Salicylic acid derivatives, their alkalemia esters containing from 1 to 6 carbon atoms in the ether group, a salt and a solvate

 

(57) Abstract:

The invention relates to new derivatives of salicylic acid f-ly Gets-NR-SO2-Ph1A Ph2(COOH)(OH), (I), where Het represents (R1, R2, R3-Het1That gets1represents a cyclic system in which the free valence is associated with a group NR; X is a group: a) -O-CH=CH-, -CH=CH-O-, -CH= CH-S - or b) -CH=CH-CH=CH-, -CH=CH-CH=N-, -CH=N-CH=CH-, -CH=CH-N=CH-, -N= CH-CH= CH-; R1, R2and R3are substituents at the carbon atom in Het and represent hydrogen, C1-C6- alkyl, halogen, hydroxy - or benzyloxy; R is hydrogen or C1-C6- alkyl; Ph1- phenylene, Ph2is phenyl which may be substituted with halogen, lower alkyl or benzyloxypropionic, provided that the carboxy - and hydroxy-group are in the ortho-position to each other; And a represents - CC-, -CH=CH-, -CH2-CH2-, -CO-CH=CH-, -CH=CH-CO-. Connections F.-ly (I) is produced by interaction of compounds (R1, R2, R3) -Het1-NRH and ClSO2Ph1A Ph2(COOH)(OH). Substances (I) have a high immunomodulatory activity and can be used to treat ulcerative colitis, rheumatoid arthritis, psoriasis. 14 C.p. f-crystals, 5 PL.

N=N-(A-), split when restoring, with ring benzosulfimide, which in turn liderovna on amine group aminosilanes heterocyclic ring which contains conjugated double bonds, can exhibit a therapeutic effect against ulcerative colitis, rheumatoid arthritis and other diseases that are autoimmune (see, for example, the U.S. patents of Accelera and other 2396 145 and Agbeko and Kiev 3915 951; article So Pullara in Brit. W. the clinically. pharmacology, volume 30, pages 501-510 (1990), L., Tumanov, I. A. Segedin, Ter. Arch., volume 59, pages 80-83 (1987), S. Pacheco, K., Hillier, K. L. Smith, Brasil. journal of honey. Biol. research, volume 23, pages 1323-34 (1990) and Ph.D. Astbury, and others, Brit. W. rheumatology, vol. 29, pp. 465-467 (1990). In addition, autoimmune diseases are described and characterized by the examples in the book And. Roitt, J. Brostoff, e Mail, Immunology, 2nd ed., 1989).

The most well-known substance having the above therapeutic effect is sulfasalazin. Although analogues of sulfasalazin described, still none of them is recognized as an acceptable drug.

Sulfasalazin is clinically effective in the treatment of autoimmune diseases, such as ulcerative colitis, rheumatoid the a and X. Chapel: Bailliers Clin. Rheumat., so 4, p. 535-551 (1990); M. Ferrasi and other J. Rheumat., so 17, S. 1482-1486 (1990); A. Gupta and other Arch. Dermatol., so 126, S. 487-493 (1990); G. Watkinson, Drugs, etc 32 (I), S. 1-11 (1986)).

Medicines, which are mainly assigned for the treatment of rheumatoid arthritis, are anti-inflammatory agents, so-called non-steroidal anti-inflammatory drugs. It is believed that these non-steroidal anti-inflammatory medicines act against the symptoms of this disease. On the other hand, sulfasalazin classified as a drug, modifying the disease. In addition, the same group of medicines belong to gold salts, penicillamine, chlorine and medicines that suppress the immune system, methotrexa, azathioprine and cyclophosphamide, which all have a fundamentally different structure.

There are a number of pharmacological model systems for evaluation of medicines that can potentially be used to treat autoimmune diseases. One of the most important properties of nonsteroidal anti-inflammatory drugs in such model systems is their ability to inhibit the synthesis of prostaglandin and related biological effects.

amento in such model systems as clinically and experimentally. Sulfasalazin has been described in several models, and it was confirmed that it can be considered to describe the effective component, modifying the disease. For example, it was shown that the activation of immune and inflammatory cells affects sulfasalazin, because it inhibits the activation and proliferation of T-lymphocytes, and activation of granulocytes and release of mediators.

In the treatment of ulcerative colitis clinical effect of sulfasalazin was attributed to 5-aminosalicylic acid, which is formed by reductive cleavage of the parent molecule in the colon. Simultaneously formed sulfapiridin. In the treatment of other autoimmune diseases such as rheumatoid arthritis, it is believed that the effective component is intact molecule sulfasalazin, or eye-catching sulfapiridin, or, most likely, both. It is believed that essentially the secondary effects of sulfasalazin associated with the eye-catching sulfapyridine.

We have now discovered a new type of analogues of sulfasalazin that have good bioavailability, and efficacy in models of COI is ti analogs have the structure above, but they azo-group (A) is substituted by a bridge, which is stable against hydrolysis and/or restoration in the body, for example in the colon. Such substances are new. Thus, in its broadest sense, the invention includes substances patterns 1

Gets-NR-SO2Ph1A Ph2(COOH)(OH)

and taumarunui forms, salts and solvate, not necessarily complex alkalemia esters with 1 to 6 carbon atoms in the carboxyl group.

In the above structure 1 Het is a heterocyclic ring, Ph1is a benzene ring, Ph2(COOH)(OH) represents a benzene ring with a carboxy - and hydroxy groups in ortho-position, R is hydrogen or lower alkyl (C1-C6. The group Gets, Ph1Ph2(COOH)(OH) and A bridge can be replaced.

These substances are distinguished by the fact that a is a bridge, which is stable against hydrolysis and /or recovery in biological systems. Preferably A represents a carbon chain of normal structure, having at most 3 carbon atom (-C-C-C-), which includes single, double or triple carbon-carbon connection, not necessarily oxo-substituent (= O) when one of the atoms ug is Satna communication, such as azo-and not necessarily unstable at the hydrolysis of ester and amide linkages, as the connecting structure between Ph1and Ph2.

In specific embodiments, the embodiment of Ph1is 1,4 - or 1,3-substituted benzene and Ph2(COOH)(OH) is ortho-carboxy-hydroxy substituted phenyl, which may not necessarily be optionally substituted with halogen or lower alkyl (C1-C6), preferably the stands, in its regulations 3, 4, or 6. Group-A is - a-CC- , -CH=CH-, -CH2CH2-, -CO-CH=CH-, -CH=CHCO-, -CH2CO.

In specific embodiments, the embodiment of the compounds of the invention heterocyclic ring Het is a five-membered or six-membered having 2 and 3 conjugated double bonds, respectively. Heterocyclic ring Het may be included in a monocyclic or bicyclic structure. Preferably Het - is a

(R1, R2, R3)-Het'-,

where Het' represents a group

< / BR>
in which the free valence is associated with NR; and X represents a

a) -N= CH-NH-, -N=CH-S, N=CH-O-NH-N=CH-O-CH=CH-, -CH=CH-O-, -NH-CH= CH, -CH=CH-NH, -CH=CH-S-, -CH=N-NH, or

b) -CH= CH-CH= CH-, -CH=CH-CH=H-, -CH=N-CH=CH-, -CH=CH-N-CH-, -N=CH-CH= CH-, where mutually adjacent, bold ASS="ptx2">

R is a hydrogen atom or a lower alkyl (C1-C6preferably hydrogen or stands.

R1, R2and R3are substituents at the carbon atom in-Het'. These groups can represent a hydrogen atom, a lower alkyl (C1-C6), halogen, hydroxy-, cyano-, carboxy-, lower alkoxy- (C1-C6), benzyloxy-, lower acyl (C1-C7), including acetyl, benzoyl, phenyl, benzyl, etc. in which any of the common benzene rings may be substituted.

In all the described parts and the claims of this application, the terms lower alkyl and lower acyl mean groups which contain, respectively, 1-6 and 1-7 carbon atoms, optionally with substituents described above.

A represents-C= C-, not necessarily substituted lower alkyl TRANS - or CIS-CH= CH-, CH2-CH2-, -CO-CH=CH-, -CH=CH - CO-, -CO-, -CH2-CO-, -CH2-, preferably-CC - or TRANS-CH= CH-; Ph2represents a C6H2R4where R4is a hydrogen atom, halogen or lower alkyl, preferably hydrogen atom or stands; and their tautomeric forms and salts with alkali metals, preferably sodium, calcium or mamacitas acceptable solvents, such as for example, water, acetone and ethyl alcohol, and their pharmaceutical compositions.

This invention also relates to the use of substances as medicines, mainly for the treatment of autoimmune diseases by analogy with the use of sulfasalazin and potentially also for the treatment of other inflammatory conditions. Other aspects of the invention include obtaining these substances and the preparation of pharmaceutical compositions containing the aforementioned substances and intended for the following medical indications.

The substances according to the invention have in biological systems immunomodulatory effects, for example by inhibiting the activation of immune and inflammatory cells and their pharmaceutical profile similar to sulfasalazin, but often higher activity. Therefore, the substances of the invention are potential drugs for the treatment of autoimmune diseases such as ulcerative colitis, rheumatoid arthritis, ankylosis spondylitis, reactive arthritis, psoriasis, psoriatic arthritis, multiple sclerosis Morbus Crohn's, type 1 diabetes, scleroderma, severe muscle weakness syndrome Jergens system in the treatment of other diseases, in particular, such diseases that have an immunological component, regardless of whether these substances in scientific medicine or are not known.

Because due to the specific structure of these new substances, they are not able to form sulfapiridin or any other toxic counterparts, it is likely that for these substances there are no side effects inherent in the free sulfapyridine. Our experiments demonstrated that the substances of the invention often have a significantly higher biological suitability for laboratory animals than sulfasalazin and its analogs.

In General, these new substances should be very profitable as drugs for the treatment of autoimmune diseases. New substances of the invention can be obtained in different ways.

One method involves the interaction of a substance II substance III

(R1, R2, R3)-Het'-NH-SO2-Ph1-X

Y-C6H2-R4, (COOR5)(OH)

where R, R1, R2, R3, R4Ph1and Gets' have the same values as above, R5is a hydrogen or preferably lower alkyl, with boliche and CH2=CH-; -CO-CH3and HCO; -CHO and CH3CO-; -CH2COZ2and H; and Z3CH2-; -CH2Z3and HCO-, in which Z1is bromine atom or iodine, Z2represents a halogen atom, preferably chlorine, and Z3is a remnant of the organophosphorus compounds of the type of Wittig reagent, for example triphenylphosphonio group or dialkylphosphate group.

Substance II and III are combined together in a known manner, after which, when R5is lower alkyl, the product of the combination is subjected to hydrolysis, preferably in the presence of alkali metal hydroxide, then the product is acidified and then allocate.

When X and Y - are-CCH and Z1or-Z1and HCC - mentioned combination process is preferably carried out in the so-called for the Heck reaction involving catalysis compound of palladium and a compound of copper in the presence of base and solvent. Suitable palladium compounds are dichlorobis(triphenylphosphine)palladium, dichlorobis-(Tris(2-methylphenylethyl)palladium or tetrakis(triphenylphosphine)palladium. Optionally, a suitable compound of palladium can be prepared in the reaction mixture by using, nbis)diphenylphosphino)propane and other Suitable copper compounds are iodata copper (I) or copper bromide (I). Suitable bases are amines, preferably tertiary amines, such as, for example, terramin or tributylamine or other inorganic or organic bases, such as for example, sodium bicarbonate or sodium acetate. Suitable solvents are, for example, N,N-dimethylacetamide, N,N-dimethylformamide, ethanol, acetone, tetrahydrofuran, dioxane, toluene, etc., preferably N,N-dimethylacetamide.

When X and Y represents-CH=CH2and Z1or-Z1and CH2-CH-mentioned combination process is preferably carried out in the so-called for the Heck reaction involving catalysis compound of palladium in the presence of base and solvent. Suitable palladium compounds are inorganic and organic salts of palladium such as palladium chloride (II) or palladium (II) acetate. Optionally, these salts can be stabilized available ligands, such as, for example triphenylphosphine, for example in the form of dichlorobis(triphenylphosphine)palladium. An alternative can be used in connection zero-valent palladium, such as for example, bis(dibenzylideneacetone)palladium is, the triethylamine or inorganic bases such as for example, sodium bicarbonate or sodium acetate. Suitable solvents are for example, N,N-dimethylacetamide, N,N-dimethylformamide, toluene, tetrahydrofuran, dioxane, acetone, etc.

Although the substance of the formula (R1, R2, R3)-Het'-NR-SO2-Ph1-X, where X is atenolol, can be obtained in different ways, each of which is known, preferably the substance is produced by the interaction of matter of the formula (R1, R2, R3)-Het'-NR-SO2-Ph1-X, where X is bromine atom or iodine, with ethylene in the presence of catalytic amounts of palladium compounds, bases and solvents, and used catalysts and solvents of the same type as in the reaction between II and III substances. Another method involves partial recovery etinilnoy connection with gaseous hydrogen in the presence of a catalyst suitable for this purpose.

The substance of formula II, where X is bromine atom or iodine, get in a known manner, for example by interaction of the corresponding halogenated.sulphonated with the appropriate heterocyclic amine in the presence of a base, for example in ivystone-CO-CH3and HCO or-CHO and CH3CO-mentioned combination is carried out in a known manner in the presence of a solvent and a basic or acidic condensing agent. Suitable bases are for example sodium hydroxide or potassium hydroxide. Suitable acids are strong mineral acids such as hydrochloric acid or sulfuric acid. Suitable solvents are water, lower alcohols or mixtures thereof. The compound of formula II, where X represents a-CO-CH3or-CHO, get in a known manner, for example by interaction of formylbenzenesulfonic or acetylbenzenesulfonyl with the appropriate heterocyclic amine in the presence of a base, for example in excess of pyridine or heterocyclic amine.

When X and Y in formulas II and III are, respectively,- CH2COz2and H-, the interaction is carried out in a known manner under the reaction conditions of Friedel -, in the presence of a Lewis acid, preferably aluminum chloride in an inert solvent, such as for example chlorinated hydrocarbons. Compound II, where X represents-CH2COz2get a known manner, for example saimona in the presence of a base, for example in excess of pyridine or heterocyclic amine, after which the amine intermediate is hydrolyzed to the corresponding carboxylic acid, and acid halogenides in a known manner, for example by interaction with thionyl chloride or phosphorus halide.

Another method involves reacting a substance of the formula IV with a substance of formula V

(R1, R2, R3)-Het'-NRH

ClSO2-Ph1-A-C6H2-R4(COOR5)(OR6)

which Gets', R1, R2, R3, R4and R5have the same meaning indicated above and R6is lower acyl, preferably acetyl, or a residue of aliphatic or aromatic sulfonic acid, preferably methylsulfonyl or paratoluenesulfonyl; in the presence of a solvent and a basic condensing agent, and a basic condensing agent may be a substance IV in excess, or preferably an organic base, for example pyridine, after which the resulting intermediate compound is subjected to hydrolysis catalyzed by a base, preferably, the interaction with the metal hydroxide in water. The above-mentioned substance of the formula V is obtained in a known manner, usaiymi agent, preferably chloride tiomila in the presence of N,N-dimethylformamide. Sulfonic acid is obtained in a known manner, in accordance with one of the above common cathodes preferably by the interaction of ethinyl or itineraries connection with arriagada or kilbrandon. The third way of obtaining the substance in accordance with the invention consists in the transformation of A bridge in the substance of the invention or the intermediate substance having the formula IV (below) in another bridge in a known manner, not necessarily with the subsequent conversion of intermediate compounds in the final product.

One example of such a method involves adding water to the compound of formula VI

(R1, R2, R3)-Het'-NR-SO2-Ph1- A-C6H2-R4(COOR7)(OR8)

where R, R1, R2, R3That gets', Ph1, R4have the same meanings as described above, R7represents a hydrogen atom, or R5where R5such as above, R8represents a hydrogen atom, or R6where R6such as described above, and A is a group-CC-. The resulting substance has the formula VI, where A= -CH2CO. Attaching water on Tr formic acid, not necessarily in the presence of salts of metals, such as mercury or palladium, with subsequent alkaline hydrolysis, when R7and/or R8are not hydrogen atoms. Another method is in accordance substances of the formula VI, where R, R1, R2, R3That gets', Ph1, R4, R7and R8such as indicated above and A is a group-CH2CO-, in the corresponding substance in which-A - represents the group-CH2CHOH-, with subsequent transformation of this substance in the presence of a mineral acid, to remove the water and to obtain the substance, where-A - is a group-CH=CH-, with subsequent alkaline hydrolysis, when R7and/or R8are not hydrogen atoms.

The third way is to restore the substances of the formula VI, where R, R1, R2, R3That gets', Ph1, R4, R7and R8such as indicated above and A is a group-CC - or-CH=CH - in the corresponding substance in which-A - represents the group-CH2-CH2-, catalytic hydrogenation in a known manner, with subsequent alkaline hydrolysis, when R7and/or R8are not hydrogen atoms. When the substance according to the invention is a salt, it is obtained, for example, the m-agent, for example, in the form of a metal hydroxide or an organic amine, in the presence of a solvent, preferably water or a mixture of water and one or more organic solvents, or by choice, in the presence of an organic solvent. When the salt is difficultly soluble in the used solvent, preferably she is allowed to crystallize from this solvent, and her evolve by filtering or other similar process. When the sparingly soluble salt is a salt of an alkali metal, preferably sodium or potassium, the final hydrolysis applied to removal of any protecting groups may be carried out in such a way that the reaction mixture is neutralized and the desired salt secretariats directly from the mixture. If the salt is readily soluble in the solvent used, preferably it is produced by interaction equimolecular quantities of reagents, after which the solvent is removed by evaporation.

In some cases, the formation of a clear MES connection with the solvent. Such a solvate, which contain a certain amount of solvent, are also covered by this invention, when used solvents are who I am as a result of crystallization from a specified solvent, not necessarily in a mixture with other solvents. Crystallization may not necessarily be carried out by the acidification of a soluble salt of a substance in the presence of a solvent, forming a MES.

This invention also includes pharmaceutical compositions that include the substance of formula I, designed especially for oral use, not necessarily in combination with organic or inorganic inert carrier suitable for oral ingestion, and/or other conventional additives. The pharmaceutical composition may be, for example, in the form of tablets, pills, capsules and other, not necessarily with enterococci coating, or solutions and suspensions containing substances of the invention. The pharmaceutical composition can be obtained in a known manner by a specialist competent in this area, by mixing the substances of formula I with the desired material of the carrier and/or additional additives and converting this mixture into a desired drug form in accordance with the criteria below. Solutions and suspensions are prepared in a known manner using a pharmaceutically suitable additives. Dosage adapts to the demands and wishes in a specific silento.

Identification of all of the final products was confirmed by NMR spectra, and their purity by thin layer chromatography (TLC) or liquid chromatography. The NMR spectra of protons (TMR) were recorded at a frequency of 500 MHz NMR spectrometer using DMSO as solvent unless otherwise stated. Chemical shifts in the NMR spectrum are given in ppm (M. D.).

Example 1. 2-Hydroxy-5-((4-((pyridinylamino)sulfonyl)phenyl) ethinyl)benzoic acid.

Example 1a. Methyl ester 5-(trimethylsilyl)ethinyl)-2-hydroxybenzoic acid.

To a solution of 275 g of methyl ester of 2-hydroxy-5-iodobenzoic acid (to 0.92 mol) in dried triethylamine (2000 ml) is added 3 g dichlorobis(triphenylphosphine)palladium (0.04 mol) and 1.6 g (0,008 mol) of copper iodide (I). The mixture is blown with nitrogen from the air. From a syringe add 100 g of trimethylchlorosilane, and the reaction mixture is heated to 50oC. After 30 min produced a voluminous precipitate of hydroiodide ammonium and 2 h according to TLC, the reaction is finished. The mixture is filtered, and the filtrate is evaporated in vacuum. The residue is purified by a method of dry flash chromatography on silica gel using toluene as eluent. Exit 211 g, 92%.

Example 1b. M is inil))- 2-hydroxybenzoic acid (or 0.57 mol) and 150 g of dihydrate potassium fluoride (or 0.57 mol) and 600 ml of dimethylformamide is stirred for 4 h at room temperature. The solution is extracted with ether (3 x 400 ml) and the combined ether extracts are washed with 1-molar hydrochloric acid (2 times 200 ml) and water (2 times 100 ml). The ether layer is dried with sodium sulfate and evaporated to dryness. Output 66.5 g (93%).

Example 1c. 4-iodo-N-(2-pyridinyl)benzosulfimide.

4-iodo-benzosulphochloride (52,3 g; to 0.17 mol) is dissolved in 300 ml of dichloromethane and add 65 g (0.69 mol) of 2-aminopyridine. The solution was stirred at room temperature for 3 days, washed with 2-molar sulfuric acid (2 times 200 ml) and water (100 ml), dried with sodium sulfate and evaporated to dryness. Output 46,9 g (76%).

Example 1d. Methyl ester of 2-hydroxy-5-((4-((pyridinylamino) sulfonyl)phenyl)ethinyl)benzoic acid.

4-iodo-N-(2-pyridinyl)benzosulfimide (35 g, 97 mmol) dissolved in a mixture of triethylamine and tetrahydrofuran (750 + 750 ml). The mixture is blown with nitrogen from the air and add 1.2 g of dichlorobis(triphenylphosphine)palladium (1.7 mmol) and 0.6 g (3.4 mmol) of copper iodide (I). Finally add 23 g of methyl ester 4-ethinyl-2-hydroxybenzoic acid (130 mmol). The mixture is heated to 60oC for 4 h and evaporated to dryness. The residue is dissolved in 1000 ml of chloroform and washed with water (3 x 200 ml) and dried sulfate MAGN on silica gel, using chloroform as eluent.

Example 1e. 2-Hydroxy-5-((4-((pyridinylamino)sulfonyl)phenyl) ethinyl)benzoic acid.

Ester from example 1d (23.7 g, 58 mmol) dissolved in 1-molar sodium hydroxide (190 ml) and refluxed for 6 hours, the Cooled solution is acidified with an excess of 6-molar hydrochloric acid. The sediment was incubated for 2 h, filtered and washed (3 times 200 ml of water. The white product is dried at 60oC in vacuum. The output of 21.7 g (95%).

Range PMR: Spin system A: 7,00 (doublet), 7,66 (doublets), 7,95 (doublet) (=salicylate ring)

Spin system B: 7,66 (doublet, 2H), 7,87 (doublet, 2H) (=Central benzene ring)

Spin system C: 7,18 (doublet), 7,73 (DDD), 6,84 (doublets), of 7.96 (doublets) (=pyridine ring)

Example 2. 2-Hydroxy-5-((4-(3-methyl-2-pyridinylamino)sulfonyl)phenyl) ethinyl)benzoic acid.

Example 2a. 4-Iodo-N-(3-methyl-2-pyridinyl)benzosulfimide.

This compound was prepared substantially as the corresponding compound in example 1c. The output 76%

Example 2b. Methyl ester of 2-hydroxy-5((4-((3-methyl-2-pyridinylamino) sulfonyl)phenyl)ethinyl)benzoic acid.

This compound was prepared significant is enylamine)sulfonyl)phenyl) ethinyl)benzoic acid.

This compound was prepared substantially as the corresponding compound in example 1e. The output of 24.7 g (85%).

Range PMR: Spin system A:? 7.04 baby mortality (doublet), 7,70 (doublets), 8,00 (doublet) (=salicylate ring)

Spin system B: 7,70 (doublet, 2H), of 7.96 (doublet, 2H) (=Central benzene ring)

Spin system C: 7,66 (broad doublet), 6,83 (Shir. singlet), 7,84 (Shir. singlet) (=pyridine ring)

Spin system D: 2,15 (singlet) (=methyl group)

The broadening of the signals in the pyridine ring is typical for 3-methylseleninic derivatives.

Example 3. 2-Hydroxy-5-(2-(4-((2-pyridinylamino)sulfonyl)phenyl) ethinyl)benzoic acid.

Example 3a. Methyl ester 5-ethinyl-2-hydroxybenzoic acid.

Obtained in accordance with example 1b methyl ester 5-ethinyl-2-hydroxybenzoic acid (8 g, to 45.4 mmol) dissolved in a mixture of 200 ml of diethyl ether and 200 ml of petroleum ether in the flask for hydrogenation. Add 1.7 ml of quinoline and 200 mg of catalyst Dendera - palladium on calcium carbonate, poisoned with lead, and the flask is connected with a device for hydrogenation at atmospheric pressure. The mixture is stirred for 2 h at room temperature, when it is absorbed by the calculated amount of hydrogen. Katal is e, using toluene as eluent. Get nearly quantitative yield of product.

Example 3b. Methyl ester of 2-hydroxy-5-(2-(4-((2-pyridinylamino) sulfonyl)phenyl)ethinyl)benzoic acid.

4-Iodo-N-(2-pyridinyl)benzosulfimide (25 g, 69 mmol) obtained in example 1c, and methyl ester 5-ethinyl-2-hydroxybenzoic acid (13.5 g, 76 mmol) dissolved in a mixture of triethylamine and tetrahydrofuran (150 + 800 ml). The mixture is heated to 80oC for 18 hours Add small portions (a total of 0.5 g), palladium acetate (P) during the entire reaction time. The formed precipitate hydroiodide filtered, and the filtrate is evaporated to dryness. The residue is dissolved in 500 ml of chloroform and purified by the method of flash chromatography on silica gel using chloroform as eluent. The solvent is evaporated in vacuo, and the residue dissolved in the minimum possible amount of tetrahydrofuran. The product is precipitated by adding diethyl ether. The output of 13.5 g (47%).

Example 3c. 2-Hydroxy-5-(2-(4-((2-pyridinylamino)sulfonyl) phenyl)ethinyl)benzoic acid.

Methyl ester of 2-hydroxy-5-(2-(4-((2-pyridinylamino)sulfonyl) phenyl)ethinyl)benzoic acid (12 g, 29 mmol) dissolved in 1-molar potassium hydroxide (120 ml), and RAS is. The formed precipitate is filtered and washed (3 times 200 ml of water. The product re-dissolved in a small amount of 1-molar sodium hydroxide. Add water and dioxane (500 ml) and the solution heated to 100oC. This solution is acidified with an excess of 1-molar hydrochloric acid, and the product precipitates upon cooling. Yield 9 g (75%).

Range PMR: Spin system A: 7,02 (doublet), 7,84 (doublets), 8,04 (doublet) (=salicylate ring)

Spin system B: 7,73 (doublet, 2H), 7,88 (=Central benzene ring)

Spin system C: 7,22 (doublet), 7,74 (m), 6.89 in (doublets), 8,04 (m) (== pyridine ring)

Spin system D: 7,19 (doublet), 7,38 (d), (=identially bridge)

Example 4. 2-Hydroxy-5-(2-(4-((3-methyl-2-pyridinylamino) sulfonyl)phenyl)ethinyl)benzoic acid.

Example 4a. Methyl ester of 2-hydroxy-5-(2-(4-((3-pyridylamino) sulfonyl)phenyl)ethinyl)benzoic acid.

This substance was prepared according to the method of example 3 from 4-iodo-N-(3-methyl-2-pyridinyl)benzosulfimide obtained by the method of example 2a, and methyl ester 5-ethinyl-2-hydroxybenzoic acid, prepared as in example 3a.

Yield 52%.

Example 4b. 2-Hydroxy-5-(2-(4-((3-methyl-2-pyridinylamino) sulfonyl)phenyl)ethinyl)benzoi the n system A: 7,02 (d), the 7.85 (doublets), 8,04 (d), (= salicylate ring)

Spin system B: 7,74 (d, 2H), 7,92 (d, 2H) (=Central benzene ring)

Spin system C: 7,63 (broad doublet), for 6.81 (W), the 7.85 (W), (= pyridine ring)

Spin system D: 7,21 (d), 7,39 (d), (=identially bridge)

Spin system E: 2,15 (singlet) (=methyl group)

The broadening of the signals in the pyridine ring is typical of 3-methyl-substituted derivatives.

Example 5. Isobutyl ester 2-hydroxy-5-(2-(4-((2- pyridinylamino)sulfonyl)phenyl)ethinyl)benzoic acid.

Example 5a. Isobutyl ester 2-hydroxy-5-iodobenzoyl acid.

2-Hydroxy-5-iodobenzoyl acid (477 g, 1.8 mol), 225 g of Isobutanol, 20 ml of concentrated sulfuric acid in 2 l of toluene is refluxed for 6 hours using a water separator. The solution is cooled and washed with water. This solution is treated with decolorizing activated carbon and evaporated toluene. The residue is recrystallized from methanol. Exit 376

Example 5b. Isobutyl ether 5-ethinyl-2-hydroxybenzoic acid.

Isobutyl ester 2-hydroxy-5-iodobenzoyl acid (16 g, 0.05 mol), 13,9 g tributylamine (75 mmol) and 0.11 g of palladium (II) acetate (0.5 mmol) is dissolved in 100 ml of dimethylacetamide argon pressure 10 bar, with subsequent discharge to atmospheric pressure. This procedure is repeated twice. The temperature was raised to 90oC. Let ethylene under a pressure of 13 bar. After stirring for 5 min the gas is discharged to atmosphere and the pressure of ethylene was again increased to 13 bar. The temperature increased to 110oC for 30 min under vigorous stirring and continuous introduction of ethylene to maintain the pressure constant at 13 bar. After 1.5 h, the temperature was lowered to 20oC, and ethylene is removed using an argon inlet.

The solvent is evaporated at 70oC. Add 150 ml of water. Bring the pH of the mixture to about 5 with hydrochloric acid, and the solution is extracted 2 times with toluene (50 ml). After re-extraction with dilute sodium bicarbonate solution (50 ml) the combined toluene extracts are evaporated receiving a remainder of the product in the form of oil. Distillation at 105oC and a pressure of 0.5 mm RT. senior network of 15.4 g (70%) of chromatographically pure material. When the distillation of the material stabilized against polymerization by adding 10 mg of hydroquinone.

Example 5c. Isobutyl ether-2-hydroxy-5-(2-(4-((2- pyridylamino)sulfonyl)phenyl)ethinyl)benzoic acid.

0.15 g of palladium (II) Acetate (0.67 mmol) is added to the mixed solution from the IDA (30 mmol) in 40 ml of dimethylacetamide and 10 ml of tributylamine (42 mmol) at 95oC. After 100 minutes the solution is filtered and evaporated at 50-60oC (bath temperature) until the solid material. The mixture is diluted with 0.5 l of isopropanol and freeze in the refrigerator. The product is filtered, receiving 71 g of substance (52%).

Range PMR: Spin system A: 7,0 (d), 7,84 (doublets), to 7.93 (d) (=salicylate ring)

Spin system B: of 7.70 (d, 2H), 8,84 (d, 2H) (=Central benzene ring)

Spin system C: 7,18 (d), 7,69 (doublets), 6,85 (doublets), 8,00 (doublets) (=pyridine ring)

Spin system D: 7,12 (d), of 7.36 (d), (=identially bridge)

Spin system E: 1,0 (d, 6H), 2,1 (m, 1H), 4,1 (d, 2H) (=isobutylene group)

Example 6. 2-Hydroxy-5-(2-(4-((2-pyridinylamino)sulfonyl)- phenyl)ethinyl)benzoic acid.

Example 6a. Isopropyl ester of 2-hydroxy-5-iodobenzoyl acid.

2-Hydroxy-5-iodobenzoyl acid (184, 0.7 mol), 50 ml of isopropanol, 5 ml of concentrated sulfuric acid and 10 g paratoluenesulfonyl in 1 l of toluene is refluxed using a water separator. Periodically add portions of isopropanol, to compensate for its loss due to dehydration. After 24 hours the solution is cooled and washed with water. The toluene is evaporated partially. Add isooctane, and filtered sieges is methanol. The output 64 g (71% adjusted for the selected starting material).

Example 6b. Isopropyl ester 5-ethinyl-2-hydroxybenzoic acid.

Isopropyl ester of 2-hydroxy-5-iodobenzoyl acid (30,6 g, 0.1 mol) dissolved in a mixture of 27.8 g of tributylamine (150 mmol) and dimethylacetamide. After addition of palladium (II) acetate and displaces air in argon atmosphere the temperature was raised to 110oC. Overlap of ethylene was carried out according to the method of example 5b.

After 1.5 h the reaction is terminated by cooling to room temperature, and simultaneously ethylene discharged into the atmosphere.

After evaporation of the solvents in vacuum at 70oC add 100 ml of water and adjusted the pH of the mixture to about 5 with hydrochloric acid. Extraction with toluene (2 times 50 ml) and subsequent evaporation to give the crude product as oil. Distilled product at 95 - 98oC and a pressure of 0.7 mm RT. Art., getting 15.5 g (75%) of chromatographically pure material.

Example 6c. 2-Hydroxy-5-(2-(4-((2-pyridinylamino)sulfonyl)- phenyl)ethinyl)benzoic acid.

Isopropyl ester 5-ethinyl-2-hydroxybenzoic acid is subjected to interaction with 4-iodo-N-2-pyridinesulfonamide (30 mmol) by the method of ohms. After drying on the filter and washing with water, the material is subjected to hydrolysis and precipitation according to the method of example 3c. Yield 40%.

An NMR spectrum confirms the identity of the substance with the product of example 3.

Example 7. 2-Hydroxy-5-(2-(4-((2-pyridinylamino)sulfonyl)phenyl) ethinyl)benzoic acid.

Isobutyl ether 5-ethinyl-2-hydroxybenzoic acid (16 g, 30 mmol) is reacted with ethylene as described in Example 5b.

The reaction mixture is cooled to 85oC and with stirring, 14.8 g of 4-iodo-N-2-pyridinesulfonamide (42,5 mmol) and 0.11 g (0.5 mmol) of palladium (II) acetate. After 4 h at 85oC all of the sulfonamide spent, but in the reaction mixture still contains a little isobutyl ester 5-ethinyl-2-hydroxybenzoic acid. Add a further quantity (2.6 g, 7.5 mmol) sulfonamida and the reaction continued for another 18 h

After adding acetic acid to the hot mixture is then poured into 350 ml of boiling isopropanol. During slow cooling to 4oC from a solution gain of 11.3 g of the product. Another 1.5 g were obtained when the concentration of the mother liquor to about 100 ml and cooled to 4oC. the Total yield is equal to 12.7 g (56%).

This material is hydrolized during the HCl solution. Recrystallization from a mixture of formic acid/water (70-30) gives, after filtration and drying of 8.5 g of substance (43%).

An NMR spectrum confirms the identity of the substance with the product of example 3.

Example 8. Isobutyl ester 2-hydroxy-5-(2-(4-((3-methyl-2 - pyridinylamino)sulfonyl)phenyl)ethinyl)benzoic acid.

0.5 g of Palladium (10%) coal added to a solution of isobutyl ester 5-ethinyl-2-hydroxybenzoic acid (6.6 g, 30 mmol) and 11.2 g of 4-iodo-N-2-pyridinesulfonamide (30 mmol) in 10 ml of dimethylacetamide and 10 ml of tributylamine (42 mmol) at 110oC. After 90 minutes the solution is filtered and diluted with 300 ml of isopropanol and freeze in the refrigerator. The product is filtered, dried and dissolved in 100 ml of boiling formic acid. The solution is filtered and added 65 ml of water. After cooling to the temperature of the refrigerator, the product is filtered and dried, obtaining 7.2 g of the substance (51%).

Range PMR: Spin system A: 7,0 (d), 7,84 (doublet, W), 7,94 (cm.) (=salicylate ring)

Spin system B: of 7.69 (d, 2H), 7,9 (d, 2H) (=Central benzene ring).

Spin system C: 7,58 (W), 6,74 (lat.) 7,8-8,0 (lat.) (=pyridine ring)

Spin system D: 7,12 (d), 7,35 (d), (=identially bridge)

Spin system E: 2,1 (s,neither E), 4,1 (d, 2H) (isobutylene group).

The broadening of the signals in the pyridine ring is typical for 3-methylseleninic derivatives.

Example 9. Ethyl ester of 2-hydroxy-5-((4-((3-methyl-2 - pyridinylamino)sulfonyl)phenyl)ethinyl)benzoic acid

Example 9a. Ethyl ester of 5-ethinyl-2-hydroxybenzoic acid

This compound is synthesized from ethyl ester of 2-hydroxy-5 - iodobenzoyl acid analogously to the methods of examples 1a and 1b for the corresponding ethyl ester.

Example 9b. Ethyl ester of 2-hydroxy-5-((4-((3-methyl-2 - pyridinylamino)sulfonyl)phenyl)ethinyl)benzoic acid.

To a solution of 10.5 g of ethyl ester of 5-ethinyl-2-hydroxybenzoic acid (55 mmol) and 4-iodo-N-(3-methyl-2-pyridinyl) benzosulfimide (18.7 g, 50 mmol) in a mixture of triethylamine and tetrahydrofuran (75 + 75 ml) is added to 0.29 g of tetrakis (triphenylphosphine)palladium (0.25 mmol) and 0,095 g (0.5 mmol) of copper iodide (I) if 55oC. After 2 h, the solid product is separated by filtration and washed with 1-molar hydrochloric acid. This material is boiled in 300 ml of formic acid for 15 min and filtered. Add 200 ml water, the product crystallizes upon cooling. Yield 17.3 g (79%).

Range PMR (solvent - penetrability):

Spin Sinoe ring)

Spin system C: 7,37 (d), only 6.64 (DD), 7,94 (d) (=pyridine ring)

Spin system D: 2,11 (S. lat.) (=methyl group)

Spin system E: 1,22 (triplet, 3H), 4,33 (Quartet, 2H)(=ethyl group)

Example 10. 2-Hydroxy-5-((4-((3-methyl-2-pyridinylamino)sulfonyl)phenyl)ethinyl) benzoic acid.

Example 10A. 4-(3-Hydroxy-3-methyl-1-butyn-1-yl)-N- (3-methyl-2-pyridinyl)benzosulfimide.

4-Iodo-N-(-3-methyl-2-pyridinyl)benzosulfimide time (37.4 g, 100 mmol) in parts added to a mixture of triethylamine (31 ml, 220 mmol) and dimethylacetamide (25 ml) at 60oC. In an atmosphere of nitrogen was added 0.14 g of dichlorobis(triphenylphosphine) palladium (2 mmol) and 0.88 g (4 mmol) of copper iodide (1). Finally added in several portions of 10.4 g (125 mmol) of 2-methyl-3-butyn-2-ol for 20 min, in order to maintain the temperature of this exothermic reaction at 65-70oC.

The mixture was stirred at 65oC for 1 h, Add 250 ml of water and after cooling to room temperature, filtered muddy sediment. Add 85% potassium hydroxide (13,2 g, 200 mmol), dissolved in 100 ml of water. In vacuum at 50oC evaporated to about 100 ml of a mixture water/triethylamine. The remaining solution is extracted with 3 times 30 ml) isobutylmethylxanthine and at the 50oC of water was added 100 ml of ethanol. Dropwise cautiously add hydrochloric acid at 60oC, until the pH reaches 4. When cooled to 8oC the product precipitates. The product is filtered, washed with water and dried. The output of 29.6 g (90%).

Example 10b. 4-Ethinyl-N-(3-methyl-2-pyridinyl)benzosulfimide.

4-(3-Hydroxy-3-methyl-1-butyn-1-yl)-N-(3-methyl-2-pyridinyl) benzosulfimide (49,6 g, 150 mol) and 900 ml of water heated to approximately 90oC in nitrogen atmosphere. Add 85% potassium hydroxide (64,9 g, 1.05 mol) at a rate that supports intense boiling. This intensive boiling is maintained for 2 h without reverse refrigerator, in order to effectively remove formed in the reaction of acetone. Add water to keep the volume constant.

This hot solution is added to 20 ml of ethanol containing a small amount of sulfur dioxide. Dropwise at 90oC add hydrochloric acid. If there is light, then add 1.5 g of activated charcoal, and the solution is filtered. Continuous addition of hydrochloric acid continued until the pH value is 4, which causes the precipitation of the product.

When cooled to 8oC the solid material is filtered and washed in the ether of 2-hydroxy-5-((4-((3-methyl-2-pyridinylamino)sulfonyl)phenyl)ethinyl) benzoic acid.

To a solution of 14.9 g of ethyl ester of 2-hydroxy-5-iodobenzoic acid (50 mmol) and 4-ethinyl-N-(-3-methyl-2-pyridinyl) benzosulfimide (14.3 g, 50 mmol) in a mixture of triethylamine (10 g, 100 mmol) and 60 ml of dimethylacetamide add 0,07 g dichlorobis (triphenylphosphine)palladium (0.1 mmol) and 0.04 g (0.2 mmol) of copper iodide (1) if 65oC. After 1 h, add hot ethanol and then 100 ml of hot water with stirring. The solid is separated by filtration after cooling in the refrigerator and recrystallized from formic acid and water, receiving 17 g of product (77%).

Example 10d. 2-Hydroxy-5-((4-((3-methyl-2-pyridinylamino)sulfonyl)phenyl)ethinyl) benzoic acid.

15.5 g of Ethyl ester of 2-hydroxy-5-((4-((3-methyl-2-pyridinylamino)sulfonyl)phenyl)ethinyl) benzoic acid (35 mmol) is boiled in 100 ml of water with 10 g of potassium hydroxide (150 mmol) for 1 h, After cooling to 70oC add 50 ml of ethyl acetate and added hydrochloric acid, bringing the pH to 7-8. When cooling with stirring and then filtering obtain a solid product, which is dissolved in 100 ml of acetone. This solution is acidified at about 50oC,cooled, filtered and washed with water. Yield 8.0 g (56%).

An NMR spectrum confirms the IDA is amino)sulfonyl)phenyl)ethinyl) benzoic acid

Example 11a. 4-(3-Hydroxy-3-methyl-1-butyn-1-yl)-N-(3-methyl-2 - pyridinyl)benzosulfimide.

The synthesis is carried out as in example 10A in the scale of 0.2 mol with acetone (100 ml) as solvent, instead of dimethylacetamide. The reaction time by boiling under reflux at 60-62oC was 2 hours Yield 60 g, 91%.

Example 11b. 4-Ethinyl-N-(3-methyl-2-pyridinyl) benzosulfimide.

This synthesis is carried out exactly as in example 10b.

Example 11c. Ethyl ester of 2-hydroxy-5-((4-((3-methyl-2-pyridinylamino)sulfonyl)phenyl)ethinyl) benzoic acid

Synthesis is carried out as in Example 10c, except that hydrochloric acid is added after the addition of ethanol and water.

Yield 72%.

Example 11d. Potassium salt of 2-hydroxy-5-((4-((3-methyl-2-pyridinylamino)sulfonyl)phenyl)ethinyl) benzoic acid.

15.5 g of Ethyl ester of 2-hydroxy-5-((4-((3-methyl-2-pyridinyl-amino)sulfonyl)phenyl)ethinyl) benzoic acid (35 mmol) is boiled in 100 ml of water with 10 g of potassium hydroxide (150 mmol) for 1 h, After cooling to approximately 70oC add 50 ml of ethyl acetate and added hydrochloric acid, bringing the pH to 7-8. When cooling with stirring and then filtering polycaste example 2.

Example 12. 2-Hydroxy-5-(2-(4-((3-methyl-2-pyridinylamino) sulfonyl)phenyl)ethinyl)benzoic acid.

Example 12a. 4-(2-Bromacil)-N-(3-methyl-2-pyridinyl)benzosulfimide.

3-Methyl-2-pyridylamine (431 g, 4 mol dissolved in 700 ml of dichloromethane and at room temperature is added 4-(2-bromoethyl) benzosulphochloride (340 g of 1.33 mol). After 1 h at 20othe solution is heated to 35oC for 2 hours Add excess dilute hydrochloric acid and separated phases. After one washing with water the organic phase is dried with magnesium sulfate and treated with activated carbon. The solvent is evaporated and add warm methanol to the residue, which crystallizes. The material is collected and subjected to recrystallization from toluene. The output 178 g; additional amount of product (36 g) is obtained from the processing of the mother liquor. The total output is equal to 45%.

Example 12b. 4-Ethinyl-N-(3-methyl-2-pyridinyl)benzosulfimide.

4-(2-Bromacil)-N-(3-methyl-2-pyridinyl)benzosulfimide (183 g, 0.5 mol), 120 g of potassium hydroxide (1,83 mol) and 1 g of gedrosian in 2 l of ethanol is refluxed 1 h Add 5 l of water and the solution acidified with acetic acid. Precipitated precipitated product is collected by filtration, Promyshlennaya)sulfonyl)phenyl)ethinyl benzoic acid.

of 70.2 g of Isobutyl ether, 2-hydroxy-5-iodobenzoic acid (0.22 mol) and 4-ethinyl-N-(3-methyl-2-pyridinyl)benzosulfimide (54,8 g, 0.20 mol) is suspended in a solution of tributylamine cases (55.5 g, 0.3 mol) and palladium acetate (11) (0,44 g, 2.2 mmol) in 200 ml of dimethylacetamide.

The mixture is heated to 100oC for 3 hours Add activated charcoal (2 g), suspended, filtered and the filtrate poured in boiling isopropyl alcohol.

The solution is slowly cooled to 10oC and the crystals filtered off. The filter cake was washed with cold isopropyl alcohol (20 ml) and the product is dried. Yield 78 g (83%).

Example 12d. 2-Hydroxy-5-(2-(4-((3-methyl-2-pyridinylamino)sulfonyl)phenyl)ethinyl) benzoic acid.

The product from example 12c (78 g) are added to a solution of potassium hydroxide (50 g, 0.78 mmol) in 600 ml of water, and the mixture is refluxed over night. After adding 2 g of activated charcoal and 0.5 g of sodium sulfite mixture is allowed to cool to room temperature with stirring and then filtered.

After filtering, add 600 ml of ethanol and the solution is heated to approximately 90oC. At one time add 80 ml of hydrochloric acid and after about 3 min the product nachine. The filter residue is thoroughly washed with water and dried. The output 64 g (78%).

An NMR spectrum confirms the identity of the substance with the product of example 4.

Example 13. Isobutyl ester 2-hydroxy-5-(2-(4-((2-pyridinylamino)sulfonyl)phenyl)ethinyl) benzoic acid.

Example 13a. 4-(2-Bromacil)-N-(2-pyridinyl)benzosulfimide

This compound was synthesized analogously to substance of example 12A. Yield 67%.

Example 13b. 4-Ethynyl-N-(2-pyridinyl) benzosulfimide.

This compound was synthesized as in example 12b, yield 66%.

Example 13C. Isobutyl ester 2-hydroxy-5-(2-(4-((2-pyridinylamino)sulfonyl)phenyl)ethinyl) benzoic acid.

Isobutyl ester 2-hydroxy-5-iodobenzoic acid (19.2 g, 60 mmol), 4-ethinyl-N-(2-pyridinyl)benzosulfimide (13 g, 50 mmol) and palladium acetate (11) (0.11 g, 0.5 mmol) is suspended in a mixture of 13.8 g of tributylamine (75 mmol) and 50 ml of dimethylacetamide.

After mixing for 160 min at 85oC add 5 ml of acetic acid, and the hot mixture was poured in boiling isopropyl alcohol (400 ml). When cooled in the refrigerator, a precipitate, which is collected by filtration. The remainder of the filtrate by prooduction example 5.

Example 14. 2-Hydroxy-5-(2-(4-((3-methyl-2-pyridinylamino)sulfonyl)phenyl)ethinyl) benzoic acid, acetone MES.

Dissolved in 160 ml of water and 240 ml of acetone 28 g of potassium salt of 2-hydroxy-5-(2-(4-((3-methyl-2-pyridinylamino)sulfonyl)phenyl)ethinyl) benzoic acid when heated to 50oC. Quickly add 6 ml of hydrochloric acid. The product crystallizes in the form of MES containing about 0.14 moles of acetone per mole of 2-hydroxy-5-(2-(4-((3-methyl-2-pyridinylamino)sulfonyl)phenyl)ethinyl) benzoic acid; output 23,7,

Range PMR: Spin system A:? 7.04 baby mortality (d), of 7.70 (DD), 8,00 (d)= (salicylate ring)

Spin system B: of 7.70 (d, 2H), 7,95 (d, 2H):(=Central benzene ring)

Spin system C: 7,99 (d, W), 6,83 (cm.) to 7.84 (s, W) (=pyridine ring)

Spin system D: 2,15 (cm.) (=methyl group)

Spin system E: 2,10 (singlet) (=acetone)

The broadening of the signals in Spiridonova ring is typical of 3-substituted derivatives. The amount of acetone corresponds to about 0.15 equivalent.

Example 15. 2-Hydroxy-5-(2-(4-((5-methyl-2-pyridinylamino)-sulfonyl)phenyl) ethinyl)benzoic acid.

Example 15a. Tributylammonium salt 4-ethynylbenzaldehyde

In 1 liter of water and 500 ml of ethanol is boiled with the hydroquinone.

This solution is concentrated to about 1 liter by evaporation in vacuo and acidified with 2-molar sulfuric acid (400 ml). Add tributylamine (71,5 g to 0.39 mol) and the solution is extracted 4 times with dichloromethane (150 ml). The combined organic phases are washed with a 0.5-molar sulfuric acid (150 ml), dried with magnesium sulfate and dehydrate. Output 134,1 g, quantitative.

Example 15b. Methyl ester of 2-hydroxy-5-(2-(4-sulfophenyl)ethinyl)benzoic acid, potassium salt.

Dissolved in 370 ml of dimethylacetamide 134 g tributylammonium salt 4-ethynylbenzaldehyde (0.36 mol), 101 g of methyl ester of 2-hydroxy-5-iodobenzoic acid ( 0.36 mol), 101 g tributylamine (0.54 mol). Add 0.8 g of palladium acetate (11) (3.6 mmol) and the solution heated under stirring 3 h at 85oC. the Suspension is filtered to remove insoluble salts of palladium, and the solution is evaporated to dryness. The residue is dissolved in 500 ml of dichloromethane. With careful stirring quickly add a solution of potassium hydroxide (94 g of 1.45 mol) in 300 ml of water. Precipitated in the sediment Pikalevo salt is filtered off and washed with dichloromethane and diethyl ether. After drying the solid material is refluxed in 200 ml of acetic CI is t diethyl ether, the output of 57.6 g (43%).

Example 15c. Methyl ester 2-atomic charges-5-(2-(4-sulfophenyl)-ethinyl)benzoic acid, potassium salt.

Potassium salt of methyl ester of 2-hydroxy-5-(2-(4-sulfophenyl)ethinyl)benzoic acid (57,5 g, 0.15 mol), 35 ml of acetic acid m 142 ml of acetic anhydride is refluxed until then, until a large part of the solids are dissolved, and then add another 142 ml of acetic anhydride and 1 ml of sulfuric acid. After boiling for 1.5 h the mixture is cooled to room temperature and add diethyl ether, in order to complete the precipitation. After filtering and drying, the yield was 43.4 g (69%).

Example 15d. Methyl ester 2-atomic charges-5-(2-(4-(chlorosulfonyl)phenyl)ethinyl)benzoic acid.

Potassium salt of methyl ester of 2-atomic charges-5-(2-(4-sulfophenyl)ethinyl)benzoic acid are suspended in dichloromethane. Add 5 ml of dimethylformamide and thionyl chloride, and the mixture with stirring and refluxed for 3 hours After cooling to room temperature, add 15 ml of water. Carefully adding 5-molar sodium hydroxide solution, bring the aqueous phase to pH approximately equal to 7. Share phase and the organic phase is prom the air traffic management of the solvent the solid residue is subjected to recrystallization from toluene and petroleum ether (mixture), the output is equal to 29.3 g (71%).

Example 15e. 2-Hydroxy-5-(2-(4-((5-methyl-2-pyridinylamino)-sulfonyl)phenyl)ethinyl) benzoic acid.

Methyl afin 2 atomic charges-5-(2-(4-(chlorosulfonyl)phenyl)ethinyl)benzoic acid (1.2 g, 3 mmol), 2-amino-5-methylpyridin (0.39 g, 3.6 mmol) are added to 10 ml of dried pyridine, and the solution was stirred at room temperature overnight. The solvents are evaporated and the solid residue is stirred with 2-molar sulfuric acid. After filtering, gain of 1.33 g of ester intermediate. This ether is refluxed 5 h in a solution of 0.6 g of sodium hydroxide in 20 ml of water and 10 ml ethanol. After cooling and acidification with hydrochloric acid, the crystalline precipitate is filtered off and washed with water. After mixing with hot water for 1 h, the material is collected and dried. This material is subjected to recrystallization by dissolving in hot 70% ethanol containing 3 equivalents of sodium hydroxide, subsequently acidified with hydrochloric acid. After filtration, washing with water and drying, the yield was 0.7 g (58%).

Range PMR: Spin system A: 7,01 (d), 7,83 (DD), 8,01 (d) (=salicylic ring)

Spin system B: 7,72 (d, 2H), 7,82 (d, 2H), (=Central benzene Kohl is th Mostyn)

Spin system E: 2,15 (C) (=methyl group).

Example 16. 2-Hydroxy-5-(2-(4-((3-(phenylmethoxy)-2-pyridinylamino)sulfonyl)phenyl) ethinyl)benzoic acid.

This substance was synthesized similarly to the substance of example 15e. The output is 53%.

Range PMR: Spin system A: 6,99 (d) of 7.82 (DD), and 8.0 (d) (=salicylate ring)

Spin system B: 7,71 (d, 2H), to 7.93 (d, 2H) (=Central benzene ring)

Spin system C: 7,3 (W), 6,9 (lat.) 7,66 (d) (=pyridine ring)

Spin system D: / 7,17 (d), 7,38 (d), (=identially bridge)

Spin system E: of 7.48 (C), 7.3 to 7.4 (multiplet) (=phenyl group)

Spin-system F: 5,15 (singlet) (=methylene group)

Example 17. 5-(2-(4-((5-Chloro-2-pyridinylamino)sulfonyl)phenyl)ethinyl)-2 - hydroxybenzoic acid.

This compound was prepared as in example 15e. Yield 82%.

Range PMR: Spin system A: 7,02 (d), 7,84 (doublets), 8,04 (d) (=salicylate ring)

Spin system B: to 7.77 (d, 2H), to $ 7.91 (d, 2H) (=Central benzene ring)

Spin system C: 7,14 (d), 7,81 (DD), 8,24 (e) (=pyridine ring)

Spin system D: 7,20 (d), 7,41 (d), (=identially bridge)

Example 18. 2-Hydroxy-5-(2-(4-((5-methyl-3-isoxazolyl)aminosulfonyl)phenyl)ethinyl) benzoic acid.

This connection Balco)

Spin system B: 7,80 (d, 2H), a 7.85 (d, 2H) (=Central benzene ring)

Spin system C: 6,18 (=isoxazolone ring)

Spin system D: 7,21 (d), 7,43 (d), (=identially bridge)

Spin system E: 2,33 (C) (=methyl group)

Example 19. 2-Hydroxy-5-(2-(4-((4-methyl-2-pyrimidyl) aminosulfonyl)phenyl)benzoic acid, ethanol MES (2:1).

This compound was prepared as in example 15e.

Yield 38%.

Range PMR: Spin system A: 7,02 (d), 7,85 (doublets), 8,04 (d), (=salicylate ring)

Spin system B: 7,74 (d, 2H), 7,92 (d, 2H), (=Central benzene ring)

Spin system C: 7,63 (broad doublet), for 6.81 (lat.) the 7.85 (lat.) (=pyridine ring)

Spin system D: 7,21 (d), 7,39 (d), (=identially bridge)

Spin system E: 2,15 (singlet) (=methyl group)

Spin system F: 1,05 (triplet, 0,5 3H), 3,42 (l, 0,5 2H) (=ethanol)

Example 20. 2-Hydroxy-5-(2-(4-((2-pyrazinyl)aminosulfonyl)phenyl)ethinyl)benzoic acid.

This compound was prepared as in example 15e.

Yield 67%.

Range PMR: Spin system A: 7,02 (d), 7,84 (doublets), 8,05 (d) (=salicylate ring)

Spin system B: for 7.78 (d, 2H), to 7.93 (d, 2H) (=Central benzene ring)

Spin system C: 8,24 (s, 2H), 8,40 (c) (=pyridazinone ring)

This compound was prepared as in example 15e. The output is 27%.

Range PMR: Spin system A: 7,0 (d), 7,85 (doublets), 8,02 (d) (=salicylate ring)

Spin system B: 7,76 (d 2H), 7,83 (d 2H) (=Central benzene ring)

Spin system C: to 7.77 (d), 7,25 (DDD) 7,30 (DD) (=benzothiazole ring)

Spin system D: 7,20 (d), 7,38 (d), (=identially bridge)

Example 22. 2-Hydroxy-5-(2-(4-(N-methyl-(2-pyridinyl)aminosulfonyl)phenyl)ethinyl) benzoic acid.

This compound was prepared as in Example 15e. Yield 81%.

Range PMR: Spin system A: 7,02 (d), 7,87 (DD), 8,04 (d) (=salicylate ring)

Spin system B: 7,56 (d, 2H), 7,73 (d, 2H), (=Central benzene ring)

Spin system C: to 7.59 (d), the 7.85 (DDD), 7,25 (DD), 8,32 (DD) (=pyridine ring)

Spin system D: 7,20 (d), 7,42 (d), (=identially bridge)

Spin system E: 3,2 (C), (=methyl group)

Example 23. 2-Hydroxy-5-(4-((2-pyridinylamino)sulfonyl)phenyl) ethinyl)benzoic acid.

Example 23a. Isobutyl ester 2-hydroxy-5-(2-(4-sulfophenyl)ethinyl)benzoic acid, dikalova salt

Tributylammonium salt 4-ethinyl-benzosulfimide (55,2 g, 150 mmol), isobutyl ester 2-hydroxy-5-iodobenzoyl acid (47,8 g, 0.36 mol), tributylamine (41,4 g, 150 mmol) roselani to 85oC for 7 hours After approximately 3 hours, add another portion of isobutyl ether, 2-hydroxy-5-iddentical acid (23.9 g, 0.18 mol). The reaction mixture is evaporated to dryness. The residue is dissolved in 750 ml of dichloromethane. Under vigorous stirring quickly add 600 ml of 0.5 molar solution of potassium hydroxide. Osadovskaya Pikalevo salt is filtered off and washed with dichloromethane, yield 42 g (68%).

Example 23b. Isobutyl ester 2-atomic charges-5-(4-sulfophenyl)-ethinyl)benzoic acid, potassium salt.

Pikalevo salt isobutyl ether, 2-hydroxy-5-(4-sulfophenyl)ethinyl)benzoic acid (37,2 g, 90 mmol) is added to the boiling solution of 20 ml of acetic acid and 80 ml of acetic anhydride. Carefully add 8 ml of acid, and the mixture is refluxed until then, until you dissolve a large part of the solids, and then add 80 ml of acetic anhydride. After boiling for 1 h the mixture is cooled to room temperature. Add 350 ml of diethyl ether, and the suspension is filtered and washed with diethyl ether, the output of the 36.1 g (88%).

Example 23c. Isobutyl ester 2-atomic charges-5-(2-(4-chlorosulfonyl)phenyl)ethinyl)benzoic acid.

Potassium salt of isobutyl Laut 20 ml of dimethylformamide and 20 ml chlorestoral of tonila, and the mixture is refluxed with stirring for 3 hours After cooling to room temperature, add 15 ml of water. The aqueous phase podslushivaet to pH about 7, cautiously adding 5-molar sodium hydroxide solution. The phases are separated, and the organic phase is washed with water. The solution is dried with magnesium sulfate, treated with activated charcoal and filtered. After evaporation of the solvent the solid residue is subjected to recrystallization from a mixture of toluene and petroleum ether, yield 19.5 g (57%).

Example 23d. 2-Hydroxy-5-(2-(4-((2-pyridinylamino)sulfonyl)-phenyl)ethinyl) benzoic acid.

Isobutyl ester 2-atomic charges-5-(2-(4-chlorosulfonyl)- phenyl)ethinyl)benzoic acid (1,99 g, 4.6 mmol) and 2-pyridylamine (1.3 g, of 13.8 mmol) is stirred in 10 ml of dichloromethane at 45oC for 1 h After cooling to room temperature, add 20 ml dichloromethane and 20 ml of 2-molar sulfuric acid. Precipitated solid residue (1.3 g) is collected and washed with water. The organic phase is evaporated to dryness and the residue is treated with boiling methane, ammonia (2 ml) for 20 min. After cooling collect another 0.6 g of solid, which combine with the first residue. The total number of terdag is atok dissolved in 70% ethanol, containing about 3 equivalents of potassium hydroxide at the boiling temperature and acidified with hydrochloric acid at boiling. After filtering and drying, the output of the solid equal to 1.25 g (70%).

An NMR spectrum confirms the identity of the substance with the product of example 3.

Example 24. 2-Hydroxy-5-(2-(4-((6-methyl-2-pyridinylamino)sulfonyl)phenyl)ethinyl) benzoic acid.

This compound was prepared as in example 23d. Yield 69%.

Range PMR: A: 7,0 (d) of 7.82 (DD), 8,02 (d) (=salicylate ring)

Spin system B: 7,71 (d, 2H), 7,83 (d, 2H) (=Central benzene ring)

Spin system C:? 7.04 baby mortality (d), to 7.61 (DD), 6,66 (d) (=pyridine ring)

Spin system D: 7,17 (d), of 7.36 (d) (=identially bridge)

Spin system E: 2,3 (C) (=methyl group)

Example 25. 2-Hydroxy-5-(2-(4-((4-methyl-2-pyridinylamino) sulfonyl)phenyl)ethinyl)benzoic acid, ethanol MES (2:1)

This compound was prepared as in example 23d. Yield 69%.

Range PMR: Spin system A: 7,0 (d), 7,83 (DD), 8,02 (d) (=salicylate ring)

Spin system B: 7,72 (d, 2H), to 7.84 (d, 2H) (=Central benzene ring)

Spin system C:? 7.04 baby mortality (d), 6,69 (DD), 7,83 (d) (=pyridine ring)

Spin system D: 7,18 (d), 7,37 (d), (=identially bridge)

The spin system is I acid.

A solution of 2-hydroxy-5-(2-(4-((2-pyridinylamino)sulfonyl) phenyl)ethinyl)benzoic acid (3 g, 7.5 mmol) in 100 ml of tetrahydrofuran and 100 ml of acetic acid hydronaut over 0.3 g of palladium (10%) coal at atmospheric pressure and room temperature for 27 hours the Catalyst is filtered off in the solvent is evaporated. The residue is dissolved in a solution of 0.3 g of sodium hydroxide in a mixture of 30 ml of acetone and 30 ml of water. The solution is acidified with hydrochloric acid at about 50oC. After cooling, the product crystallizes, giving 1.6 g of the substance (52%).

Range PMR: Spin system A: for 6.81 (d), 7,29 (DD), to 7.61 (d) (=salicylate ring)

Spin system B: to 7.35 (d, 2H), 7,76 (d, 2H) (the Central benzene ring)

Spin system C: 7,13 (W), to 7.67 (DDD), at 6.84 (DDD), 7,98 (d) (=pyridine ring)

Spin system D: 2,7 - 2,9 (m, 4H), (=identially bridge)

Example 27. 2-Hydroxy-5-((4-((3-methyl-2-pyridinylamino(sulfonyl)phenyl)acetyl benzoic acid.

A solution of 2-hydroxy-5-((4-((3-methyl-2-pyridinylamino(sulfonyl) phenyl)ethinyl)benzoic acid (4.1 g, 10 mmol) in 100 ml of formic acid is boiled for 27 hours Add 200 ml of water and the product crystallizes, giving 3.0 g of the substance (71%).

Range PMR: Spin system A: 7,08 (d), to 8.20 (DD), 8,48 (=salicylate ring)
Spin system D: 4,45 (C) (=methylene bridge)

Spin system E: 2,15 (cm.) (=methyl group).

Example 28. 2-Hydroxy-5-(2-(4-((2-pyridinylamino(sulfonyl)-phenyl)acetyl) benzoic acid.

This substance was prepared from 2-hydroxy-5-((4-(2- pyridinylamino)sulfonyl)phenyl)ethinyl)benzoic acid according to the method of example 27.

Range of PMR. Spin system A: 7,05 (d) to 8.14 (DD) 8,44 (d) (=salicylate ring)

Spin system B: 7,38 (d, 2H), 7,81 (d, 2H), (=Central benzene ring)

Spin system C: 7,16 (DD) of 7.69 (DDD) 6,84 (DDD), 7,98 (DD) (=pyridine ring)

Spin system D: 4,4 (C) (=methylene bridge)

Example 29. 2-Hydroxy-5-(1-oxo-3-(4-((2-pyridinylamino)sulfonyl)phenyl)-2 - propyl)benzoic acid

4-Formyl-N-(2-pyridinyl)benzosulfimide (5.7 g, 22 mmol), 5-acetyl-2-hydroxybenzoic acid (6,64 g, 44 mmol) in 20 ml of 5 molar sodium hydroxide solution is stirred 3 days at room temperature. The solution was diluted with 100 ml of water and added dropwise an excess of acetic acid. The precipitate is collected by filtration and washed with water. After drying, the material is subjected to recrystallization from acetic acid and dried at 120oC in vacuum, the yield of 6.4 g (66 %).

Range PMR: Spin system A:

Spin system C: of 7.23 (d), 7,76 (DDD), to 6.88 (DDD), 8,02 (m) (=pyridine ring)

Spin system D: / to 7.77 (d), 8,02 (=oxopropanoic bridge)

Example 30. 2-Hydroxy-5-((4-((3-methyl-2-pyridinylamino) sulfonyl)phenyl)ethinyl)benzoic acid.

Example 30a. 4-Methylphenylene ether 4-iodobenzonitrile.

4-Iodo-benzosulphochloride (604 g, 2 mol) is added with stirring to a solution of 227 g (2.1 mol) of 2-METHYLPHENOL and 222 g (2.2 mol) of triethylamine in 1.5 l of toluene. The suspension is stirred at 60oC 2 h the Reaction mixture was added to excess dilute hydrochloric acid. The precipitate is filtered and washed with ethanol. The second collection of the product obtained when the concentration of toluene mother liquor and collect solid matter in the same way. Both collection is subjected to recrystallization from 2.5 liters of 2-propanol. The output of 680 g (91 %).

Example 30b. 4-Methylphenacyl ester 4-(2-trimethylsilylethynyl)- benzosulfimide

4-Methylphenylene ether 4-identicality (374 g, 1 mol) is dissolved in 1 l of tetrahydrofuran. Add 200 g (2 mol) of triethylamine, 1.1 g of dichlorobis(triphenylphosphine)palladium (1.6 mmol) and 1.9 g (10 mmol) of copper iodide (1). The solution is heated to 40oC for 15 minutes Add 108 g trimethylsilyl the effect the color of the reaction mixture changes from yellow to brownish-green. The reaction mixture was kept at approximately 40oC 30 min, filtered from the solid material, and the solvent is evaporated. The residue is dissolved in toluene and washed with diluted hydrochloric acid. After drying and treatment with activated charcoal, the solution is evaporated. Receive 392 g of oily product containing some toluene. This material is directly used in the next stage without additional purification.

Example 30C. 4-Methylphenacyl ester 4-(2-trimethylsilylethynyl) benzosulfimide with the previous stage (392 g) dissolved in 800 ml of dimethylformamide. Add 20 ml of water and potassium fluoride (50 g, 860 mmol). The solution becomes dark. After 20 min, it was diluted with water, and precipitated precipitated oily product soon hardens. This material is collected and dissolved in boiling heptane (4 l). The solution is treated with activated charcoal and dried with magnesium sulfate. After filtering the solution through a layer of 1 cm of aluminum oxide receive a crystalline product in the three stages of crystallization and evaporation. Get a total of 242 g of product (89%) in stage 2 of the 4-methylphenylene ether 4-iodobenzonitrile.

Example 30d. Ethyl ester of 2-hydroxy-5-((4-((4- methylp (58.5 g, 200 mmol), 4-methylphenylene ether 4-ethynylbenzaldehyde (54,4 g, 200 mmol) and triethylamine (40 g, 400 mmol) is dissolved in 100 g of tetrahydrofuran. The solution is heated to 50oC and simultaneously added with stirring 0.5 g dichlorobis(triphenylphosphine)palladium (to 0.72 mmol) and 1 g (5.2 mmol) of copper iodide (1). The reaction mixture becomes dark, and after about 10 min it starts to precipitate idiscovery the triethylamine. After keeping at 45oC 45 min, the suspension was poured into diluted hydrochloric acid, and the mixture is extracted with toluene. Toluene solution is evaporated to dryness. The residue is triturated in acetonitrile, filtered and dried. The yield was 73 g (84%). Combines material from several downloads (270 g) is subjected to recrystallization from 1.2 l of acetonitrile and receive 250 g of the product.

Example 30e. Ethyl ester of 2-hydroxy-5-((4-sulfophenyl)ethinyl) benzoic acid, potassium salt.

Mix 500 ml of ethanol and 100 ml of toluene and 200 ml distilled added in several Portions of 11.5 g (0.5 mol) of metallic sodium. The solution ethoxide sodium is heated to boiling, add 43,6 g (100 mmol) of ethyl ester of 2-hydroxy-5-((4-(4-methylphenylsulfonyl)phenyl)ethinyl)benzoic acid and the solution is refluxed 30 minutes RAS washed with ethanol; dissolve in boiling water and add 90 g of potassium acetate. The solution is cooled to room temperature, and the crystalline product filtered off, washed with acetone and dried at 100oC. the Yield is almost quantitative. The product contains some inorganic salts.

Example 30f. Ethyl ester of 2-hydroxy-5-((4-chlorosulfonylphenyl) ethinyl)benzoic acid.

Suspended in 100 ml of toluene 19 g (50 mmol) of potassium salt of ethyl ester of 2-hydroxy-5-((4-sulfophenyl)ethinyl)benzoic acid. Add 2 ml of dimethylformamide and 12 g of chloride tonila, and the suspension is boiled for 1 hour under reflux. The reaction mixture was added to an almost saturated solution of sodium chloride, and precipitated precipitated oil is extracted with toluene. The solution is dried to dryness. This product is sufficiently pure for use in the next stage. Yield 16 g, 88%.

Example 30g. Ethyl ester of 2-atomic charges-5-((4-chlorosulfonylphenyl) ethinyl)benzoic acid.

Ethyl ester of 2-hydroxy-5-((4-chlorosulfonylphenyl)ethinyl) benzoic acid (16 g, 44 mol) is dissolved in 40 ml of acetic anhydride at 120oC. are added dropwise in about 0.4 ml of sulfuric acid. After 5 min the solution was diluted with toluene (primer the Aulnay solution is dried and evaporated. Add toluene and evaporation is repeated. The oily product crystallized. This product is sufficiently pure for use in the next stage. Yield 17 g, 95%.

Example 30h. 2-Hydroxy-5-((3-methyl-2-pyridinylamino)sulfonyl) phenyl)ethinyl)benzoic acid.

3-Methyl-2-pyridylamine (1.3 g, 12 mmol) dissolved in dried pyridine (20 ml) and add ethyl ester 2-atomic charges-5-((4 - chlorosulfonylphenyl)ethinyl)benzoic acid (4.1 g, 10 mmol). The solution is incubated 18 h at room temperature. The solvent is evaporated and the residue is dissolved in a small amount of tetrahydrofuran. This solution is added to the boiling solution of potassium hydroxide (6 g) in 100 ml of water and 50 ml of ethanol (under reflux). After 15 min the solution is acidified with formic acid to fell the sediment. The solid is collected by filtration, washed and dried. Yield 1.2 g (29 %).

An NMR spectrum confirms the identity of the substance with the product of example 2.

Example 31. 2-Hydroxy-5-((4-((3-phenylmethoxy)-2-pyridinylamino) sulfonyl)phenyl)ethinyl)benzoic acid.

This substance was prepared according to the method of example 30h. The product was recrystallized from acetic acid and then from nitromethane. is the based ring)

Spin system B: 7.7 (d, 2H, overlap with other signals), 8,02 (d, 2H) (=Central benzene ring)

Spin system C: 7,40 (d, W), 6,97 (Shir. t), 7,7 (overlap with other signals) (=pyridine ring)

Spin system D: 7,53 (d, 2H), 7,43 (t, 2H), was 7.36 (t) (=phenyl group)

Spin system F: 5,10 (C) (=methylene bridge)

Example 32. 5-((4-((5-Chloro-2-pyridinylamino)sulfonyl)phenyl)- ethinyl)-2-hydroxy-benzoic acid.

This substance was synthesized according to the method of Example 30h. The product was recrystallized from a mixture of dimethoxyethane/methylcyclohexane. Yield 58%.

Range PMR: Spin system A: 7.04 (d), of 7.70 (DD), 7,99 (d) (=salicylate ring)

Spin system B: 7,73 (d, 2H), 7,94 (d, 2H) (=Central benzene ring)

Spin system C: 7,12 (d), 7.82 (DD) 8,23 (d) (=pyridine ring)

Example 33. 2-hydroxy-5-((4-((4-methyl-2-pyridinylamino)sulfonyl) phenyl)ethinyl)benzoic acid.

This substance was synthesized according to the method of example 30h. The product was dissolved in a potassium hydroxide at a pH of about 9. Was added potassium acetate and precipitated precipitated potassium salt is collected by filtration. This salt is dissolved in 100 ml of water and 50 ml of ethanol, and the product precipitated in the acidification with formic acid. Then add Solano, 61%.

Range PMR: Spin system A:? 7.04 baby mortality (d), and 7.7 (DD), 7,98 (d) (=salicylate ring)

Spin system B: to 7.68 (d, 2H), 7,89 (d, 2H) (=Central benzene ring)

Spin system C: 6,70 (DD), 7,07 (W), of 7.82 (d) (=pyridine ring)

Spin system D: 2,24 (s) (=methyl group)

Example 34. 2-Hydroxy-5-((4-((6-fluoro-(2-benzo/d/thiazolylazo) sulfonyl)phenyl)ethinyl)benzoic acid.

This substance was synthesized according to the method of example 30h. The product was dissolved in sodium hydroxide and carefully neutralized to pH about 7. A certain amount of a solid substance is filtered off and the solution is again precipitated by the addition of formic and hydrochloric acids, as in the previous example. The release of substances 2.2 g, 47%.

Range PMR: Spin system A: 7,03 (d), and 7.7 (DD), 7,99 (d) (=salicylate ring)

Spin system B: 7,74 (d, 2H), of 7.90 (d, 2H) (=Central benzene ring)

Spin system C: 7,79 (DD), 7,27 (DDD), 7,33 (DD) (=benzothiazole ring)

Example 35. 2-Hydroxy-5-((4-(N-methyl-(2-pyridinyl)amino)sulfonyl) phenyl)ethinyl)benzoic acid.

This substance was synthesized according to the method of example 30h. Yield 2.6 g, 64%.

Range PMR: Spin system A: 7,05 (d), and 7.7 (DD overlapping with other signals), 8,01 (d) (=salicylate ring)

Spin -) (=pyridine ring)

Spin system E: 3,2 (C) (=methyl group)

Example 36. 2-Hydroxy-5-((4-((5-methyl-3-isoxazolyl)aminosulfonyl) phenyl)ethinyl)benzoic acid.

Example 36a. Ethyl ester of 2-hydroxy-5-((4-((5-methyl-3-isoxazolyl). aminosulfonyl)phenyl)ethinyl)benzoic acid

5-Methyl-3-isoxazolin (1.2 g, 13 mmol) dissolved in dried pyridine (20 ml) and add ethyl ester 2-atomic charges-5-((4-chlorosulfonyl)phenyl)ethinyl)benzoic acid (4.1 g, 10 mmol). The solution is incubated for 72 h at room temperature. The solvent is evaporated and the residue is dissolved in a small amount of tetrahydrofuran. This solution is added to the boiling solution of potassium hydroxide (2.5 g, 38 mmol) in 100 ml of water (under reflux). After 5 min add 50 ml of ethanol and the solution is acidified with formic acid to fell the sediment. The solid is collected by filtration, washed and dried. After recrystallization from ethanol (3 times) yield 1.5 g (35%).

Example 36b. 2-Hydroxy-5-((4-((5-methyl-3-isoxazolyl)aminosulfonyl) phenyl)ethinyl)benzoic acid.

Ethyl ester of 2-hydroxy-5-((4-((5-methyl-3-isoxazolyl)aminosulfonyl) phenyl)ethinyl)benzoic acid (1.5 g) is added to the boiling solution of potassium hydroxide (6 g, 92 mmol) in 100 ml podpromie with water and dried. Output 1.4 g, quantitative.

Range PMR: Spin system A: 7,02 (d), to 7.68 (DD), 7,97 (d) (=salicylate ring)

Spin system B: 7,74 (d, 2H), 7,87 (d, 2H) (=Central benzene ring)

Spin system C: 6,14 (C) (=isoxazolone ring)

Spin system E: 2,25 (C) (=methyl group)

Example 37. 4-fluoro-2-hydroxy-5-(2-(4-((3-methyl-2-pyridinylamino) sulfonyl)phenyl)ethinyl)benzoic acid.

Example 37a. Ethyl ester of 4-fluoro-2-hydroxybenzoic acid.

10.8 g of 4-fluoro-2-hydroxybenzoic acid (70 mmol), sodium acetate (6.9 g, 84 mmol), modesty ethyl (55 g, 0.35 mol) and dimethylformamide is stirred at room temperature for 48 hours the Mixture was poured into water and extracted with her n-heptane. The solution is filtered through a layer of silica gel and evaporated. The remainder is composed of almost pure product and is used directly in the next stage. The output of 10.2 g, 80%.

Example 37b. Ethyl ester of 4-fluoro-2-hydroxy-5-iodobenzoyl acid.

10.2 g of Ethyl ester of 4-fluoro-2-hydroxybenzoic acid (55 mmol) dissolved in n-heptane. Monochloride iodine (12 g, 74 mmol) added dropwise with stirring at room temperature. After 1 h, water is added and then small portions of solid sodium sulfite until pochesnuy phase is dried and concentrated. The product crystallizes upon cooling. It is collected by filtration and washed with cold n-heptane. Output in raw form was 10, the Product is a mixture of the ethyl ester of 4-fluoro-2-hydroxy-5-iodobenzoyl acid (about 80%) and about 20% of its 5-chloro-analogue.

Example 37c. Ethyl ester of 4-fluoro-2-hydroxy-5-((4-((3-methyl - 2-pyridinylamino)sulfonyl)phenyl)ethinyl)benzoic acid.

Ethyl ester of 4-fluoro-2-hydroxy-5-iodobenzoyl acid (3.6 g, 80%, 10 mmol), 4-ethinyl-N-(3-methyl-2-pyridinyl)benzosulfimide (2.7 g, 10 mmol) and triethylamine (5 g, 50 mmol) suspended in tetrahydrofuran (20 ml) and the mixture is heated to 50oC. 45 mg Dichlorobis(triphenylphosphine)palladium (0.06 mmol) and 76 mg (0.4 mmol) of copper iodide (I) is added under stirring. After about 15 min, is formed almost clear solution. After 3 h at 50oC the solution is evaporated to dryness and the residue triturated with isobutylmethylxanthine and diluted hydrochloric acid. The organic phase is separated and the solvent is evaporated. The oily residue is triturated with a small amount of acetonitrile, to form crystals. The latter is recrystallized from acetic acid. The product is dissolved in a small amount of chloroform, and which the product is obtained after evaporation of the solvent, output 2 g (44%).

Example 37d. 4-fluoro-2-hydroxy-5-((4-((3-methyl-2-pyridinylamino) sulfonyl)phenyl)ethinyl)benzoic acid.

2,0 Ethyl ester 4-fluoro-2-hydroxy-5-((4-((3-methyl - 2-pyridinylamino)sulfonyl)phenyl)ethinyl)benzoic acid (4.4 mmol) is added to a boiling solution of 2.0 g of potassium hydroxide in 50 ml of water. After 15 min add 50 ml water and 50 ml of ethanol, and the solution is acidified with formic acid and hydrochloric acid. After cooling, the precipitate is filtered off and dried. The quantitative output.

Range PMR (solvent triperoxonane acid):

Spin system A: 6,80 (d), 8,21 (d), (=salicylate ring)

Spin system B: 7,72 (d, 2H), to $ 7.91 (d, 2H) (=Central benzene ring)

Spin system C: to 7.64 (DD), 8,31 (d), 8,46 (d) (=pyridine ring)

Spin system D: 2,35 (C) (=methyl group)

Example 38. 4-fluoro-2-hydroxy-5-(2-(4-((3-methyl-2-pyridinylamino) sulfonyl)phenyl)ethinyl)benzoic acid.

Example 38a. Ethyl ester of 4-fluoro-2-hydroxy-5-(2-(4-((3-methyl - 2-pyridinylamino)sulfonyl)phenyl)ethinyl)benzoic acid.

Ethyl ester of 4-fluoro-2-hydroxy-5-iodobenzoyl acid (3.6 g, 80%, 10 mmol), 4-ethinyl-N-(3-methyl-2-pyridinyl)benzosulfimide (2.7 g, 10 mmol), 5 ml of triethylamine and 5 ml of N,N-dimethylacetamide UP>oC. the Solution was poured into water and the precipitate is dissolved in chloroform. The solution is dried, served on top short silikagelevye column and elute his isobutylmethylxanthine (30%) in toluene. Pure fractions are collected and evaporated to dryness. After trituration with acetonitrile product kristallizuetsya, exit 1,1,

Example 38b. 4-fluoro-2-hydroxy-5-(2-(4-((3-methyl-2-pyridinylamino) sulfonyl)phenyl)ethinyl)benzoic acid.

1.1 g of Ethyl ester of 4-fluoro-2-hydroxy-5-(2-(4-((3-methyl - 2-pyridinylamino)sulfonyl)phenyl)ethinyl)benzoic acid (2.4 mmol) is added to a boiling solution of 2.0 g of potassium hydroxide in 50 ml of water. To obtain a clear solution add 10 ml of ethanol. After 15 min add 25 ml of ethanol, and the solution neutralized to pH about 7 with formic acid. Slightly opalescent solution is treated with activated charcoal and acidified with formic acid. After cooling, the precipitate is filtered off and dried. The output of 0.8 g

Range PMR (solvent triperoxonane acid):

Spin system A: 6,79 (d), 8,29 (d), (=salicylate ring)

Spin system B: 7,72 (d, 2H), of 7.90 (d, 2H) (=Central benzene ring)

Spin system C: a 7.62 (DD), 8,29 (d), 8,44 (d) (=pyridine ring)

Spin system D: 7,21 (d), 7,35 (d) (=atendimento)sulfonyl) phenyl)ethinyl)benzoic acid.

Example 39a. 3-Iodine-N-(3-methyl-2-pyridinyl)benzosulfimide.

32,4 g 3-Methyl-2-pyridylamine (0.3 mol) is dissolved in 200 ml of isobutylmethylxanthine and with stirring, add 3-iodobenzonitrile (30,2 g, 100 mmol). The solution is incubated for 8 h at 40oC and then added to dilute hydrochloric acid. The precipitate is filtered off and the organic phase is separated and evaporated. The residue is combined with the first solid material is recrystallized from ethanol. The crystals are dissolved in 1-molar sodium hydroxide solution (about 200 ml) and extracted 3 times with isobutylmethylxanthine (100 ml). The aqueous phase is partially evaporated to remove the remnants of isobutylmethylxanthine. Add 100 ml of ethanol, and the solution is acidified with acetic acid. The precipitate is filtered off, washed with water and dried. Output is 23 g, 61%.

Example 39b. Ethyl ester of 2-hydroxy-5-((3-((3-methyl - 2-pyridinylamino)sulfonyl)phenyl)ethinyl)benzoic acid.

3-Iodine-N-(3-methyl-2-pyridinyl)benzosulfimide (18.7 g, 50 mmol), ethyl ester of 5-ethinyl-2-hydroxybenzoic acid (9.5 g, 50 mmol), 65 ml of triethylamine and 65 ml of tetrahydrofuran was stirred at 60oC. With stirring, add dichlorobis(triphenylphosphine)palladium (250 mg, 0.36 mmol) and the acetate. The organic phase is washed with water, dried, treated with activated charcoal, and the solvent is evaporated. The residue is subjected to recrystallization from methanol, then from toluene, and finally from acetic acid. The output amounted to 12.7 g, 58%.

Example 39c. 2-Hydroxy-5-((3-((3-methyl-2-pyridinylamino)sulfonyl) phenyl)ethinyl)benzoic acid.

Ethyl ester of 2-hydroxy-5-((3-((3-methyl-2-pyridinylamino)sulfonyl) phenyl)ethinyl)benzoic acid (4 g, 9.2 mmol) is added to the boiling solution of potassium hydroxide (6 g, 90 mmol) in 100 ml of water. After 15 min add 50 ml of ethanol, and the solution is acidified with hydrochloric acid. The product is collected by filtration and dried at 110oC. the Output is 3.5 g, 93%.

Range PMR: Spin system A: 7,00 (d), to 7.68 (DD), 7,97 (d) (=salicylate ring)

Spin system B: 7,55(t), 7,69(d), of 7.90(d), of 8.06(C): the Central benzene ring)

Spin system C: a 7.62(d, Shir. ), 6,78 (t Shir. ), 7,81 (S. lat.) (pyridine ring)

Spin system D: b 2,10 (C) (methyl group).

The broadening of the signals of the pyridine ring is typical for 3-methylseleninic derivatives.

Example 40. Effects of substances on the proliferation of human lymphocytes.

Menagerie cells in peripheral blood is h, as described by Bain and Zilch in the journal Transplantation Proc., volume 4, S. 163-164 (1972). The multiplication of cells, caused by Concavalin A, measured in the standard analysis, as described by Cederstrom and others in Scand. J. Immunol., volume 32, S. 503-516 (1990) using 5% fetal bovine serum in the culture medium. The reaction mixture (final concentration) contained 200 thousand cells stimulated with 2.5 μg/ml Concavalin A, and the subjects of the substance in a total volume of 0.2 ml of Subjects substances were added at the beginning of the test, which was conducted in total over 3 days with the addition of radioactive (tritium)-thymidine during the last 18 hours. Radioactivity binding to cells was measured in a liquid acquired scintillation counter.

In table.1 illustrates the inhibitory effect of the tested substances (250 µmol/l) on proliferation of human lymphocytes caused by Concavalin A. Data obtained from two experiments and are shown as percent inhibition of reproduction in the absence of the tested substances

Example 41. The effect of the tested substances on the formation of superoxide granulocytes person.

Granulocytes were isolated from heparinized blood of healthy donors. Superoxide analysis was almost so, is Toxicol., Tom. 65, S. 121-127 (1989). The reaction mixture (final concentration) contained 125 µmol/l cytochrome C in phosphate buffer Dulbeccos, with magnesium and calcium, 10 µmol/l of substance used and 400 thousand granulocytes treated with 5 mg/l of cytochalasin B immediately before the experience. The reaction mixture was pre-incubated at 37oC for 10 min, then add 10 nanomoles/l N-formyl-L-methionyl-L-phenylalanine (FMLF) to start the reaction, bringing the final volume up to 1 ml After 10 min the tubes centrifuged and measure the absorption of the supernatant at 540 and 550 nm. The amount of the formed superoxide is expressed as the difference between the absorptions at these wavelengths.

In table.2 illustrates the inhibitory activity of the test substances (10 µmol/l) on the formation of superoxide induced FMLF. Data are given as percentage of inhibition of the formation of superoxide in the absence of the tested substances.

Example 42. The effect of the tested substances on the formation of superoxide granulocytes person at a concentration of 100 µmol/L.

Granulocytes were isolated from heparinized blood of healthy donors. Superoxide analysis was the same as described Mac-Cord and Fridav the th mixture (final concentration) contained 125 µmol/l cytochrome C in phosphate buffer Dulbeccos, with magnesium and calcium, 100 µmol/l of the test substance and 600 thousand granulocytes treated with 5 mg/l of cytochalasin B immediately before the experience. The reaction mixture is previously kept at 37oC for 10 min, then was added 100 nanomoles/l N-formyl-L-methionyl - 1-phenylalanine (FMLP) to start the reaction, bring the final volume to 1 ml After 10 minutes, the tubes centrifuged and measure the absorption of the supernatant at 540 and 550 nm. The amount of the formed superoxide is expressed as the difference between the absorption at these wavelengths.

In tab. 3 illustrates the inhibitory effect of the tested substances (100 µmol/l) on the formation of superoxide induced FMLF. Data are given as percentage of inhibition of the formation of superoxide in the absence of the tested substances.

Example 43. Compound a: 2-hydroxy-5-[[4[(5-hydroxy-3-methyl - 2-pyridinylamino)sulfonyl]phenyl]ethinyl]benzoic acid.

This compound was synthesized analogously to example 39 the interaction of 4-iodo-N-(5-hydroxy-3-methyl-2-pyridinyl) benzosulfimide with ethyl-5-ethinyl-2-hydroxybenzoate and followed by hydrolysis.

1H-NMR: spin. A: 7,06 (d), 7,73 (dd, overlaps with other sigeco)

The spin. system: 7,14 (d), 7.62mm (d) : (=pyridine ring).

The spin. system E: 2,2 (S) : (=methyl group).

Example 44. Connection: 2-hydroxy-3-[2-[4-[(3-methyl-2 - pyridinylamino)sulfonyl]phenyl]ethinyl]-benzoic acid.

This compound was synthesized analogously to example 12 by the interaction of 4-ethinyl-N-(3-methyl-2-pyridinyl)benzosulfimide with ethyl 2-hydroxy-3-iodobenzoate and followed by hydrolysis.

1H-NMR: Spin. A: 6,99 (t), 7,80 (dd), 7,94 (dd) : (=salicylate ring).

The spin. system: 7,73 (d, 2H), 7,92 (d, 2H) : (=Central benzene ring).

The spin. system: at 6.84 (dd), 7,66 (dd), 7,87 (dd) (=pyridine ring).

The spin. system D: 7,40 (d), 7,54 (d) : (=atanomy bridge).

The spin. system E: 2,15 (s) : (=methyl group).

Example 45. Connection: 2-hydroxy-4-[[3-[(3-methyl-2-pyridinylamino) sulfonyl]phenyl]-ethinyl]benzoic acid.

This compound was synthesized analogously to example 10 by the interaction of 4-ethinyl] -N-(3-methyl-2-pyridinyl)benzosulfimide with methyl-4-iodo-2-hydroxybenzoate and followed by hydrolysis.

1H-NMR: Spin. system a: 7,16 (d), 7,12 (dd), 7,84 (d) : (salicylate ring).

The spin. system: 7,74 (d, 2H), of 7.97 (d, 2H) : (=Central ber CLASS="ptx2">

The spin. system D: 2,15 (s) : (=methyl group)

Expansion of signals in the pyridine ring is typical for 3-methylseleninic derivatives.

Biological test results of new connections:

1'. According to the method of example 42 applications. Connection example 2' the application was included for comparison (see table. 4).

Note to the table.4: Connection And could not be tested on this system during a chemical reaction with one of the components of the system.

2'. According to the method of example 40 applications. Connection example 2' in the application included for comparison. (see tab. 5)

1. Salicylic acid derivatives of General formula

Gets - NR-SO2-Ph1A Ph2(COOH) (OH) (I),

where Het represents (R1, R2, R3)-Het1;

Gets the1is a cyclic group.

< / BR>
in which the free valence is associated with a group NR;

X represents a group:

a) -O-CH=CH-, -CH=CH-O-, -CH=CH-S - or

b) - CH=CH-CH=CH-, -CH=CH-CH=N-, -CH=N-CH=CH-, -CH=CH-N=CH-, -N=CH-CH= CH-,

moreover, the cyclic group may contain precondensation benzene ring;

R1, R2and R3are substituents at the carbon atom in Het and represent hydrogen, C - C6-alkyl;

Ph1- phenylene;

Ph2is phenyl which may be substituted with halogen, lower alkyl or benzyloxypropionic,

provided that the carboxy - and hydroxy-group are orthopaedie to each other;

A represents-CH=CH-, -CH2-CH2-, -CO-CH=CH-, -CH=CH-CO - or-CH2-CO-,

their alkalemia esters containing from 1 to 6 carbon atoms in the ether group, a salt and a solvate.

2. Connection on p. 1, in which A and SO2located in the para - or meta-position to each other in Ph1and the hydroxy-group and A are in the para-position to each other in Ph2.

3. Connection PP.1 and 2, in which A represents an or-CH= CH-.

4. Connection PP.1 to 3, in which R is hydrogen.

5. Connection PP.1 to 3, in which R is C1- C6-alkyl.

6. Connection PP.1 to 3, in which R is the stands.

7. Connection PP. 1 to 6, in which X represents-O-CH=CH-, -CH=CH-O-or-CH=CH-S-.

8. Connection PP.1 to 6, in which X represents-CH=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH - or-N=CH-CH=CH-.

9. Connection PP.1 to 8, in which Het1represents a monocyclic structure.

10. Connection PP.1 - rich R1and R2represent hydrogen, R3has specified in paragraph 1.

12. Connection PP.1 to 10, in which R1, R2and R3represent hydrogen.

13. Connection PP.1 to 12, in which Het1represents pyridine.

14. Connection on p. 13, in which A represents an or-CH=CH - and R3represents methyl.

15. Connection on p. 14, in which R is hydrogen.

 

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