of mass spectrometry (m/z): 684 (M+)

Elemental analysis data (for C34H38N3O6S2Cl 0.5 H2O)

Calculated, %: C 58,90; H 5,67; N 6,06; S 9,25; Cl 5,11;

Found, %: C 58,94; H The 5.45; N 6,02; S 9,31; Cl 5,12.

According to the method of example 45 synthesize the following compound.

EXAMPLE 46

3-[(4-tert-Butyl-2-thiazolyl)methoxy]-5'-[3-(4- (chlorophenylsulfonyl)propyl]-2'-(2 - methylsulfonylamino)benzanilide.

The pace.melting is 125.5-126oC

The data of mass spectrometry (m/z): 720 (M+)

Elemental analysis data (for C33H38N3O7S3Cl)

Calculated, %: C 55,03; H 5,32; N Of 5.83; S 13,35; Cl 4,92;

Found, %: C 54,97; H 5,32; N 5,77; S 13,54; Cl 4,84.

In the same way described in example 1 given the following compounds of examples 47 to 59.

EXAMPLE 47

Ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy] -5-chlorobenzylamino] -4-[3-(4-chlorophenylsulfonyl)propyl]PHENOXYACETIC the/SUB>, TMS internal standard).

: of 1.29 (3H, t, J=7,3 Hz), 1,35 (N, s), 2.00 in 2,07 (2H, m), 2,69 (2H, ush-t, J= 7,3 Hz), 3,06-3,10 (2H, m), or 4.31 (2H, K, J=7,3 Hz), 4,71 (2H, s), 5,43 (2H, s), at 6.84 (2H, ush-C) 6,94 (1H, s), 7,24 (1H, ush-C), 7,53 (2H, ush-d, J= 8,3 Hz), to 7.61-the 7.65 (2H, m), 7,82 (2H, ush-d, J=8,3 Hz), of 8.25 (1H, ush-C), a 9.35 (1H, ush-C).

EXAMPLE 48

Ethyl 2-[5-[(4-tert-butyl-2-thiazolyl)methoxy] -2-chlorobenzylamino] -4- [3-(4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

The data of mass spectrometry (m/z): 719 (M+N)+< / BR>
Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: to 1.25 (3H, t, J=6.8 Hz), 1,35 (N, C) 2,02-of 2.08 (2H, m), 2,70 (2H, ush-t, J= 7,3 Hz), is 3.08-of 3.12 (2H, m), 4,25 (2N, K, J=6,8 Hz), of 4.66 (2H, s) 5,38 (2H, s), is 6.78 (1H, ush-d, J=8,3 Hz), at 6.84 (1H, ush-d, J =8,3 Hz), 6,92 (1H, s), 7,07 (1H, DD, J=8,8, 2.0 Hz), 7,37 (1H, ush-d, J=8,8 Hz), 7,49 (1H, d, J= 2.0 Hz), 7,54 (2H, ush-d, J=8,8 Hz), 7,83 (2H, ush-d, J=8,8 Hz), with 8.33 (1H, d, J=2.0 Hz), 9,01 (1H, s).

EXAMPLE 49

Ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy] -4-methoxy]- benzoylamine] -4-[3-(4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

The data of mass spectrometry (m/z: 715 (M+)

Spectrum of nuclear magnetic resonance (CDCl3), TMS internal standard).

: of 1.29 (3H, t, J = 6.8 Hz), 1,33 (N, C), 1,99-2,07 (2H, m), 2,69 (2H, ush-t, J= 7,3 Hz), 3,06-3,10 (2H, m), of 3.96 (3H, s), 4,29 (2N, K, J=6,8 Hz), 4,70 (2H, s), of 5.50 (2H, s), to 6.80 (1H, ush-d, J=8,3 Hz), 6 is C), of 8.28 (1H, s), 9,27 (1H, s).

EXAMPLE 50

Ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy] -4 - chloro-benzoylamine]-4-[3-(4-chlorophenylsulfonyl)propyl] PHENOXYACETIC.

The data of mass spectrometry (m/z): 719(M+H)+]

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: of 1.30 (3H, t, J=6.8 Hz), 1,34 (N, C) 2,02-to 2.06 (2H, m), 2,70 (2H, ush-t, J= 7,3 Hz), 3,06-3,11 (2H, m), 4,32 (2N, K, J=6,8 Hz), 4,71 (2H, s), of 5.55 (2H, s) 6,86 (2H, ush-d, J=8,3 Hz) 6,94 (1H, s), 7,53 (2H, ush-d, J=8,8 Hz), 7,54 (1H, s), 7,82 (2H, ush-d, J=8,8 Hz), the 7.85 (1H, d, J=2.0 Hz), compared to 8.26 (1H, s), for 9.47 (1H, s).

EXAMPLE 51

Ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy] -4 - methylpentylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

The data of mass spectrometry (m/z) : 699 (M+)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: of 1.30 (3H, t, J =7,3 Hz), 1,35 (N, C), 2,00-of 2.08 (2H, m), of 2.38 (3H, s), 2,69 (2H, ush-t, J=7,3 Hz), 3,07-3,11 (2H, m), 4,32 (2N, K, J=7,3 Hz), 4,71 (2H, s), of 5.48 (2H, ush-C), 6,85 (2H, ush-C), 6,92 (1H, ush-C), 7,30 (1H, d, J= 7.8 Hz), 7,53 (2H, DD, J=8,3, 2.0 Hz), 7,58 (1H, d, J=7.8 Hz), 7,69 (1H, ush-C) of 7.82 (2H, ush-d, J=8,3 Hz), 8,30 (1H, s), a 9.35 (1H, s).

EXAMPLE 52

Ethyl 2-[-3-[(4-tert-butyl-2-thiazolyl)methoxy]-4 - nitrobenzylamine]-4-[3-(4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

The data of mass spectrometry (m/z. of 1.31 (3H, t, J=7,3 Hz), 1,33 (N, C) 2,01-of 2.08 (2H, m), 2,71 (2H, ush-t, J= 7,3 Hz), 3,07-3,11 (2H, m), 4,33 (2N, K, J=7,3 Hz), to 4.73 (2H, s), 5,63 (2H, s), 6.89 in (2N, C), to 6.95 (1H, s), 7,54 (2H, ush-d, J=8,8 Hz), 7,78 (1H, DD, J=8,3, 1.5 Hz), 7,83 (2H, ush-d, J=8,8 Hz), to 7.99 (1H, d, J=8,3 Hz), with 8.05 (1H, d, J=1.5 Hz), of 8.25 (1H, s), 9,67 (1H, s).

EXAMPLE 53

Ethyl 2-[3-[(4-tert-butyl-5-methyl-2-thiazolyl)methoxy] benzoylamine]-4-[3-(4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

The data of mass spectrometry (m/z): 699 (M+N)+< / BR>
Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard)

: of 1.29 (3H, t, J = 7,3 Hz), 1,40 (N, C) 2,04 e 2.06 (2H, m), of 2.51 (3H, s), 2,69 (2H, ush-t, J=7,3 Hz), 3,07-3,11 (2H, m), 4,29 (2N, K, J=7,3 Hz), 4,71 (2H, s), 5,33 (2H, s), PC 6.82 (2H, ush-C), from 7.24 (1H, d, J=7.8 Hz), 7,42 (1H, t, J=7.8 Hz), 7,53 (2H, ush-d, J=8,3 Hz), a 7.62 (1H, d, J=7.8 Hz), 7,69 (1H, ush-C) of 7.82 (2H, ush-d, J=8,3 Hz), 8,30 (1H, s), a 9.25 (1H, s).

EXAMPLE 54

Ethyl 2-[6-[(4-tert-butyl-2-thiazolyl)methoxy] -2-pyridyl - carbylamine] -4-[3-(4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

The data of mass spectrometry (m/z): 686 (M+)

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: to 1.21 (3H, t, J=7.2 Hz), 1,34 (N, C) 2,01-of 2.08 (2H, m), 2,19 (2H, t, J= 7,3 Hz), 3,06-3,10 (2H, m), 4,18 (2N, K, J=7,2 Hz) and 4.65 (2H, s), of 5.83 (2H, s), 7,76 (1H, d, J=8,4 Hz), for 6.81 (1H, d, J=8,4 Hz), make 6.90 (1H, s), 7,05 (1H, d, J=8,4 Hz), 7,52 (2H, d, J=8,4 Hz), 7,80-a 7.85 (3H, m), 7,92 (1H, d, J=7,2 Gfenilalanin)propyl]-2,3-dichlorophenoxyacetic.

The data of mass spectrometry (m/z): 755 (M+N)+< / BR>
Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: of 1.28 (3H, t, J=7,3 Hz), 1,35 (N, C) 2,03-2,12 (2H, m), 2,90 (2H, ush-d, J= 7,3 Hz), 3,12-3,17 (2H, m), or 4.31 (2H, K, J=7,3 Hz), 4,78 (2H, s), vs. 5.47 (2H, s), 6,93 (1H, s), 7,24 (1H, ush-d, J = 8,3 Hz), was 7.45 (1H, ush-t, J= 8,3 Hz), 7,54 (2H, d, J=8,8 Hz), the 7.85 (1H, ush-C), 7,86 (2H, d, J=8,8 Hz), 8,31 (1H, s), 10,14 (1H, ush-C).

EXAMPLE 56

Ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy] benzoylamine] -6-chloro-4- [3-(4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

The data of mass spectrometry (m/z): 719 (M+N)+< / BR>
Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: to 1.16 (3H, t, J=7,3 Hz), 1,30 (N, C), 1,78-to 1.87 (2H, m), 2.26 and-a 2.36 (2H, m), 3.33 and-to 3.38 (2H, m), 4,18 (2N, K, J=7,3 Hz), 4,82 (2H, s) 5,52 (2H, s), 7,10 (1H, ush-C), 7,32-7,34 (2H, m), 7,51 (IH, ush-t, J=7.8 Hz), to 7.64 (1H, ush-d, J=7.8 Hz), 7,72 to 7.75 (3H, m), to $ 7.91 (2H, DD, J=8,8, 2.0 Hz), 10,14 (1H, ush-C).

EXAMPLE 57

Ethyl 2-[2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamine]-4- [3-(4-chlorophenylsulfonyl)propyl]phenoxy]-2-fluoroacetate.

The data of mass spectrometry (m/z.) : 703 (M+N)+< / BR>
Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: to 1.31 (3H, t, J=7,3 Hz), 1,36 (N, C) 2,02 is 2.10 (2H, m), 2.71 to a 2.75 (2H, ush-t, J= 7,3 Hz), 3,07-3,11 (2H, m), 4,36-4,43 (2H, m), 5,44 (2,63 (1H, t, J=2.0 Hz), 7,82-7,89

(2H, m), 8,39 (1H, d, J=2.0 Hz), the rate of 8.75 (1H, s).

EXAMPLE 58

Ethyl 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3- [(4,5,6,7-tetrahydro-2-benzothiazolyl)methoxy]benzoylamine] phenoxyacetate

The data of mass spectrometry (m/z) : 683 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: of 1.28 (3H, t, J=6.0 Hz), 1,83-1,90 (4H, m), 2,01-2,07 (2H, m), 2,69 (2H, t, J=6.0 Hz), 2,78-of 2.81 (4H, m), 3,07-3,10 (2H, m), 4,28 (2N, K, J=7,0 Hz), 4,70 (2H, s), lower than the 5.37 (2H, s), PC 6.82 (2H, s), 7,19 (1H, d, J=6.4 Hz), 7,42 (1H, t, J=6.4 Hz), 7,53 (2H, d, J=6.8 Hz), a 7.62 (1H, d, J=6.4 Hz), 7,68 (1H, s) of 7.82 (2H, d, J=6.8 Hz), 8,30 (1H, s), which 9.22 (1H, s).

EXAMPLE 59

Tert-Butyl 2-[3-[2-(4-tert-butyl-2-thiazolyl)ethoxy] benzoylamine] -4- [3-(4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,34 (N, C) 1,48 (N, C), 1,98-2,07 (2H, m), 2,69 (2H, t, J=7,3 Hz), 3,06-3,10 (2H, m), 3,49 (2H, t, J=6.4 Hz), 4,32 (2H, t, J=6.4 Hz), 4,58 (2H, s), 6,77-6,83 (3H, m), 7,11 (1H, d, J=8.6 Hz), 7,40 (1H, t, J=8.0 Hz), 7,53 (2H, d, J=8,4 Hz), 7,58-of 7.60 (2H, m), 7,82 (2H, d, J=8,4 Hz), 8,29 (1H, s), 9,23 (1H, s).

In the same way described in example 8, to obtain the following compounds of examples 60 through 72.

EXAMPLE 60

4-[3-(4-Chlorophenylsulfonyl)propyl] -2-[3-(4,5,6,7-tetrahydro-2 - benzothiazolylazo)benzoylamino C32H31N2S2O7Cl)

Calculated, %: C 58,66; H of 4.77; N 4,28; S 9,79; Cl 5,41;

Found, %: C 58,50; H 4,75; N 4,19; S 9,80; Cl 5,22.

EXAMPLE 61

2-[3-[(4-tert-Butyl-2-thiazolyl)methoxy] -5-chlorobenzylamino] -4- [3-(4-chlorophenylsulfonyl)propyl]venexiana acid.

The pace. melting point: 143-145oC.

Elemental analysis data (for C32H32N2O7S2Cl2)

Calculated, %: C 55,57; H of 4.66; N 4,05; S 9,27; Cl of 10.25;

Found, %: C 55,59; H 4,59; N 4,14; S Was 9.33; Cl 10,17.

EXAMPLE 62

2-[5-[(4-tert-Butyl-2-thiazolyl)phenoxy] -2-chlorobenzylamino] -4- [3-(4-chlorophenylsulfonyl)propyl]phenoxyalkanoic acid 0.85 hydrate.

Elemental analysis data (for C32H32N2S2O7Cl20,85 H2O)

Calculated, %: C 54,Ç7; H 4,80; N 3,96; S 9,07; Cl there is a 10.03;

Found, %: C 53,97; H 4,40; N 3,91; S 9,03; Cl 10,00.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,30 (N, C), a 1.75-of 1.85 (2H, m), 2,58-2,63 (2H, m), 3,34-to 3.38 (2H, m), is 4.21 (2H, s), 5,46 (2H, s), 6,85 (1H, ush-d, J=8,3 Hz), of 6.96 (1H, ush-d, J= 8,3 Hz), 7,18 (1H, DD, J=8,8, 2.0 Hz), 7,33 (1H, s), 7,38 (1H, d, J=2.0 Hz), 7,45 (1H, ush-d, J=8,8 Hz), to 7.67 (1H, ush-C), 7,73 (2H, ush-d, J=8,3 Hz), of 7.90 (1H, ush-C), to $ 7.91 (2H, ush-d, J=8,3 Hz), 11,95 (1H, ush-C).

EXAMPLE 63

2-[3-[(4-you 0.5 hydrate.

Elemental analysis data (for C33H35N2S2O8Cl 0.5 H2O)

Calculated, %: C 56,93; H to 5.21; N Was 4.02; S Of 9.21; Cl 5,09;

Found, %: C 56,80; H 5,11; N 4,08; S To 9.32; Cl 5,09.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,30 (N, C), 1,81 of-1.83 (2H, m), 2,61 (2H, ush-t, J=7.8 Hz), 3,32-3,37 (2H, m), 3,88 (3H, s), 4,74 (2H, s), the 5.45 (2H, s), 6.89 in (1H, d, J=8,3 Hz), of 6.99 (1H, d, J=8,3 Hz), to 7.15 (1H, d, J=8,3 Hz), 7,31 (1H, s), 7,66 (1H, d, J= 8,3 Hz), 7,73 (2H, ush-d, J=8,3 Hz), 7,44 (1H, ush-C), 7,78 (1H, d, J=1.5 Hz), of 7.90 (2H, ush-d, J=8,3 Hz), 9,50 (1H, s), 13,19 (1H, s).

EXAMPLE 64

2-[3-[(4-tert-Butyl-2-thiazolyl)methoxy] -4-chlorobenzylamino] -4- [3-(4-chlorophenylsulfonyl)propyl]venexiana acid.

The pace. melting point: 179,5-181,5oC.

Elemental analysis data (for C32H32N2S2O7Cl2)

Calculated, %: C 55,47; H of 4.66; N 4,05; S 9,27; Cl of 10.25;

Found, %: C 55,75: With 4.64; N 4,16; S 9,34; Cl To 10.09.

EXAMPLE 65

2-[3-[(4-tert-Butyl-2-thiazolyl)methoxy] -4-methylpentylamino]-4- [3-(4-chlorophenylsulfonyl)propyl]phenoxyalkanoic acid hydrate.

Elemental analysis data (for C33H35N2S2O7Cl H2O)

Calculated, %: C 57,51; H 5,41; N 4,06; S Of 9.30; Cl 5,14;

Found, %: C 57,79; H 5,33; N 4,05; S 9,34; Cl 40 (N, C) a 1.75-to 1.87 (2H, m), is 2.30 (3H, s), 2,61 (2H, ush-t, J=7.8 Hz), 3,32-3,37 (2H, m), 4,74 (2H, s), the 5.51 (2H, s) 6,91 (1H, d, J=8,3 Hz), of 6.99 (1H, d, J=8,3 Hz), 7,31 (1H, s), 7,35 (1H, d, J = 7.8 Hz), 7,53 (1H, d, J= 7.8 Hz), 7,68 (1H, s), 7,73 (2H, ush-d, J=8,3 Hz), 7,78 (1H, s), of 7.90 (2H, ush-d, J=8,3 Hz), of 9.56 (1H, s), 13,20 (1H, s).

EXAMPLE 66

2-[3-[(4-tert-Butyl-2-thiazolyl)methoxy] -4-nitrobenzylamine]-4- [3-(4-chlorophenylsulfonyl)propyl]phenoxyalkanoic acid 0.5 hydrate.

The pace. melting point: 85,5 to 87.5oC.

Elemental analysis data (for C32H32N3S2O9Cl 0.5 H2O)

Calculated, %: C 54,04; H to 4.68; N 5,91; S 9,02; Cl to 4.98;

Found, %: C, 53,99; H 4,82; N By 5.87; S 8,87; Cl 4,65.

EXAMPLE 67

2-[6-(4-tert-Butyl-2-triazolylmethyl)-2-pyridylcarbonyl] -4- [3-(4-chlorophenylsulfonyl)propyl]phenoxyalkanoic acid 0.5 hydrate.

The pace. melting point: 169-171oC.

Elemental analysis data (for C31H32N3S2O7Cl 0.5 H2O).

Calculated, %: C 55,81; H 4,99; N 6,30; S Being 9.61; Cl 5,31;

Found, %: C 55,99; H Is 4.85; N Is 6.19; S 9,58; Cl 5,39.

EXAMPLE 68

6-[3-[(4-tert-Butyl-2-thiazolyl)methoxy] benzoylamine] -4- [3-(4-chlorophenylsulfonyl)propyl]-2,3-dichlorophenoxyacetic acid.

The pace. melting point: 191-193oC.

Elemental analysis data (for the but, %: C 52,80; H 4,40; N 3,83; S 8,84; Cl 14,53.

EXAMPLE 69

2-[3-[(4-tert-Butyl-2-thiazolyl)methoxy] benzoylamine] -6-chloro-4- [3-(4-chlorophenylsulfonyl)propyl]venexiana acid.

The pace.melting point: 201-203oC.

Elemental analysis data (for C32H32N2O7S2Cl2)

Calculated, %: C 55,57; H of 4.66; N 4,05; S 9,27; Cl of 10.25;

Found, %: C 55,32; H 4,65; N 4,27; S 9,19; Cl 10,43.

EXAMPLE 70

2-[3-[(4-tert-Butyl-2-thiazolyl)methoxy]cibenzoline]-4- [3-(4-chlorophenylsulfonyl)propyl]phenoxyalkanoic acid 0.5 hydrate.

Elemental analysis data (for C32H33N2S3O6Cl20.5 H2O)

Calculated, %: C 56,33; H 5,02; N 4,11; S 14,10; Cl 5,20;

Found, %: C 56,41; H 4,84; N 4,01; S 13,86; Cl 4,99.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,30 (N, C), 1,79 of-1.83 (2H, m), 2.63 in (2H, t, J=7,3 Hz), 3.33 and-to 3.36 (2H, m), and 4.68 (2H, s), of 5.48 (2H, s), 7,00 (1H, d, J=8,4 Hz), 7,07 (1H, d, J= 8,4 Hz), 7,24 (1H, d, J= 8,4 Hz), 7,32 (1H, s), 7,40 (1H, t, J=8.0 Hz), 7,52-to 7.59 (3H, m), 7,73 (2H, d, J=8,3 Hz), 7,89 (2H, d, J=8,3 Hz), and 11.2 (1H, s), 13,1 (1H, s).

EXAMPLE 71

2-[N-[3-[(4-tert-Butyl-2-thiazolyl)methoxy] benzoyl] -N - methylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]venexiana acid.

Data elementno;

Found, %: C 58,67; H 5,19; N 4,13; S 9,45; Cl 5,12.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,29 (N, s), 1.56 to its 1.68 (2H, m), 2,35-2,60 (2H, m), 2,94 is 3.15 (2H, m), 3,23 (3H, s), of 4.67 (2H, s), 5,23 (2H, m), 6,74-7,07 (7H, m), 7,28 (1H, m), 7,73 (2H, d, J=8,3 Hz), to 7.84 (2H, d, J=8,3 Hz), 13,1 (1H, C).

EXAMPLE 72

2-[3-[(4-tert-Butyl-5-methyl-2-thiazolyl)methoxy] benzoylamine]-4-[3- (4-chlorophenylsulfonyl)propyl] phenoxyalkanoic acid 0.5 hydrate.

Elemental analysis data (for C33H35N2S2O7Cl 0.5 H2O)

Calculated, %: C 58,27; H 5,33; N 4,12; S 9,43; Cl to 5.21;

Found, %: C 58,66; H Of 5.34; N 4,07; S A 9.09; Cl 5,00.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,36 (N, C), 1,79-of 1.85 (2H, m), of 2.51 (3H, s), 2,61 (2H, ush-t, J=7,3 Hz), 3,32-3,37 (2H, m), 4,74 (2H, s), lower than the 5.37 (2H, s) 6,91 (1H, ush-d, J=7,3 Hz), 7,00 (1H, d, J=7,3 Hz), 7,28 (1H, DD, J=8,3, 2.0 Hz), 7,47 (1H, t, J = 8,3 Hz), to 7.59 (1H, ush-d, J=8,3 Hz), 7,63 (1H, ush-C), 7,73 (2H, d, J=8,3 Hz), 7,79 (1H, ush-C), of 7.90 (2H, d, J=8,3 Hz), 9,65 (1H, s), 13,20 (1H, ush-C).

In the same way described in example 38, are provided the following compounds of examples 73 and 74.

EXAMPLE 73

3-(4-tert-Butyl-2-thiazoleacetate)-5'-[3-(phenylsulfonyl)propyl] -2- (1H-tetrazol-5-ylethoxy)benzanilide.

Data seminarian, %: C 59,02; H 5,28; N IS 12.85; S 10,01.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,30 (N, C), 1,76-of 1.84 (2H, m), 2,61 (2H, t, J=7,3 Hz), 3,28-and 3.31 (2H, m), vs. 5.47 (2H, s), of 5.55 (2H, s), to 6.95 (1H, d, J=8.0 Hz), to 7.15 (1H, d, J= 8,8 Hz), 7,28-7,33 (2H, m), 7,47 (1H, t, J=8.0 Hz), at 7.55 (1H, d, J=7,6 Hz), to 7.61 (1H, s) of 7.64-of 7.69 (3H, m), 7,70-to 7.77 (1H, m), 7,89 (2H, d, J = 7,2 Hz), 9,48 (1H, s).

EXAMPLE 74

5'-[3-(4-Chlorophenylsulfonyl)propyl]-3-[(4 - cyclobutyl-2-thiazolyl)methoxy]-2'-(1H-tetrazol-5-ylethoxy)benzanilide

The pace. melting point: 178,5-180,0oC.

Elemental analysis data (for C32H31N6S2O5Cl)

Calculated, %: C 56,59; H 4,60; N 12,37; S 9,44; Cl 5,22;

Found, %: C 56,62; H 4,60; N KZT 12.39; S 9,54; Cl 5,14.

EXAMPLE 75

A mixture of ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy] benzoylamine]-4-[3- (4-chlorophenylsulfonyl)propyl]phenoxyacetate

(176 mg, 0.26 mmol), dephosphorylated (69 mg, 0.31 mmol), sodium bicarbonate (20 mg, 0.33 mmol) and 1,2-dimethoxyethane (5 ml) is stirred for 5 hours at the boil under reflux, and the insoluble matter is removed by filtration. The obtained filtrate is diluted with ethyl acetate, washed with water and brine in sequence, dried over anhydrous sodium sulfate and then concentrated under the = hexane: ethyl acetate = 3:1-2:1). Obtain ethyl 2-[3-[(4-tertbutyl-2 - thiazolyl)methoxy] cibenzoline] -4-[3-(4-chlorophenylsulfonyl)propyl] phenoxyacetate (143 mg, 0.20 mmol, 78%).

The data of mass spectrometry (m/z): 701 (M+).

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,25 (3H, s), 1,35 (N, C) 2,02-2,12 (2H, m), by 2.73 (2H, t, J=7.2 Hz), 3,11-3,15 (2H, m), 4,25 (2N, K, J=7,2 Hz), 4,71 (2H, s), 5,43 (2H, s), 6,88-6,98 (3H, m), to 7.15 (1H, d, J=8,4 Hz), 7,37 (1H, t, J=8.0 Hz), 7,54 (2H, d, J=8,8 Hz), to 7.61 (1H, d, J=7,2 Hz), 7,68 (1H, s), to 7.84 (2H, d, J=8,8 Hz), 8,79 (1H, s) to 10.4 (1H, s).

EXAMPLE 76

Under ice cooling to a mixture of tert-butyl 2-[3-[2-(4-tert-butyl-2-thiazolyl) ethoxy]benzoylamine]-4-[3-(4-chlorophenylsulfonyl propyl] phenoxyacetate (185 mg, 0.25 mmol) and dichloromethane (2 ml) is added triperoxonane acid (1.2 ml). The resulting reaction solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure, the obtained residue is added saturated aqueous sodium bicarbonate solution, and the resulting product is extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue is dissolved in water, and the pH of the solution was adjusted to 2 by adding 10% aqueous RA is Oh chromatography on silica gel (eluent = chloroform: methanol = 50:1). Get hemihydrate 2-[3-[2-(4-tert-butyl-2-thiazolyl)ethoxy] benzoylamine] -4- [3-(4-chlorophenylsulfonyl)propyl]phenoxyalkanoic acid (58 mg, 0,086 mmol, 34%).

Elemental analysis data (for C33H35N2S2O7Cl 0.5 H2O)

Calculated, %: C 58,27; H 5,33; N 4,12; S 9,43; Cl to 5.21;

Found, %: C 58,56; H And 5.30; N 4,12; S At 9.53; Cl 4,90.

Spectrum of nuclear magnetic resonance (DMSO-d6, TMS internal standard).

: 1,28 (N, C), 1,78-to 1.87 (2H, m), 2,61 (2H, t, J=7.2 Hz), 3,30-to 3.35 (2H, m), 3,44 (2H, t, J=5.8 Hz), to 4.41 (2H, t, J=5.8 Hz), 4,74 (2H, s) 6,91 (1H, d, J=7,6 Hz), 7,00 (1H, d, J=8,4 Hz), 7,12 (1H, s), 7,19 (1H, d, J=8.0 Hz), was 7.45 (1H, t, J= 7.8 Hz), 7,52-EUR 7.57 (2H, m), 7,73 (2H, d, J=8,3 Hz), 7,79-7,80 (1H, m), 7,89 (2H, d,J=8,3 Hz), 9,62 (1H, s), and 13.2 (1H, s).

EXAMPLE 77

Under ice cooling, the ethyl 2-[3-[(4-tert-butyl-2-thiazolyl) methoxy]benzoylamine]-4-[3-(4-chlorophenylsulfonyl)propyl] phenoxyacetate (266 mg, 0,39 mmol) are added to a mixture of 60% sodium hydride (19 mg, 0.48 mmol) and dimethylformamide (2 ml), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was again cooled with ice, add methyliodide (29 μl, 0.47 mmol) and the mixture stirred at room temperature for 2 hours. To the reaction mixture, water is added, and the resulting product is extracted with the sodium and then concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (eluent = chloroform:methanol = 50:1). Obtain ethyl 2-[N-[3-[(4-tert - butyl-2-thiazolyl)methoxy]benzoyl]-N-methylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]phenoxyacetate (213 mg, 0.31 mmol, 78%).

The data of mass spectrometry (m/z): 699 [(M+N)+]

Spectrum of nuclear magnetic resonance (CDCl3, TMS internal standard).

: 1,29 (2H, t, J=6.8 Hz), 1,35 (N, C), a 1.75-of 1.85 (2H, m), 2,41 - of 2.58 (2H, m), 2,69-of 2.86 (2H, m) to 3.38 (3H, s), 4.26 deaths (2N, K, J=8,8 Hz), to 4.62 (2H, s), is 5.18 (2H, ush), 6,56-6,74 (2H, m), 6,80-7,10 (6N, m), 7,52 (2H, d, J=8,3 Hz), EUR 7.57 (2H, d, J =8,3 Hz).

EXAMPLE 78

Dimethylformamide (13 ml) is added to a mixture of 3-[(4-tert-butyl-2-thiazolyl) methoxy] -5'-[3-(4-chlorophenylsulfonyl)propyl] -2'-cinemacasinoenligne (1,30 g, 2.04 mmol), ammonium chloride (0.20 g, 4,08 mmol) and sodium azide (0.25 g, 4,08 mmol) and the resulting mixture was stirred at 70oC for 12 hours. To the reaction solution was added ice and 5% aqueous solution of sodium hydrosulphate, and the resulting product is extracted with ethyl acetate. The obtained organic layer was washed with water and brine in sequence, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue Ocarina. Receive 3-[(4-tert-butyl-2-thiazolyl) methoxy]-5'-[3-(4-chlorophenyl-sulfonyl)propyl] -2'- (1-tetrazol-5-ylethoxy)benzanilide (1,02 g, 78%) as colorless crystals.

The pace. melting point: 161-163oC.

Elemental analysis data (for C32H33N6O5S2Cl)

Calculated, %: C 56,42; H 4,88; N 12,34; S 9,41; Cl 5,20;

Found, %: C 56,27; H 4,90; N 12,38; S 9,43; Cl 5,18.

In the same way described in example 8, to obtain the following compound of example 79.

EXAMPLE 79

Hydrate 2-[2-[3-(4-tert-butyl-2-thiazolyl)methoxy] benzoylamine]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxy-2-forexpros acid.

The pace. melting point: 88-90oC.

Elemental analysis data (for C32H32N2FS2O7Cl H2O)

Calculated, %: C 55,44; H 4,94; N OF 4.04; F 2,74; S 9,25;

Found, %: C 55,55; H 5,00; N Was 4.02; F 2,54; S 9.28 Are.

EXAMPLE 80

A mixture of 5'-[3-(4-chlorophenylsulfonyl)propyl]-2'- hydroxy-3-(6-methoxy-2-benzothiazolylazo)benzanilide (301 mg, 0.48 mmol), potassium carbonate (135 mg, 0.98 mmol), ethylbromoacetate (81 mg, 0.48 mmol) and dimethylformamide (5 ml) was stirred at room temperature for 12 hours. To the reaction solution was added water, and the resulting product is extracted with ethyl is the atrium and then concentrated under reduced pressure. To the obtained residue, add tetrahydrofuran (2 ml), methanol (1 ml) and 1N sodium hydroxide, and the mixture is stirred at room temperature for 12 hours. The reaction solution is concentrated, and to the obtained residue, add water. Then pH of the mixture was adjusted to 3 with 10% aqueous citric acid solution. After that, the formed solid is collected by filtration and washed with acetonitrile. Receive 4-[3-(4-chlorophenylsulfonyl)propyl]-2-[3-[(6-methoxy-2-benzothiazolyl) methoxy] benzoylamine] Phenoxyethanol acid (145 mg, 0.21 mmol, 44%).

The pace. melting point: 187-189oC.

Elemental analysis data (for C33H29N2S2O8Cl)

Calculated, %: C 58,19; H 4,29; N 4,11; S 9,41; Cl 5,20;

Found, %: C 58,09; H 4,48; N 4,12; S 9,46; Cl 5,00.

The structure of the compounds of examples 43 to 80 are shown in tables 31-38.

EXAMPLE 81

Under ice cooling to a mixture of 4-[2-(2-benzothiazolyl)vinyl] -5'-[3-(4-chlorophenylsulfonyl)propyl] -2'-hydroxybenzamide (307 mg, 0.52 mmol), potassium carbonate (145 mg, 1.05 mmol) and dimethylformamide (10 ml) is added dropwise, ethylbromoacetate (87 mg, 0.52 mmol) and the resulting reaction solution was stirred at room temperature for 12 hours. To the reaction solution we use is in the sequence, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel (eluent=hexane:ethyl acetate=4:1). Get ethyl 2-[4-[2-(2- benzothiazolyl)vinyl] benzoylamine] -4-[3-(4-chlorophenylsulfonyl) propyl] phenoxyacetate (219 mg, 0.32 mmol, 62%) as a colourless solid.

In the same way described in example 81, synthesize the following compounds of examples 82 to 89. Structure and physico-chemical properties of these compounds are shown in tables 21-24.

In this regard, the position of the binding, are shown in the tables, indicates the position of the binding.

< / BR>
in the General formula (1). The same shall apply below.

EXAMPLE 82

Ethyl 2-[3-(2-benzothiazolylthio)benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl] PHENOXYACETIC.

EXAMPLE 83

Ethyl 2-[3-[2-(2-benzothiazolyl)vinyl] benzoylamine] -4[3- (4-chlorophenylsulfonyl)cut phenoxyacetate.

EXAMPLE 84

Ethyl 2-[3-[2-benzothiazolyl)thiomethyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]PHENOXYACETIC.

EXAMPLE 85

Ethyl 2-[3-[2-(5-chloro-2-benzothiazolyl)vinyl] benzoylamine] -4-[3-(4-chlorophenylsulfonyl)propyl] PHENOXYACETIC roxicet.

EXAMPLE 87

Ethyl 2-[3-(5-chloro-2-benzothiazolylazo)benzoylamine] -4-[3-(4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

EXAMPLE 88

Ethyl 4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-(5- trifluoromethyl-2 - benzothiazolylazo)benzoylamine of phenoxyacetate 0.5 hydrate.

EXAMPLE 89

1,1-Dimethylethyl 2-[3-(2-benzothiazolylthio)benzoylamine] -4- [3-(4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

EXAMPLE 90

To a mixture of ethyl 2-[4-[2-(2-benzothiazolyl)vinyl]benzoylamine]-4- [3-(4-chlorophenylsulfonyl)propyl] phenoxyacetate (196 mg, 0.29 mmol) and tetrahydrofuran (10 ml) at room temperature, add 10% aqueous sodium hydroxide solution (6 ml), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, to the residue water is added, and then pH of the solution was adjusted to 1 by adding concentrated hydrochloric acid. After that, the formed solid is collected by filtration, washed with water and ether in this order, dried under reduced pressure and then recrystallized from ethanol (50 ml). Get 2-[4-[2-(2-benzothiazolyl)vinyl]benzoylamine]-4-[3-(4-chlorophenylsulfonyl)propyl] Phenoxyethanol acids which have the following connection examples from 91 to 97, represented by the General formula (1). Structure and physico-chemical properties of these compounds are shown in tables 25-26.

EXAMPLE 91

2-[3-(2-Benzothiazolylthio)benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid 0,3 H2O.

EXAMPLE 92

2-[3-[2-(2-Benzothiazolyl)vinyl] benzoylamine] -4- [3-(4-chlorophenylsulfonyl)propyl]venexiana acid 0.5 H2O.

EXAMPLE 93

2-[3-[(2-Benzothiazolyl)thiomethyl] benzoylamine]-4-[3-(4- chlorophenylsulfonyl]propyl]venexiana acid.

EXAMPLE 94

2-[3-[2-(5-Chloro-2-benzothiazolyl)vinyl]benzoylamine]-4-[3- (4-chlorophenylsulfonyl)propyl]venexiana acid 0.5 H2O.

EXAMPLE 95

2-[3-(2-Benzoxazolinone)benzoylamine] -4-[3-(4-chlorophenylsulfonyl) propyl]venexiana acid.

EXAMPLE 96

2-[3-(5-Chloro-2-benzothiazolylazo)benzoylamine]-4-[3- (4-chlorophenylsulfonyl)propyl]venexiana acid.

EXAMPLE 97

4-[3-(4-Chlorophenylsulfonyl)propyl] -2-[3-(5- trifluoromethyl-2-benzothiazolylazo)benzoylamine]phenoxyalkanoic acid hydrate.

In the same way described in example 81, synthesize the following compounds of examples from 98 to 102. Structure and physico-hemicellulose)benzoylamine] -4-[3-(4-chlorophenylsulfonyl)propyl]PHENOXYACETIC.

EXAMPLE 99

Ethyl 2-[3-[2-(2-benzothiazolyl)ethyl]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]PHENOXYACETIC.

EXAMPLE 100

2-[2-[3-(2-Benzothiazolyl)methoxy]benzoylamine]-4-[3-(4- chlorophenylsulfonyl)propyl]PHENOXYACETIC.

EXAMPLE 101

3-[2-(2-Benzothiazolylthio)benzoylamine] -5'-[3- (4-chlorophenylsulfonyl)propyl]-2'-(cyanoethoxy)benzanilide.

EXAMPLE 102

Ethyl 2-[3-(2-benzoxazolyl)benzoylamine] -4-[3-(4 -chlorophenylsulfonyl)propyl]PHENOXYACETIC.

In the same way described in example 90, synthesize the following compounds of examples from 103 through 106. Structure and physico-chemical properties of these compounds are shown in table 29.

EXAMPLE 103

2-[3-(6-Chloro-2-benzothiazolylazo)benzoylamine] -4- [3-(4-chlorophenylsulfonyl)propyl]venexiana acid 0.5 hydrate.

EXAMPLE 104

2-[3-[2-(2-Benzothiazolyl)ethyl] benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl] venexiana acid, 0.3 hydrate.

EXAMPLE 105

2-[3-(2-Benzothiazolylthio)benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]venexiana acid.

EXAMPLE 106

N-[[2-[3-(2-Benzothiazolylthio)benzoylamine] -4-[3- (4-chlorophenylsulfonyl)propyl]phenoxy]acetyl]glycine.

The pace. melting point: 153oC.

Elemental analysis data (for C33H30N3O8S3Cl0,5H2O)

Calculated, %: C 53,76; H 4,24; N 5,70; S Of 13.05; Cl 4,81;

Found, %: C 53,95; H 4,11; N Of 5.82; S 13,00; Cl 4,85.

In the same way described in example 107, synthesize the following compound.

EXAMPLE 108

2-[2-[3-(2-Benzothiazolylthio)benzoylamine] -4-[3-(4- chlorophenylsulfonyl)propyl]phenoxy]-N-(2-methylphenylsulfonyl)ndimethylacetamide.

The pace. melting point: 157oC.

Elemental analysis data (for C39H34N

EXAMPLE 109

Under ice cooling to a mixture of 2-[3-(2-benzothiazolylthio) benzoylamine] -4-[3-(4-chlorophenylsulfonyl)propyl] phenoxyalkanoic acid (400 mg, of 0.62 mmol), hydrochloride of glycinamide (86 mg), 1-hydroxybenzotriazole (125 mg), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (130 mg) and N,N-dimethylformamide (10 ml), add triethylamine (220 μl).

The resulting mixture was stirred at room temperature for 12 hours. To the reaction solution was added water and ethyl acetate. The resulting insoluble solid is collected by filtration, washed with ethyl acetate, water, 1N hydrochloric acid, water, ether, 1N aqueous sodium hydroxide solution, water and ether in this order, and then dried under reduced pressure. To the obtained solid substance added acetonitrile (13 ml) and the mixture is refluxed for 5 minutes with stirring and then cooled. The resulting crystals are collected by filtration.

Get N- [[2-[3-(2- benzothiazolylthio)benzoylamine]-4-[3-(4-chlorophenylsulfonyl)propyl] phenoxy]acetyl]glycinamide (170 mg, 0.24 mmol, 39%) as colorless crystals.

The pace. melting point: 186-188oC.

Data ele is>/BR>Found, %: C 57,57; H 4,32; N To $ 7.91; S 9,29; Cl 4,89.

In the same way described in example 109, synthesize the following compound.

EXAMPLE 110

Hydrate Ethyl N-[[2-[3-(2-benzothiazolylthio)benzoylamine] -4-[3- (4-chlorophenylsulfonyl)propyl]phenoxy]acetyl]glycine.

The pace.melting point: 132-133oC.

Elemental analysis data (for C36H34N3O8S2Cl H2O)

Calculated, %: C 57,33; H to 4.81; N 5,57; S 8,50;

Found, %: C 57,68; H Of 4.54; N 5,55; S 8,60.

EXAMPLE 111

A mixture of 3-[2-(2-benzothiazolylthio)benzoylamine] -5'-[3- (4-chlorophenylsulfonyl)propyl] -2'-(cyanoethoxy)benzanilide (390 mg of 0.62 mmol), azide presence of TBT (4,2 g) and toluene (6 ml) is stirred for 2 hours while boiling under reflux. The reaction solution is cooled and concentrated under reduced pressure. To the obtained residue is added methanol (15 ml) and 1N hydrochloric acid (15 ml), and the mixture is stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure, and to the obtained residue, add water and hexane. The resulting insoluble solid is collected by filtration and washed with 1N hydrochloric acid and hexane in the specified posledovatelyam for 5 minutes with stirring and then cooled. The obtained solid is collected by filtration. Get 3-(2-benzothiazolylthio)-5'-[3-(4-chlorophenylsulfonyl)propyl] -2'- (1H-tetrazol-5-ylethoxy) benzanilide (270 mg, 0,39 mmol, 63%) as colorless crystals.

The pace. melting point: 189-191oC.

Elemental analysis data (for C32H27N6O5S2Cl)

Calculated, %: C 56,93; H is 4.03; N 12,45; S 9,50; Cl 5,25;

Found, %: C 56,64; H 3,94; N 12,31; S 9,42; Cl 5,28.

The structure of the compounds of examples 107 through 111 are shown in tables 38 and 39.

1. Derivative azole General formula I

< / BR>
where R1represents a hydrogen atom, a C3- C6cycloalkyl group, lower alkyl or phenyl which may be substituted by lower alkyl;

R2represents hydrogen or lower alkyl,

or R1and R2combined with ring

< / BR>
may form a condensed ring represented by the formula

< / BR>
which may be substituted by lower alkyl which may be substituted by halogen atoms; a halogen atom or a lower alkoxyl; or by the formula

< / BR>
R3represents a hydrogen atom, an amino group, a nitro-group, a halogen atom, a lower alkoxy or lower alkyl;

R6, R7and R
R4represents a cyano, tetrazolyl, a group of the formula-COOR9or a group of formula-E - NH - F - R10,

R9represents a hydrogen atom or lower alkyl;

E represents a single bond or a carbonyl group;

F represents a single bond or lower alkylene;

R10represents a hydrogen atom, karbamoilnuyu group, carboxyl group, lower alkoxycarbonyl group, a lower alkanoyl, lower alkylsulfonyl; or arylsulfonyl, which may be substituted by lower alkyl;

R5represents a hydrogen atom or lower alkyl;

D is the lowest alkylene, which may be substituted by a halogen atom;

X represents a sulfur atom or an oxygen atom;

Z represents an oxygen atom or a sulfur atom;

Y represents a nitrogen atom (-N=) or methine group (-CH=);

A represents a group of formula: -B - O-, -S - B-, -B - S - or-B- ;

B represents the lower alkylene or lower albaniles;

n = 2,

or its pharmaceutically acceptable salt, hydrate or MES.

2. Derived asola, its pharmaceutically acceptable salt, hydrate or MES under item 1, where R4is 1) tetrazolyl, 2) a group of the formula-COOR9where R9- atom F - single bond or a lower alkylene, and R10is a hydrogen atom, carnemolla group, carboxyl, lower alkoxycarbonyl, lower alkanoyl, lower alkylsulfonyl or arylsulfonyl, which may be substituted by lower alkyl.

3. Derived asola, its pharmaceutically acceptable salt, hydrate or MES under item 1, where X represents a sulfur atom.

4. Derived asola, its pharmaceutically acceptable salt, hydrate or MES under item 1, where Y represents a methine group (-CH=).

5. Derived asola, its pharmaceutically acceptable salt, hydrate or MES under item 2, where R1represents a hydrogen atom, a C3- C6cycloalkyl group, a lower alkyl, a phenyl group which may be substituted by lower alkyl, R2represents a hydrogen atom or lower alkyl, or R1and R2can be combined with ring

< / BR>
forming a condensed ring represented by the formula

< / BR>
which may be substituted by lower alkyl which may be substituted by 1 to 3 halogen atoms; a halogen atom or a lower alkoxygroup; or by the formula

< / BR>
D - represents the lowest alkylene, which may be substituted by a halogen atom.

6. Derived Azola alkiline group, lower alkyl or phenyl group which may be substituted by lower alkyl, R2represents a hydrogen atom or lower alkyl, each of R3, R6and R7represents a hydrogen atom, R8represents a halogen atom, R5represents a hydrogen atom, D represents a methylene, X represents a sulfur atom, Y represents the group (-CH=), Z represents an oxygen atom, A represents a group of formula: -CH2O - and n = 2.

7. Derived Azola under item 1, selected from the group consisting of:

2-[3-(4-tert-butyl-2-thiazoleacetate)benzoylamine] -4-[3-(4-chlorophenylsulfonyl)propyl] Phenoxyethanol acid,

4-[3-(4-chlorophenylsulfonyl)propyl] -2-[3-[(4-cyclobutyl-2-thiazolyl)methoxy]benzoylamine]Phenoxyethanol acid,

3-[(4-tert-butyl-2-thiazolyl)methoxy]-5'-[3-(4-chlorophenylsulfonyl)propyl] -2'-(1H-tetrazol-5-ylethoxy)benzanilide,

3-(2-benzothiazolylthio)-5'-[3-(4-chlorophenylsulfonyl)propyl] -2'-(1H-tetrazol-5-ylethoxy)benzanilide, or their pharmaceutically acceptable salt, hydrate or solvate.

8. The derived 2-hydroxyanisole, represented by the following formula IVc

< / BR>
where R6aand R7athat may be the same or different, and each represents a hydrogen atom Il is represented by the following General formula IIIa

< / BR>
where R1arepresents a hydrogen atom, a C3- C6cycloalkyl group, lower alkyl or phenyl group;

R2arepresents a hydrogen atom,

or R1aand R2acan be combined with ring

< / BR>
forming a condensed cycle represented by the formula

< / BR>
R3represents a hydrogen atom, an amino group, a nitro-group, a halogen atom, a lower alkoxygroup or lower alkyl;

Rarepresents a hydrogen atom or lower alkyl,

or its pharmaceutically acceptable salt.

10. The pharmaceutical composition active antagonist of leukotriene and thromboxane A2comprising an active ingredient and a pharmaceutically acceptable carrier, characterized in that as the active ingredient it contains a derived azole according to any one of paragraphs.1 - 7, its pharmaceutically acceptable salt, hydrate or MES in an effective amount.

Priority points and features:

14.10.1994 - PP.1 - 6, 10: if R1is a hydrogen atom, a C3- C6cycloalkyl group, lower alkyl or phenyl which may be substituted, R2is hydrogen, R3is a hydrogen atom, amino group, the nitro-group, a halogen atom or is a group of the formula-COOR9or a group of formula-E - NH - F - R10; R9is a hydrogen atom or lower alkyl; E is a single bond or a carbonyl group; F is a single bond or lower alkylene; R10is a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl; R5is a hydrogen atom; D is the lowest alkylene; X is a sulfur atom (S); Z is an oxygen atom (O); Y is a methine group (-CH= ); A group of the formula: -B - O-, -S - B-, -B - S - or-B-; B - lower alkylene or lower albaniles, and n = 2; p. 7: the first three in the course of the narrative connection; p. 8: if R6aand R7ais a hydrogen atom; p. 9: if R1ais a hydrogen atom, a C3- C6cycloalkyl group, lower alkyl or phenyl group; R2ais a hydrogen atom, R3is a hydrogen atom, amino group, the nitro-group, halogen atom or lower alkyl, Rais a hydrogen atom or lower alkyl;

18.10.1994 - PP.1 - 6, 10: if R2is lower alkyl, R4is cyano, R10- carnemolla group, carboxyl group, lower alkoxycarbonyl group or arylsulfonyl, which may be substituted by lower alkyl; X is an oxygen atom (O); p. 7: fourth during the presentation of the connection;

12.10.1995 - PP.1 - 6, 10 at R1and R2that combined with the ring

< / BR>
may form a condensed ring, predstavlja or lower alkoxyl; or formula

< / BR>
R3lowest alkoxyl; R6, R7and R8that may be the same or different from each other and each represents a hydrogen atom or halogen atom; R5is lower alkyl; D is the lowest alkylene, which may be substituted; Z is a sulfur atom (S); Y is a nitrogen atom (-N=); p. 8: when6aand R7athat may be the same or different, and each represents a hydrogen atom or a halogen atom; p. 9: if R1aand R2awhich can be combined with ring

< / BR>
forming a condensed cycle represented by the formula

< / BR>
R3- lower alkoxygroup; p. 11.

 

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The invention relates to new derivatives of azetidinone General formula (I) in which R, R1, Ar1-Ar3X, Y, m, n, q and r are specified in the claims values, and their pharmaceutically acceptable salts, which are the active ingredient of the pharmaceutical composition with anti-atherosclerotic or hypocholesterolemic activity

The invention relates to medicine

The invention relates to new nitrogen-containing heterocyclic compounds which possess valuable biological properties, in particular derived cycloalkane-indole-azaindole, mixtures of their isomers, or individual isomers and their pharmaceutically acceptable salts, derivatives of carboxylic acid as starting compounds and pharmaceutical compositions inhibiting the release associated with apolipoprotein B - 100 lipoproteins
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