CZ120794A3 - Novel substituted salicylic acids - Google Patents

Abstract

Salicylic acid derivs. of formula Het-NR-SO2-Ph1-A-Ph2(COOH)(OH) (I), their tautomeric forms, salts, solvates and lower alkyl esters are new. In (I), Ph1 and Ph2 are opt. substd. benzene provided that the COOH and OH gps. are ortho; A is a bridge which is stable to redn. because it is not azo; Het is opt. substd heterocycle which includes conjugated double bonds; and R is H or lower alkyl. A is pref. a straight carbon chain having at most 3C atoms, esp including one -C-C-, -C=C- or -C=C- opt. together with a C=O gp., Het is pref. (R1, R2, R3)-Het', where Het' is gp. of formula (a); X is -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-, -CH=CH-CH=CH-, -CH=CH-CH=N-, -CH=N-CH=CH-, -CH=CH-N=CH- or -N=CH-CH=CH- (where same mutually adjacent hydrogens can be substd. in pairs by -CH=CH-CH=CH- to form a bicyclic ring); and R1, R2 and R3 are H, lower alkyl, halo, OH, CN, COOH, lower alkoxy, benzyloxy, lower acyl, phenyl or benzyl.

Description

BACKGROUND OF THE INVENTION

It is known that compounds containing a salicylic acid structure bound by a reductively cleavable bridge of -N = N- (= -A-) to benzenesulfonic acid at the ring position, which in turn is amidated at the amino group of the heterocyclic ring substituted with an amine, which includes conjugated double bonds, may exert a therapeutic effect against ulcerative colitis, rheumatoid arthritis and other diseases believed to be autoimmune, see, for example, Askelof et al., U.S. Patent No. 2,396,145A, Agback and Lindblom, U.S. Patent No. 5,901,549. No. 3,915,951, T. Pillar, Br. J. Clin. Pharmacol., 30, 501-510 (1990), I. G. Tumanova and Ja. A. Sigidin: Ther-Arkh. 59, 80-83 (1987); S. Pacheco, K.

Hillier and C.L. Smith, Brasilian J. Med. Biol. Res. 22, 1323-1343 (1990) and C. Astbury, J. Hill, J.R. Lowe, D. Campbell and H.A. Bird, British J. Rheumatology, 29, 465-467 (1990). Autoimmune diseases have been described and exemplified by, for example, I. Roitt and J. Brostoff in Immunology, 2nd Ed. (1989).

The best known compound having the above therapeutic effect is sulasalazine. Although sulfasalazine analogs have been described, none of them have the resulting properties that are required for an acceptable drug substance.

Sulfasalazine is clinically effective for the treatment of autoimmune diseases such as ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, reactive arthritis, psoriasis and psoriatic arthritis, including, for example, D. R. Porter and H. A. Caps, B. J. Clins Clin. Rheurol. 4.,

535-551 (1990), Μ. Ferraz B., Tugvell P., C. H. C-oldsmith.

and E. Atra, J. Rheumatol., 17, 1482-1486 (1990), A. K.

Gupta, C.N. Ellis, Μ. T. Siegel, E.A. Duell, C.E. 14. Griffiths, T.A. Hamilton, B.J. Nickoloff and J.J. Voorhees: Arch. Dermatol. 126, 489-493 (1990), G. Watkinson: Drugs,

32 ´ (suppl. 1), 1-11 (1986).

The drugs most commonly prescribed for the treatment of rheumatoid arthritis are anti-inflammatory drugs, so-called NSAIDs (Nonsteroidal Anti-Inflammatory Drugs)

non-steroidal anti-inflammatory drugs). These active substances are believed to counteract the symptoms of the disease. In contrast, sulfasalazine is classified as a disease modifying drug. It also belongs to the same class of drugs as gold salt, penicillamine, chloroquine and the immunosuppressive drugs methotrexate, azathioprine and cyclophosphamide, all of which have distinctly different structures.

A number of pharmacological model systems are available for evaluating active substances ⁷ that are potentially useful in the treatment of autoimmune diseases. One of the most important properties of non-steroidal anti-inflammatory drugs in such model systems is their ability to prevent prostaglandin synthesis and associated biological effects.

Sulfasalazine differs significantly from the active types of related non-steroidal anti-inflammatory drugs in such model systems both clinically and experimentally. Sulfasalazine is characterized in a number of models which are believed to be relevant to the disclosed disease modifying active ingredient. For example, it has been found that activation of immunocompetent anti-inflammatory cells is influenced by sulfasalazine because it inhibits T-cell activation and proliferation as well as granulocyte activation and mediator release.

The clinical effect of sulfasalazine when treating ulcerative colitis is attributed to 5-aminosalicylic acid, which is formed by reductive cleavage of the parent molecule in the colon. At the same time, sulfapyridine is formed. If other autoimmune diseases are treated, such as rheumatoid arthritis, the intact sulfasalazine molecule or the released sulfapyridine, or most likely both, should be considered as the active ingredient. The secondary effects of sulfasalazine are particularly considered related to the released sulfapyridine.

SUMMARY OF THE INVENTION

The present inventors have now discovered a new type of sulfasalazine analogues that exhibit time bioavailability and effects in models used to study autoimmune diseases such as rherumatoid arthiritis and ulcerative colitis. The analogs have the above structure but with the azo group (A) replaced by a bridge, and are stable to hydrolysis and / or reduction in vivo, for example in the colon.

Such compounds are novel. Thus, in its broadest sense, the invention includes compounds of the structure of Formula I

Het-NR-SO ₂ -Ph ¹ -A-Ph ² (COOH) (OH) (I), and tautomeric forms, salts and solvates and, optionally, C 1 -C 6 alkyl esters of the carboxy group.

In the above structure given by the formula I, Het is a heterocyclic ring as described above, Ph ¹ is a benzene ring, Phg (COOH) (OH) is a benzene ring with a carboxy and hydroxy group in the crtho position relative to each other,

R represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms;

carbon atoms. Het, Ph ¹ , Ph ² (COOH) (OH) and bridge A may be substituted.

The compounds are characterized in that A is a bridge that is stable to hydrolysis and / or reduction in biological systems. Preferably, A represents a straight carbon chain containing at most three carbon atoms (-CCC-), which comprises a single bond, a double bond or a triple carbon-carbon bond, optionally together with an oxo substituent (= O) on one of the carbon atoms in the chain. The term stable to hydrolysis and / or reduction means that A does not have a nitrogen-nitrogen bond, such as an azo group, and optionally also for the hydrolysis of a labile ester and amide bond, as a binding structure between Ph ¹ and Ph ² .

In a particular embodiment, Ph ¹ is a 1,4- or 1,3-substituted benzene moiety and Ph ² (COOH) (OH) is an ortho phenyl substituted with a carboxy and hydroxy group, which may optionally be further substituted with a halogen atom or a lower alkyl group with 1 to 6 carbon atoms, preferably methyl, in the 3, 4 or 6 position. A is -C-C-, -CH = CH-, -CH ₂ CH ₂ -, -CO-CH = CH-, -CH = CHCO - or -ch ₂ co-.

In a particular embodiment of the compounds found, the heterocyclic ring Het represents a five or six membered ring containing two or three conjugated double bonds. The heterocyclic ring Het may be incorporated into a monocyclic or bicyclic structure. Preferred Het- represents a group of formula (R ₁ , R ₂ , R ₃ ) -Het ¹ -, wherein Het ¹ - represents a group of formula

^ = 0 where the free valence in this group is bound to NR-α

X represents a group of the formula

i) -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 (ii) -CH = CH-CH = CH-, -CH = CH-CH = N-, -CH = N-CH = CH-,

-CH = CH-N = CH-, -N = CH-CH = CH-, in which adjacent hydrogen atoms represented by bold (H) can be replaced in pairs by a group of formula -CH = CH-CH = CH- to a bicyclic structure could be formed.

R represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, preferably a hydrogen atom or a methyl group.

R ₁ , R 2 and R 3 are substituents on the carbon atoms of the Het group. These substituents may be a hydrogen atom having a C 1-6 alkyl group, a halogen atom, a hydroxy group, a cyano group, a carboxy group, a lower alkoxy group having 1 to 6 carbon atoms, a benzyloxy group, a lower acyl group having 1 to 7 carbon atoms. , including acetyl, benzoyl, nnyl, benzyl and the like, wherein some of the benzene rings present may be substituted.

In the specification and claims of this patent, azy lower alkyl group and a lower acyl group exchange groups containing 1 to 10 carbon atoms and 1 carbon atoms and optionally containing substituents above.

of this kind.

O

C? t i

í ro cn

X οι f

nc / 1. /

A is -C -CC-, optionally lower alkyl substituted by trans- or cis -CH = CH-, -CH ₂ -CH ₂ -, -CO-CH = CH-, -CH = CH-CO-, - CO -, - CH ₂ CO-, -CH ₂ -, Preferably —C = C - or trans-CH-CH-.

Ph ² is C ₈ H ₂ R ₄ , wherein R ₄ represents a hydrogen atom, a halogen atom or a lower alkyl group, preferably a hydrogen atom or a methyl group. They are also tautomeric forms of these compounds and salts with alkali metals, preferably sodium, calcium or magnesium or with pharmaceutically acceptable amines, as well as crystalline solvates which include pharmaceutically acceptable solvates such as water, acetone and ethanol, as well as pharmaceutical compositions of these compounds.

The present invention also relates to the use of the compound as a drug substance, in particular for the treatment of autoimmune diseases in an analogous manner to that of sulfasalazine, and optionally also for the treatment of other infectious conditions. Other features of the invention include the manufacture of the compounds of the invention and the use of these compounds for the manufacture of pharmaceutical compositions containing such compounds and intended for the medical indication mentioned below, particularly for the treatment of an autoimmune disease.

The compounds of the invention have an immunomodulatory effect on biological systems, for example they inhibit the activation of immunocompetent and inflammatory cells and their pharmacological profile is similar to that of sulfasalazine, but they are often more potent. Therefore, the compounds of the present invention are potent drugs for the treatment of such autoimmune diseases, such as rheumaroidini arthritis, ulcerative colitis, ankylosing spondylitis, reactive in

6a arthiritis, psoriasis, psoriatic arthritis, Morbus Crohn, multiple sclerosis, type 1 diabetes, scleroderma, severe

γMjf masthenie, Sjögrens disease, systemic lupus, erythematous and chronic asthma. The compounds of the invention may also optionally be used for the treatment of other diseases, particularly those diseases having an immunological component, regardless of whether the compounds are known in the medical field or not.

Since the new compounds are unable to form sulfapyridine or some other toxic analogs, due to the precise nature of these compounds, it is extremely likely that the compounds lose side effects due to free sulfapyridine. The experiments carried out by the present inventors show that the bioavailability for laboratory animals is often much greater for the compounds of the invention than for sulfasalazine and its analogs.

In summary, the novel compounds have been tested as highly effective therapeutic agents for the treatment of autoimmune diseases.

The novel compounds of the invention can be prepared in several ways.

One method involves reacting a compound of formula II (R _T, R _2, R ₃₎ -Het'-NR-SO ₂ -Ph ¹ -X (II) with a compound of formula III YC ₆ H ₄ R ₂ (COOR ₅ (OH) (III), in which formulas

R, R 1, R ₂ of R 3, R ₄ , Ph ¹ and Het have the same meanings as above,

R 8 represents a hydrogen atom or preferably a lower alkyl group having at most 6 carbon atoms and

X and Y as a pair are -C =CH and Z - ^ ^, -Z ^ and RC =C-, -CH = CH ₂ and Z ₁ ~, -Z ₁ and -CH = CH ₂ , -CO- CH ₃ and HCO-, -COH and CH ₃ -CO-, -CH ₂ CO _{2 2} and H-, -CHO and Z ₃ CH ₂ -, -CH ₂ Z ₃ and HCO-, where Z 1 represents a bromine atom or an iodine atom,

Z ₂ represents a halogen atom, preferably a chlorine atom and

Z ₃ is a Wittig-type organophosphorus compound residue, for example, a triphenylphosphonium group or a dialkylphosphonate residue.

Compounds of the formula II and of formula III are combined together in a known manner, and then, if R ₅ is lower alkyl, the reaction product is hydrolyzed, preferably in the presence of alkali metal hydroxide and then the resulting substance is acidified and then isolated.

When X and Y are -C =CH and Zj- or and HC = C-, the above coupling procedure is preferably carried out by the so-called Heck reaction, using catalysis with a palladium compound and a copper compound in the presence of a base and a solvent. Suitable palladium compounds are dichlorobis (triphenylphosphine) palladium, dichlorobis / tris (2-methylphenyl) palladium or tetrakis (triphenylphosphine) palladium. A suitable palladium compound may optionally be produced in situ using, for example, palladium (II) chloride or tricaldehyde together with triphenylphosphine, tris (2-meriphenyl) phosphinene, or

1,3-bis (diphenylphosphino) propane and the like. Appropriate copper

the compound is cuprous iodide or cuprous bromide. Suitable bases are amines, preferably tertiary amines, such as triethylamine or tributylamine or other inorganic or organic bases such as sodium bicarbonate or sodium acetate. Suitable solvents are, for example, Ν, Ν-dimethylacetamide, N, N-dimethylformamide, ethanol, acetone, tetrahydrofuran, dioxane, toluene and the like, preferably Ν, Ν-dimethylacetamide.

When X and Y are -CH = CH ₂ and -Z 2 and -CH ₂ and -CH = CH ₂ , the above-mentioned coupling is preferably carried out by a so-called Heck reaction, using palladium compound catalysis in the presence of a base and a solvent. Suitable palladium compounds are derived from inorganic or organic palladium salts, for example palladium chloride or palladium acetate. The salts may optionally be stabilized by conventional ligands, such as triphenylphosphine, in the form of, for example, dichlorobis (triphenylphosphine) palladium. In another embodiment, a zero valence palladium compound, for example bis (dibenzylideneacetone) palladium or terakis (triphenylphosphine) palladium, may be used. Suitable bases are tertiary amines such as triethylamine, or inorganic bases such as sodium bicarbonate or sodium acetate. Suitable solvents are, for example, Ν, Ν-dimethylacetamide, N, N-dimethylformamide, toluene, tetrahydrofuran, dioxane, acetone and the like.

Although a compound of formula (R ₁ , R ₂ , R ₃ ) -Het ¹ -NR-SO ₂ -lh ¹ -X, where X is ethenyl, can be produced by several methods, each of which is known as

such a compound is preferably produced by reacting a compound of formula (R ₁ , R ₂ , R ₃ ) -Het ¹ -NR-SO ₂ -Ph ¹ -X, where X is bromine or iodine, with ethylene in the presence of a catalytic amount of a palladium compound , bases and solvents, wherein the catalysts and solvents are of a similar type to that used in the reaction of a compound of formula II with a compound of formula III. Another method involves the partial reduction of the corresponding ethynyl compound with hydrogen gas in the presence of a catalyst suitable for this purpose.

The compound of formula II in which X is bromine or iodine is produced in a manner known per se, for example by reacting the corresponding halobenzenesulfonyl chloride with the corresponding heterocyclic amine in the presence of a base, for example pyridine or a heterocyclic amine in excess.

When X and Y in formulas II and III are -CO-CH3 and HCO- or -CEO and CH3 -CO-, the coupling described above is carried out in a manner known per se in the presence of a solvent and a basic or acidic condensing agent. Suitable bases are, for example, sodium hydroxide and potassium hydroxide. Suitable acids are strong mineral acids such as hydrochloric acid or sulfuric acid. Suitable solvents are water and lower alcohols or mixtures thereof. The compound of formula (II) wherein -X is -CO-CH 2 or -CHO is prepared in a manner known per se, for example by reacting the corresponding formylbenzenesulfonyl chloride or acetylbenzenesulfonyl chloride with a cyclic heterocyclic amine in the presence of a base such as pyridine or heterocyclic of the amine in excess.

When X and Y in the compound of formula II or III are -CH 2 CO 2 and a hydrogen atom, the reaction is carried out in a manner known per se, under Friedel-Crafts conditions, in the presence of a Lewis acid, preferably aluminum chloride, an inert solvent such as;

for example in chlorinated hydrocarbons. The compound of formula (II) in which X is -CH ₂ CO ₂ z ^is prepared in a known manner, for example by reacting the corresponding alkoxycarbonylbenzenesulfonyl chloride with the corresponding heterocyclic amine in the presence of a base such as pyridine or heterocyclic amine in excess; the carboxylic acid and the acid are halogenated in a known manner, for example by reaction with thionyl chloride or phosphorous halide.

Another method consists in reacting compounds of formula IV (R _{1, R,} R ₃₎ -Het-NRH (IV) with a compound of formula V

Cl-SO ₂ -Ph ¹ -AC ₆ X ₂ -R ₄ (COOR ₅ ) (OR ₆ ) (V) in which

Het, Ph ¹ , R, R ¹ , R ₂ , R ₃ , R ₄ and R ₅ have the meanings given above and;

R 8 represents a lower acyl group, preferably acetyl, or an aliphatic or aromatic sulfonic acid residue, preferably methylsulfonyl or p-toluenesulfonyl, in the presence of a basic condensing agent and solvent, wherein the basic condensing agent may be an excess of a compound of formula IV or preferably an organic base, e.g. pyridine. The resulting intermediate compound is then subjected to base-catalyzed hydrolysis, preferably by reaction with an alkali metal hydroxide in water.

The above compound of formula (V) is produced in a known manner by reacting the corresponding sulfonic acid or alkali metal sulfonate derived therefrom with a suitable chlorinating agent, preferably thionyl chloride, in the presence of N, N-dimethylformamide. The sulfonic acid is produced in a known manner according to any of the above-mentioned general processes, preferably by converging the corresponding ethinylaryl or ethenylaryl compound with an aryl iodide or aryl bromide. A third method of making the compounds of the present invention is by transforming the bridge A in the compounds of the present invention or in intermediates thereof of formula VI below to another bridge in a known manner, optionally followed by converting the intermediate to the final compound.

Examples of such methods involves the addition of water to 'krčeninu formula VI (R, R _2, R ₃₎ -Het', -NR-SO ₂ -Ph ¹ -AC ₆ H -R _{il 2 (COOR?)} (0R _Q) (VI ): terrain

R ₂ , R ₃ , Het ', Ph ¹ and R 6 have the meanings given above, means a hydrogen atom or R ₅ , wherein R ₅ has the same meaning as above, means a hydrogen atom or Ik-, b' wherein R 8 has the same meaning as above and

A is -C = C-.

The resulting compound has the formula VI wherein A is -CH 2 CO-. The addition of water to the triple bond occurs in the presence of a mineral acid or a strong organic acid, preferably formic acid, optionally in the presence of metal salts such as mercury or palladium, followed by hydrolysis under alkaline conditions, unless R ₇ and / or Rg are hydrogen. Another method is to reduce a compound of formula (VI) wherein R, R 1, R ₂ , R 8, Het ¹ , P ¹¹ , R ₄ ,

R ₇ and R 8 have the meanings given above and A represents a group of formula -CH ₂ CO to the corresponding compound, wherein A represents a group of formula -CHgCHOH-), and then converting this compound by treatment with a mineral acid to eliminate water and produce a compound where A is -CH = CH-, followed by hydrolysis under alkaline conditions, unless R ₇ and / or R 8 are hydrogen.

A third method is the reduction of a compound of formula VI wherein R, R j, R ·,, Rg, Het, Ph ¹ _and R, R ₇ and P have _the meanings indicated above and A represents a group of formula -C = C- to the corresponding compound, wherein A represents a group of the formula -CH ₂ CH ₂ -, by catalytic hydrogenation in a known manner, followed by hydrolysis under alkaline conditions, unless R ₇ and / or R 8 are hydrogen. If the compound of the invention is a salt, such a compound is produced, for example, by first producing the corresponding acid and then reacting it with the corresponding salt, 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. at least one organic solvent, or optionally such substance itself, in the presence of an organic solvent. If the salt is not readily soluble in the solvent used, the salt is preferably crystallized from the solvent and isolated by filtration or some similar process. If the readily dissolving salt is an alkali metal salt, preferably a sodium or potassium salt, the final hydrolysis used to remove the protecting groups may be carried out by neutralizing the mixture from the synthesis and crystallizing the desired salt directly from the mixture. If the salt is relatively soluble in the solvent used, the salt is preferably prepared by reacting equimolar amounts of the components and then evaporating the solvent.

In some cases, it is possible for the compound to form a distinct solvent solvate. Such solvates that contain a clear amount of solvents are also included in the invention if the solvents are pharmaceutically acceptable, such as in the case of water, acetone and ethanol. The solvate is produced by crystallization from a concentrated solvent, which is optionally mixed with other solvents. Optionally, crystallization can be performed by acidifying the soluble salt of a compound of the invention in the presence of a solvate-forming solvent.

The invention also encompasses pharmaceutical compositions comprising a compound of formula I, especially for oral use, optionally in combination with an inorganic or ganic inert carrier suitable for oral administration or other conventional excipients. For example, the pharmaceutical composition may be in the form of a tablet, dragee, capsule or the like,

enteric coated or solutions and suspensions containing the compounds of the invention. Pharmaceutical Ostředek ¹ can be prepared by methods known to one skilled alem this field, by mixing a compound of formula with the desired carrier and / or other additives converting this mixture to the desired form by gale.nickcu ora indicated data. Solutions and suspensions are formulated in a direct manner using pharmaceutically acceptable excipients. The dose is tailored to the requirements and needs of the individual situation, although doses ranging from 50 to 2000 mg per day for adult patients may be given as a general indication.

DETAILED DESCRIPTION OF THE INVENTION

The identification of all final compounds was confirmed by their NMR spectra and purity by thin layer chromatography (TLC) or liquid chromatography. NMR proton spectra were determined on a 500 MHz NMR spectrometer, with deuterated dimethylsulfoxide, unless otherwise indicated. NMR chemical shifts are given in ppm.

Example 1

Process for the preparation of 2-hydroxy-5 - [[4 - [(2-pyridylamino) sulfonyl] phenyl] ethynyl] benzoic acid

Example 1a

Process for the preparation of methyl [5 - [(trimethylsilyl) ethynyl] -2-hyaroxybenzoate]

To a solution of 275 g (0.92 mol) of methyl 2-hydroxy-5-iodobenzoate in 2000 ml of dry triethylamine was added 3 g (0.004 mol) of palladium dichlorobis (triphenylphosphine) and 1.6 g (0.008 mol) of copper (I) iodide. . The mixture was purged with nitrogen. To the reaction mixture was added 100 g (1.0 mol) of trimethylsilylacetylene, which was introduced via syringe, and the mixture was heated to 50 ° C. After 30 minutes a large precipitate of amine hydroiodide is formed: ¾ after 2 hours the reaction is complete according to thin layer chromatography. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue is purified by means of a specially prepared dry-flash chromatography on silica, eluting with toluene. Yield: 211 g (92%).

Example 1b

Process for the preparation of methyl (5-ethynyl-2-hydroxybenzyl)

A mixture of 100 g (0.57 mol) of methyl [5 - [(trimethylsilyl) ethynyl] -2-hydroxybenzoate] and 150 g (1.59 mol) of potassium fluoride dihydrate in 600 ml of N, N-dimethylformamide is stirred at temperature room for 4 hours. The solution is extracted three times with 400 ml of ether each time and the combined ether extracts are washed twice with 200 ml of 1M hydrochloric acid each and twice with 100 ml of water each time. The ether layer was dried over sodium sulfate and evaporated to dryness. Yield: 66.5 g (93%).

Example 1c

4-Iodo-N- (2-pyridyl) benzenesulfonamide

52.3 g (0.17 mol) of 4-iodo-benzenesulfonyl chloride are dissolved in 300 ml of dichloromethane and 65 (0.69 mol) of 2-aminopyridine are added to the solution. The solution was stirred at room temperature for 3 days, washed twice with 200 ml of molar sulfuric acid and 100 ml of water each time, dried over sodium sulfate and evaporated to dryness. Yield 46.9 g, corresponding to 76 theory, for example Id by the preparation of methyl- [2-hydroxy-5- [4 - [(2-pyridylamino) sulfonyl] phenylethyl] benzene (g). 97 mmol) of 4-iodo-N- (2-pyridyl) -benzenesulfonamide

ř ....

Dissolve in a mixture of 750 ml of triethylamine and 750 ml of tetrahydrofuran. The resulting mixture was degassed with nitrogen and then 1.2 g (1.7 mmol) of palladium dichlorobis (triphenylphosphine) and 0.6 g (3.4 mmol) of copper (I) iodide were added, followed by 23 g (130 mmol) of methyl ( 5-ethynyl-2-hydroxybenzoate). Heat the mixture at 60 ° C for 4 hours and then evaporate to dryness. The residue is dissolved in 1000 ml of chloroform, washed three times with 200 ml of water each time and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. Yield: 31 g (77%). The material can be purified by flash chromatography on silica, eluting with chloroform.

Example le

Process for the preparation of 2-hydroxy-5 - [[4 - [(2-pyridylamino) sulfonyl] phenyl] ethynyl] benzoic acid

The ester of Example 1d (23.7 g, 58 mmol) was dissolved in 1 M NaOH (190 ml) and refluxed for 6 hours. The cooled solution was acidified with an excess of 6 molar hydrochloric acid. The precipitate was allowed to stand for 2 hours, then filtered and washed three times with 200 ml of water each time. The white solid was dried at 60 ° C under reduced pressure. Yield 21.7 g (95%).

1 H-NMR Spectrum:

switch system A: δ 7.00 (d), 7.66 (dd), 7.95 (d):

(= salicylate ring), spin system B: δ 7.66 (d, 2H), 7.87 (d, 2H):

(= central benzene ring), spin system C: δ 7.18 (d), 7.73 (ddd), 6, S4 (dd), 7.96 (dd):

(= pyridine ring).

Example 2

Process for preparing 2-hydroxy-5 - [[4 - [(3-methyl-2-pyridyl amino) sulfonyl] phenyl] ethynylbenzoic acid

Example 2a

A process for the preparation of 4-iodo-N- (3-methyl-2-pyridyl) benzenesulfonamide

This compound was prepared essentially as the corresponding compound of Example 1c. Yield: 76%.

Example 2b

Process for the preparation of methyl [2-hydroxy-5 - [[4 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethynyl] benzoate]

This compound was prepared essentially as the corresponding compound of Example 1d. Yield: 76%.

Process for the preparation of 2-hydroxy-5 - [[4 - [(3-methyl-2-pyridylmino) sulfonyl] phenyl] ethynyl] benzoic acid

This compound is prepared essentially as the corresponding compound of Example 1e. The yield was 24.7 g, which corresponds to 15% of theory.

Η - N with p o k t. R u m: gentleman's system A: S 7.04 í d), 7.70 (dd), S, Q0 (d) - salicylate ring), pin system E: δ 7.70 (d, 2 íE, 7. ss (d. <E) central benzene km ; uh),

switching system C: δ 7.66 (d, broad signal), 6.83 (s, broad signal), 7.84 (s, broad signal):

(= pyridine ring), spin system D: S 2.15 (s): (= methyl). ·

Signal propagation in the pyridine ring is typical of methyl substituted derivatives at the 3-position.

Example 3

Process for the preparation of 2-hydroxy-5- [2- [4 - [(2-pyridylamino) sulfonyl] phenyl] ethenyl] benzoic acid

Example 3a

Preparation of methyl (5-ethenyl-2-hydroxybenzoate) g (45.4 mmol) methyl (5-ethynyl-2-hydroxybenzoate), prepared according to Example 1b, was dissolved in a mixture of 200 ml diethyl ether and 200 ml petroleum ether in hydrogenation flask.

1.7 ml of quinoline and 200 mg of palladium on lead poisoned calcium carbonate (Lindlar catalyst) are then added and the flask is connected to a hydrogenation apparatus at atmospheric pressure. The mixture was stirred at room temperature for 2 hours while consuming the calculated amount of hydrogen. The catalyst was filtered off and the solution was evaporated to dryness. The material was purified by flash chromatography on silica eluting with toluene. Almost quantitative yield is obtained.

Example 3b

A process for the preparation of methyl [2-hydroxy-5- (2- [4 - [(2-pyridylamino) sulfonyl] phenyl] ethenyl] benzcarbonyl (69 nasol) 4-iodo-N-2-pyridylbenzenesulfonamide, prepared according to of Example 1c, and 13.5 g (76 nasol) of methyl (5-ethynyl-2-hydroxybenzoate) are dissolved in a mixture of 150 ml of triethylamine and 100 ml of tetrahydrofuran and heated at 80 ^° C for 18 hours. 0.5 g of palladium acetate is added in small portions, the amine hydroiodide is filtered off and the filtrate is evaporated to dryness, and the residue is dissolved in 500 ml of chloroform and purified by flash chromatography on silica, eluting with chloroform. The solvent was evaporated under reduced pressure and the residue was dissolved in the smallest amount of hot tetrahydrofuran (13.5 g, 47%) by precipitation with diethyl ether.

Example 3c

Process for the preparation of 2-hydroxy-5- [2- [4 - [(2-pyridylamino) sulfonyl] phenyl] ethenyl] benzoic acid g (29 mmol) methyl [2-hyaroxy-5- [2- [4 - [(2-pyridylamino) sulfonyl]] The phenyl-ethynyl benzoate is dissolved in 120 ml of 1M potassium hydroxide and the solution is refluxed for 7 hours. The cold solution was acidified with an excess of 1M hydrochloric acid. The precipitate was filtered off and washed three times with 200 ml of water each time. The material was redissolved in a small amount of 1M sodium hydroxide solution. To the solution is added a mixture of 500 ml of water and 500 mo dioxane, and the resulting solution is heated to 100 ° C. The solution was acidified with an excess of 1M hydrochloric acid and the product precipitated by cooling. The yield was 9 g, which corresponds to 75% of theory.

^x Hh ^T MR spectrum:

switching system A: δ 7.02 (d), 7.84 (dd), 8.04 (d):

(= salicylate ring), spin system B: δ 7.73 (d, 2H), 7.83 (d, 2H):

(= central benzene ring), spin system C: δ Ί, 22 (d), 7.74 (m), 6.89 (ddd),

8.04 (m):

(= pyridine ring), spin system D: δ 7.19 (d), 7.38 (d):

(= ethendiyl bridge).

Example 4

Process for preparing 2-hydroxy-5- [2- [4 - [(3-methyl-2-pyridyl-amino) -sulfonyl] -phenyl] -ethenyl] -benzoic acid

Example 4a

Process for the preparation of methyl [2-hydroxy-5- [2- [4 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethenyl] benzoate]

This compound was prepared analogously to Example 3 from 4-iodo-N- (3-methyl-2-pyridyl) benzenesulfonamide, prepared according to Example 2a, and methyl [5-ethenyl-2-hydroxybenzoate], prepared according to Example 3a. Yield: 52%.

Example 4b

Process for the preparation of 2-hydroxy-5- [2- [4 - [(3-methyl-2-pyridyl-amino) sulfonyl] -phenyl] -ethenyl] -benzoic acid

This compound was prepared in an analogous manner to Example 3. The yield was 82% of theory.

1 H-NMR spectrum:

switching system A: δ 7.02 (d), 7.85 (dd), 3.04 (d):

(= salicylate ring)

I spin system B: δ 7.74 (d, 2H), 7.92 (d, 2H):

(= central benzene ring), spin system C: δ 7.63 (d, broad signal), 6.31 (broad signal), 7.85 (broad signal):

(= pyridine ring), spin system D: δ 7.21 (d), 7.39 (d):

(= ethendiyl bridge), spin system E: δ 2,15 (s):

(methyl group).

The extension of the signals in the pyridine ring is typical of the methyl substituted derivatives at the 3-position.

Example 5: Production of isobutyl [2-hydroxy-5- [2- (4 - [(2-pyridylamino) 11phonyl] phenyl] ethenyl] benzoate Example 5a isobutyl (2-hydroxy-5-iodobenzoate) isobutyl

477 g (1.8 mol) of 2-hydroxy-5-iodobenzoic acid, 225 rounds and 20 ml of concentrated sulfuric acid in 2 parts of toluene are refluxed for 6 hours using a water trap. The treated solution is then contacted with the active im to decolorize and the toluene is evaporated. The residue was recrystallized from methanol. Yield 376 g.

ad 5b on the preparation of isobutyl (5-ethynyl-2-hydroxybenzoate) g (0.05 mol) isobutyl (2-hydroxy-5-iodobenzyl),

13.9 g (0.075 mol) of tributylamine and 0.11 g (0.5 mol) of palladium acetate are dissolved in 100 ml of dimethylacetamide and the solution is introduced into a 250 ml pressure reactor.

The air is removed by introducing argon at 1 MPa, followed by venting to ambient pressure. This procedure is repeated twice. The temperature is raised to 90 ^DEG C. and ethylene at a pressure of 1.3 MPa is then introduced. After stirring for 5 minutes, the gas is vented and the ethylene pressure is again raised to 1.3 MPa. Thereafter, the temperature was raised to 110 ° C over 30 minutes with vigorous stirring and continuous ethylene feed to maintain a constant pressure of 1.3 MPa. After 90 minutes the temperature dropped to 20 ° C and ethylene was removed by introducing argon.

The solvent is evaporated at 70 ° C and 150 ml of water are added. The pH is adjusted to about 5 by the addition of hydrochloric acid and the solution is extracted twice with 50 ml of toluene each time. After re-extraction with 50 ml of dilute sodium bicarbonate solution, the combined toluene extracts were evaporated to give the product as an oil. Distillation at 100-105 ° C and 0.07 mm Hg afforded 15.4 g of pure chromatograph, corresponding to 70% of theory. During distillation, the substance is protected from polymerization by addition of 10 mg hydroquinone.

Example 5c

Process for the preparation of isobutyl [2-hydroxy-5- [2- [4 - [(2-pyridylamino) sulfonyl] phenyl] ethenyl] benzoate]

To a stirred solution of 6.6 g (30 mmol) of isobutyl (5-ethenyl-2-hydroxybenzoate) and 10.3 g (30 mmol) of 4-iodo-N- (2-pyridyl) benzenesulfonaraid in 4.0 ml of dimethylacetamide and 10 ml (42 mmol) tributylamine ce at 0 5 ° C adds 0.15 g (0.67 mmol) of palladium acetate. After 100 minutes, the solution was filtered and then evaporated at a bath temperature of 50-60 ° C until a solid appeared. The mixture is diluted with 500 ml of isopropanol and cooled in the freezer. The material was filtered to give 7.1 g (52%).

¹ H-NMR spectrum:

Switch system A: 5 7.0 (d), 7.84 (dd), 7, 93 (d):

(= salicylate ring), spin system B: δ 7.70 (d, 2H), 7.84 (d, 2H):

(= central benzene ring), spin system C: δ 7.18 (d), 7.69 (ddd), 6.85 (ddd),

8.0 (dd):

(= pyridine ring), spin system D: δ 7,12 (d), 7,36 (d):

(- ethendiyl bridge), spin system E: δ 1,0 (d, 6H), 2,1 (m, 1H), 4,1 (d, 2H):

(= isobutyl group).

Example 6

Process for preparing 2-hydroxy-5- [2- [4- (2-pyridylamino) sulfonyl] phenyl] ethenyl] benzoic acid

Example 6a

Process for the preparation of isopropyl (2-hydroxy-5-iodobenzoate)

134 g (0.7 mol) of 2-hydroxy-5-iodobenzoic acid, 50 ml of isopropanol, 5 ml of concentrated sulfuric acid and 10 g of p-toluenesulfonic acid in 1 liter of toluene are refluxed with a water separator attached. Ispropanol is added intermittently in portions to compensate for the loss of the 2-proparcine running denydrate. After 24 hours, the solution was cooled and washed with water. The toluene is partially evaporated. isooctane and 2-hydroxy-5-benzoic acid are added

The mass i g is filtered off. The solution was evaporated to dryness and the residue was recrystallized from methanol. The yield was 64 g, which corresponds to 71% (corrected for the converged starting compound).

Example 6b

Process for the preparation of isopropyl (5-ethenyl-2-hydroxybenzoate)

30.6 g (0.1 mol) of isopropyl (2-hydroxy-5-iodobenzoate) are dissolved in a mixture of 27.8 g (0.15 mol) of tributylamine and dimethylacetamide. After addition of palladium acetate, air is forced out and the temperature is raised to 110 C under an argon atmosphere. Ethylene was added and the procedure of Example 5b was followed.

The reaction was terminated in 90 minutes by cooling the reaction mixture to room temperature and simultaneously venting ethylene.

After evaporation of the solvents at 70 ^C under reduced pressure, 100 ml water and the pH was adjusted to approximately 5 by addition of hydrochloric acid. Extraction twice with 50 ml of toluene each followed by evaporation gave the crude compound as an oil.

The material is distilled at a temperature of 95 to 93 ° C and a pressure of 93 Pa. Yield: 15.5 g of chromatographically pure compound (75%).

Example 6c

Process for the preparation of 2-hydroxy-5- [2- [4 - [(2-pyridylamino) sulfonyl / phenyl] ethenyl] benzoic acid

Isopropyl (5 ^'- ethenyl-2-hydrr.yyten .-' OAr) was reacted with 4-iodo-N- (2-pyridyljbenzensulfonamidem similar manner as described in Example 5c.'Po reaction, the solvent was evaporated Toluene was added and the resulting slurry was filtered and washed with toluene, dried on the filter, washed with water, hydrolyzed and precipitated in a manner similar to that of Example 3c (40%).

The NMR spectrum shows identity with the compound of Example 3

Example 7

Process for the preparation of 2-hydroxy-5- [2- [4- (2-pyridylamino) sulfonyl] phenyl] ethenyl] benzoic acid (0.05 mol) isobutyl (2-hydroxy-5-iodobenzoate) is reacted with ethylene as described in Example 5b.

The reaction mixture is cooled to 85 ^DEG C. and 14.8 g (0.0425 mol) of 4-iodo-N- (2-pyridyl) benzenesulfonamide and 0.1 g (0.5 mmol) of palladium acetate are added with stirring. .

After 4 hours at 85 ° C, all sulfamide was consumed, but the reaction mixture still contained some isobutyl [5-ethenyl-2-hydroxybenzoate]. Therefore, an additional 2.6 g (0.0075%) of sulfonamide was added and the reaction was allowed to continue for 18 hours.

After addition of acetic acid to the hot reaction mixture, the mixture was poured into 450 ml of boiling isopropanol.

zeni ro flow temperature •-and C, 11.3 g s1oučeni Next 1.5 g of compound se gets stripped n a o b j e m at 100 m 1 a o c h 1 a z e n i t n ρ 1 O tu 7 C Total the yield is 12, 7 g equivalent to 56% theory..

The foil is hydrolyzed with 150 ml of 1 molar. ro 'OKU

V and precipitating the substance by adding an excess of 1 molar hydrochloric acid. Recrystallization from 70:30 formic acid / water gave, after filtration and drying, 8.5 g of the title compound, corresponding to 43% of theory.

The NMR spectrum shows identity with the compound of Example 3.

Example 8

Process for the preparation of isobutyl [2-hydroxy-5- [2- [4 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethenyl] benzoate]

To a solution of 6.6 g (30 mmol) of isobutyl (5-ethenyl-2-hydroxybenzoate) and 11.2 g (30 mmol) of 4-iodo-N- (3-methyl-2-pyridyl) benzenesulfonamide in 10 ml of dimethylacetamide and 10 ml (42 mmol) of tributylamine are added at 110 DEG C. to 0.5 g of 10% palladium on charcoal. After 90 minutes, the solution is filtered, diluted with 0.3 L of isopropanol and cooled in a freezer. The product is filtered off, dried and diluted with 100 ml of boiling formic acid. The solution is filtered and 65 ml of water are added. After cooling to freezer temperature, the substance is filtered off and dried. Yield: 7.2 g (51%).

• 1 H-NMR spectrum:

switching system A: δ 7.0 (d), 7.84 (d, wide signal), 7.94 (s, wide signal):

(= salicylate ring), spin system B: δ 7.69 (d, 2H), 7.9 (d, 2H):

(= central benzene ring), spin system C: δ 7.58 (broad signal), 6.74 (broad signal), 7.8 to 8.0 (broad signal):

(= pyridine ring), spin system D: δ 7,12 (1), 7,35 (d):

(= ethendiyl bridge), spin system E: δ 2.1 (s, broad signal) (= methyl group), spin system F: δ 1.0 (d, 6H), 2.1 (m, unclear due to methyl from spin system E), 4.1 (d, 2H): isobutyl group).

The extension of the signals in the pyridine ring is typical of the methyl-substituted derivatives at the 3-position.

Example 9

Process for the preparation of ethyl [2-hydroxy-5 - [[4 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethinyl] benzoate1

Example 9a

Process for the preparation of ethyl (5-ethynyl-2-hydroxybenzoate)

This compound was synthesized from ethyl [2-hydroxy-5-iodobenzoate in a manner similar to that described in Examples a and 1b for the corresponding ethyl ester.

: Example 9b for the preparation of ethyl [2-hydroxy-5- [4 - [(3-methyl-2-pyridinyl) sulfonyl] phenyl] ethynyl] benzoate)

0.29 g (0.25 mmol) of tetrakis (triphenylphosphine) palladium 0.095 g (0.05 mmol) of copper (I) iodide was added to a solution of 10.5 (55 mmol) of ethyl (5-ethynyl-2-hydroxybenzoate) and 18.7 g (50%) of 4-iodo-N- (3-methyl-2-pyridyl) benzenesulfonamide in 75 ml of trahydrofuran and 75 ml of triethylamine at 55 ° C. After graying, the solid is collected by filtration and washed with a leach of hydrochloric acid. Lit-obtained _by:.,. With the dimensions w formic vapor stationery dock K5 fiitruje minutes. Then add

200 ml of water and crystallized upon cooling. Yield: 17.3 g (79%).

¹ H-NMR spectrum (pyridine d ₅ as solvent): spin system A: δ 7.11 (d), 7.70 (dd), 8.14 (d):

(= salicylate ring), spin system B: δ 7.71 (d, 2H), 8.33 (d, 2H):

(= central benzene ring),

switching system C: δ 7.37 (d) , 6.64 (dd), 7.94 (d (- pyridine ring), switching system D: δ 2,11 (with, wide signal): (= methyl), switching system E: δ 1,22 (t, 3H), 4 33 (q, 2H);

(= ethyl).

Example 10

Process for the preparation of 2-hydroxy-5 - [[4 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl-ethynyl] benzoic acid

Example 10a

Process for preparing 4- (3-hydroxy-3-methyl-1-butin-1-yl) -N- (3-methyl-2-pyridyl) benzenesulfonamide

37.4 g (0.1 mmol) of 4-iodo-N- (3-methyl-2-pyridyl) benzenesulfonamide are added portionwise to a mixture of 31 ml (0.22 mol) of triethylamine and 25 ml of dimethylacetamide at 60 ° C. .

0.14 g (0.022 mol) of dichlorobis (triphenylphosphine) palladium and 0.08 g (0.004 mol) of copper (I) iodide are then added under a nitrogen atmosphere. Finally, 10.4 g (0.125 mol) of 2-methyl-3-butin-2-ol are added in portions over a period of 20 minutes to maintain an exothermic reaction temperature of 65-70 ° C.

O

The mixture was stirred at ^r 65 C for 1 hour. 250 ml of water are then added and, after cooling to room temperature, the cloudy precipitate is filtered off and 13.2 g (0.2 mol) of a 85% potassium hydroxide solution in 100 ml of water are added to the filtrate.

The reaction mixture was distilled off under reduced pressure at 50 ° C about 100 ml of a mixture of water and triethylamine. The remaining solution is extracted three times with 30 ml each of siccuthylmethyl ketone and approximately 50 ml of the isobutylmethylketone / water mixture is evaporated from the aqueous phase at 50 ° C.

The volume of the reaction mixture is adjusted to 300 ml with water and then 100 ml of ethanol are added. Hydrochloric acid was carefully added dropwise at 60 ^° C until pH 4 was reached. After cooling the reaction mixture to 8 ^° C, the material precipitated. The precipitated substance is filtered off, washed with water and dried. Yield 29.6 g, corresponding to 90% of theory.

Example 10b

4-Ethinyl-N- (3-methyl-2-pyridyl) benzenesulfonamide g (0.15 mol) 4- (3-hydroxy-thin-1-yl) -N

- (3-Methyl-2-pyridyl) phenylene sulphonamide and 900 ml of water are heated to a temperature of approximately 90 ° C under a nitrogen atmosphere. To the reaction mixture was added 64.9 g (1.05 mol) of 85% potassium hydroxide solution maintaining a high boiling rate. The reaction mixture is kept at reflux for 2 hours without refluxing in order to efficiently remove acetone formed during the reaction. Water is added to maintain an approximately constant volume of the reaction mixture.

200 ml of ethanol are added to the hot solution, i.e. a small amount of sulfur dioxide is added and the hydrochloric acid is added dropwise with heat. When sc .-. Beware opalescence, 1.5 ^e C of charcoal is added to the solution and the solution is filtered. Continuous addition of hydrochloric acid results in a pH of 4, causing precipitation of the compound.

After cooling to 50 ° C, the solid was filtered off and washed with water. The title compound is dried at 80 ° C under reduced pressure for 18 hours. Yield: 38.2 g (94%).

Example 10c

Process for the preparation of ethyl [2-hydroxy-5 - [[4 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethinyl] benzoate]

0.07 g (0.1 mmol) of dichlorobis (triphenylphosphine) palladium and 0.4 g (0.2 mmol) of copper (I) iodide are added to a solution of 14.9 g (50 mmol) of ethyl 2-hydroxy-5-iodo-benzoate ) and 14.3 g (50 mmol) of 4-ethynyl-N- (3-methyl-2-pyridyl) benzenesulfonamide in 10 g (0.1 mol) of triethylamine and 60 ml of dimethylacetamide at 65 ° C. After one hour, hot ethanol was added to the reaction mixture, followed by 100 mL of hot water with stirring. The solid was filtered off, after cooling in a refrigerator, and recrystallized from 2 aqueous formic acid. Yield: 17.0 g (77%).

Example 10d

Process for preparing 2-hydroxy-5 - [[4 - [(3-methyl-2-pyridylamino) sulfonyl / phenyl] ethynyl] benzoic acid

15.5 g (35 mmol) of ethyl [2-hydroxy-5 - [[4 - [(3-methyl-2-pyridyl-amino) -sulfonyl] -phenyl] -ethyl] -benzoate] was refluxed in a solution of 10 g (0.15 mol) of potassium hydroxide in 100 ml of water for 1 hour. After cooling to about 70 ^DEG C., 50 ml of ethyl acetate are added, followed by hydrochloric acid until a pH of 7-8 is reached. Cooling during stirring and then filtration affords a solid which is dissolved in 100 ml of acetone and 100 ml of water. The solution was acidified at about 50 ^° C and cooled, filtered and washed with water to yield 8.0 g (56%).

The NMR spectrum shows identity with the compound of Example 2.

Example 11

Process for the preparation of the potassium salt of 2-hydroxy-5 - [[4 - [(3-methyl-2-pyridinylamino) sulionyl] phenyl] ethynyl] benzoic acid

Example 11a

Process for preparing 4- (3-hydroxy-3-methyl-1-butin-1-yl) -N (3-methyl-2-pyridyl) benzenesulfonamide

Synthesis is done in range 0,2 y nol as in Ex i k 1 and d u 10a, while using 100 ml ace ton to place dimethylacet amide as solvents . Reakčni time at boiling p C O Z. p G t π y ΓΠ c h 1 a d i - čem at 60 to 6 2 ^c C is 2 h odiny. The yield is 6 0,0 g,

which corresponds to 91% of theory.

Example d lib. times the production of 4-ethynyl-N- (3-methyl-2-pyridyl) benzenesulfonamides

This synthesis proceeds exactly as in Example 10b.

.. i k lad 11 c

Process for the preparation of ethyl 1- [• 2-hydroxy-5 - [[4 - [(3-methyl-2-pyridyl; no) sulfonyl] phenyl] ethynyl] benzoate]

The synthesis was carried out as in Example 10c except that the hydrochloric acid was added after the addition of ethanol and water. Yield: 72%.

Example people

Process for preparing the potassium salt of 2-hydroxy-5 - [[4 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethynyl] benzoic acid

15.5 g (35 mmol) of ethyl [2-hydroxy-5 - [[4 - [(3-methyl-2pyridylamino) sulfonyl] phenyl] ethynyl] benzoate] are refluxed in a mixture of 10 g (0.15 mol) of potassium hydroxide. and 100 ml of water for 1 hour. After cooling to about 70 ^DEG C., 50 ml of ethyl acetate are added, followed by hydrochloric acid until a pH of 7-8 is reached. Cooling with stirring and then filtration yields directly 8.5 g of the desired compound, corresponding to 51% of theory.

The corresponding acid demonstrates identity with the compound of Example 2.

Example 12

Process for the preparation of 2-hydroxy-5- [2- [4 - [(3-methyl-2-pyridyl amino) sulfonyl] phenyl] ethenyl] benzoic acid

Example 12a

4- (2-Bromoethyl) -N- (3-methyl-2-pyridyl) benzene. sulfonamide

431 g (4.0 mol) of 3-methyl-2-pyridinamine are dissolved in 700 ml of dichloromethane and 340 g (1.33 mol) of 4- (2-bromoethyl) benzenesulph are added to the resulting reaction mixture; ony .i. chlorine at room temperature. After 1 hour at 20 ^C the solution was warmed to 35 ° C for 2 hours. Excess dilute hydrochloric acid was added to the reaction mixture and the phases were separated. After washing with water, the organic phase is dried over magnesium sulphate and treated with decolorizing charcoal. The solvent was evaporated and hot methanol was added to the residue causing crystallization. The material was collected and recrystallized from toluene. Yield: 178 g. A further 36 g of product is obtained by treating the mother liquors. The total yield is 45% of theory.

Example 12b

4-Ethenyl-N- (3-methyl-2-pyridyl) benzenesulfonamide

183 g (0.5 mol) of 4- (2-bromomethyl) -N- (3-methyl-2-pyridyl) benzenesulfonamide, 120 g of potassium hydroxide and 1 g of hydroquinone in 2 liters of ethanol are refluxed for for 1 hour. Water (5 L) was then added and the solution was acidified with acetic acid. The precipitated substance was filtered off, washed with water and dried. Yield 137 g (quantitative).

Example I2c

Process for preparing isobutyl 1- [2-hydroxy-5- [2- (4 -) - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethenyl] benzoate

70.2 g (0.22 mol) of isobutyl (2-hydroxy-5-iodobenzate) and 54.8 g (0.20 mol) of 4-ethenyl-N- (3-methyl-2-pyridyl) benzenesulfonamide are suspended. in a solution of 55.5 g (0.3 mol) of tributylamine and 0.44 g (0.0022 mol) of palladium acetate in 200 L of dimethylacetamide.

was heated at 100 C ^£ Nou in then treated with 2 g charcoal and the suspension was filtered and the filtrate poured into boiling isopropanol.

The solution was slowly cooled to 10 ° C and the crystals were filtered off. The filter cake is washed with 20 ml of cold isopropanol and dried.

Yield: 73 g (83%).

Example 12d

Process for the preparation of 2-hydroxy-5- [2- [4 - [(3-methyl-2-pyridyl amino) sulfonyl / phenyl] ethenyl] benzoic acid g of the compound of Example 12c was added to a solution of 50 g (0.78 mol) of potassium hydroxide in 600 ml of water and the mixture was refluxed overnight. After addition of 2 g of activated carbon and 0.5 g of sodium sulfite, the mixture was allowed to cool, stirred at room temperature and then filtered.

After filtration, 600 ml of ethanol are added and the solution is heated to about 90 ° C. Then 80 ml of hydrochloric acid are added in one portion and after about 3 minutes a precipitate begins to form.

The suspension was slowly cooled to room temperature and the material was filtered off. The filter cake is washed thoroughly with water and dried. Yield: 64 g, corresponding to 78% of theory.

The NMR spectrum shows identity with the compound of Example 4.

Example 13

Process for preparing isobutyl 1- [2-hydroxy-5- [2- [4-; 2-pyridylamino) 36 sulfonyl / phenyl] ethenyl] benzoate]

Example 13a

Process for preparing 4- (2-bromoethyl) -N- (2-pyridyl) benzenesulfonamide

This compound was synthesized in analogy to Example 12a. Yield: 67%.

Example 13b

4-Ethenyl-N- (2-pyridyl) benzenesulfonamide

This compound was synthesized in analogy to Example 12b. Yield: 66%.

Example 13c

Process for the preparation of isobutyl [2-hydroxy-5- {2- [4 - [(2-pyridylamino) sulfonyl / phenyl) ethenyl] benzoate]

19.2 g (0.06 mol) of isobutyl 1- (2-hydroxy-5-iodo-benzoate), 13 g (0.05 mol) of 4-ethenyl-N- (2-pyridyl) benzenesulfonamide and 0.11 g (0, [0005 mol] of palladium pentane are suspended in a mixture of 13.8 g (0.075 mol) of tribut-ylaraine and 50 ml of dimethylacetamide.

The reaction mixture was heated and stirred at 85 ^° C for 160 minutes, then 5 ml of acetic acid was added and the hot mixture was poured into 400 ml of boiling isopropanol. After cooling in the freezer, the precipitate formed is filtered off. The filter cake was washed with water and isopropanol. Yield: 4.37 g, corresponding to 21.2% of theory.

The NFR spectrum shows identity to the compound of Example 5.

Example 14

A process for the preparation of the 2-hydroxy-5- [2- [4 - [(3-methyl-2-pyridylamino) sulfonyl / phenyl] ethenyl] benzoic acid acetonic solvate of the potassium salt of 2-hydroxy-5- [2- [4- The (3-methyl-2-pyridylamino) sulfonyl / phenyl] ethenyl] benzoic acid was dissolved in 160 mL of water and 240 mL of acetone with heating to 50 ° C. 6 ml of hydrochloric acid are added rapidly to the heated reaction mixture. The compound crystallizes as a solvate containing about 0.14 moles of acetone per mole of 2-hydroxy-5- [2- [4 - [(3-methyl-2-pyridylamino) sulfonyl / phenyl] ethenyl] benzoic acid. Yield 23.7 g.

1 H-NMR spectrum:

spin system A: δ 7.04 (d), 7.70 (dd), 8 (= salicylate ring), spin system B: δ 7.70 (d, 2H), 7.55 (d, (= central benzene) ring), switching system C: δ 7.66 (d, wide signal), 7.84 (s, wide signal):

(= pyridine ring), spin system D: δ 2.15 (s, broad ring): (= methyl group), spin system E: δ 2.10 (s) (= acetone).

(d):

2H):

6.8 3 (s, broad

The spread of the signals in the pyridine ring is typical of the derivatives substituted by the methyl in the 3-position. The amount of acetone corresponds to about 0.15 equivalents.

Example 15

A process for the preparation of 2-isopropyl-5- [2- [4 - [(5-methyl-pyridylamino) sulfonyl] phenyl] ethenyl] benzoic acid

Example 15a

Process for producing tributylammonium 4-ethenylbenzenesulfonate

89.1 g (0.36 mol) of 4- (2-bromoethyl) benzenesulfonyl chloride, 86.2 g (1.44 mol) of potassium hydroxide and 0.5 g of hydroquinone are refluxed in 1 liter of water and 500 ml of ethanol under reflux. for 3 hours.

The solution is concentrated to a volume of approximately 1 liter by evaporation under reduced pressure and then acidified with approximately 400 ml of 2M sulfuric acid. 71.5 g (0.39 mol) of tributylamine are added to the reaction mixture, and the solution is then extracted four times with 150 ml of dichloroethane each time. The combined organic phases were washed with 150 ml of 0.5M sulfuric acid, dried over magnesium sulphate and evaporated to dryness. Yield 134.1 g is quantitative.

Example 15b

Process for preparing the methyl salt of methyl- [2 = hydroxy-5- / 2- (4-sulfophenyl) -ethenyl] -benzoate]

134 g (0.36 mol) of tributylammonium 4-ethenylbenzenesulfonate, 101 g (0.36 mol) of methyl (2-hydroxy-5-iodobenzoate) and 101 g (0.54 mol) of tributylamine are dissolved in 370 ml of dimethylacetamide. Palladium (II) acetate (0.8 g, 0.0036 mol) was added and the solution heated to 85 ° C with stirring for 3 hours. The suspension is filtered to remove insoluble palladium salts, and the filtrate is evaporated to dryness. The residue is dissolved in 500 ml of dichloromethane.

A solution of potassium hydroxide (1.45 ml) in 300 ml of water was added rapidly with vigorous stirring. The resulting dipotassium salt was filtered off and washed with di-methanol and diethyl ether. After drying, the solid is boiled in 200 ml

of acetic acid under reflux for 30 minutes. After cooling to room temperature, the solids were filtered off and washed with diethyl ether. Yield: 57.6 g (43%).

Example 15c

Process for the preparation of methyl [2-acetyloxy-5- / 2- (4-sulfophenyl) ethenyl] benzoate potassium salt

57.5 g (0.15 mol) of methyl [2-hydroxy-5- [2- (4-sulfophenyl) ethenyl] benzoate] potassium salt, 35 ml of acetic acid and 142 ml of acetic anhydride are refluxed, until most of the solid had dissolved and then a further 142 ml of acetic anhydride and 1 ml of sulfuric acid were added. Boil for 90 minutes, cool to room temperature and add diethyl ether to precipitate completely. After filtration and evaporation, the yield was 43.4 g (69%).

Example 15d

Method for the preparation of methyl [2-acetyloxy-5- [2- / 4- (chlorosulfonyl) phenyl / ethenyl] benzoate]

42.4 g (0.104 mol) of methyl [2-acetyloxy-5- [2- (4-sulfophenyl) ethenyl] benzoate potassium salt was suspended in dichloromethane. 5 ml of dimethylformamide and thionyl chloride were then added to the solution, and the resulting mixture was refluxed under stirring for 3 hours. After cooling to room temperature, 15 ml of water are added to the mixture. A 5 molar sodium hydroxide solution was then carefully added to the reaction mixture and the pH of the aqueous phase was adjusted to about 7.

The phases are separated and the organic phase is washed with water. the solution is dried over magnesium sulphate, treated with activated carbon (...

and filters. After evaporation of the solvent, the solid residue is recrystallized from toluene / petroleum ether. Yield 29.3 g (71%).

Example 15e

Process for the preparation of 2-hydroxy-5- [2- [4 - [(5-methyl-2-pyridinyl) sulfonyl] phenyl] ethenyl] benzoic acid

1.2 g (0.003 mol) of methyl [2-acetyloxy-5- [2- / 4 (chlorosulfonyl) phenyl / ethenyl] benzoate] and 0.39 g (0.0036 mol) of 2-amino-5-methylpyridine are added to 10 ml dry pyridine and the solution was stirred at room temperature overnight. The solvent was evaporated and the solid residue was stirred with 2M sulfuric acid. After filtration, 1.33 g of the ester intermediate is obtained. This compound was refluxed with 0.6 g of sodium hydroxide in 20 ml of water and 10 ml of ethanol for 5 hours. After cooling and acidification with hydrochloric acid, the crystalline precipitate was filtered off and washed with water. After stirring with hot water for one hour, the substance is collected and dried. The material was recrystallized after dissolution in hot 70% ethanol containing 3 equivalents of sodium hydroxide and acidification with hydrochloric acid. After filtering off, the product is washed with water and dried to yield 0.7 g (58%).

1 H-NMR Spectrum:

switch system A: δ 7.01 (d), 7.83 (dd), 8.0.1 (d):

(= salicylate ring), spin system B: δ 7.72 (d, 2H), 7.82 (d, 2H):

(= central benzene ring), spin system C: δ 7,11 (d), 7,56 (dd), 7,68 (d):

(= pyridine ring), spin system D: S 7.17 (d), 7.37 (d):

(= ethene.lyl bridge), spin system E: δ 2.15 (s): (= methyl group).

Example 16

Process for the preparation of 2-hydroxy-5- [2- [4 - [[3- (phenylmethoxy) -2-pyridylamino / sulfonyl] phenyl] ethenyl] benzoic acid

This compound was synthesized in analogy to Example 15e. Yield: 53%.

¹ H-NMR spectrum:

switching system A: δ 6.99 (d), 7.32 (dd), 3.0 (d):

(= salicylate ring), spin system B: δ 7.71 (d, 2H), 7.93 (d, 2H):

(= central benzene ring), switching system C: δ 6.9 (broad signal), 7.3 (broad signal) 7.66 (d):

(= pyridine ring), spin system D: δ 7.17 (d), 7.33 (d):

(= ethendiyl bridge), spin system E: δ 7.48 (s), 7.3 to 7.4 (m):

(= phenyl group), spin system F: δ 5.15 (s):

(= methylene group).

Example 17

5- [2- [4 - [(5-chloro-2-pyridilamino) sulfonyl] phenyl] ethenyl] -2-hydroxybenzoic acid

This compound was synthesized in analogy to Example 15e. Yield: 32%.

1 H-NMR Spectrum:

switching system A: δ 7,02 (d), 7, S4 (dd), 3.04 (d) (= salicylate ring) switching system B: δ 7.77 (d, 2H); T / 91 (d, 2H) (= central benzene kr uh) switching system C: δ 7.14 (d), 7.81 (dd) 8.24 (d) (= pyridine ring), switching system D: δ 7,20 (d) 7.41 (d):

(= ethendiyl bridge).

Example 18

Process for the preparation of 2-Hydroxy-5- [2- [4 - [(5-methyl-3-isoxazolyl) -aminosulfonyl] -phenyl-ethenyl] -benzoic acid

This compound was synthesized in analogy to Example 15e. Yield: 78%.

1 H-NITR spectrum:

switching system A: δ 7.03 (d), 7.85 (dd), 8.05 (d):

(= salicylate ring)

spin system B: δ 7.80 (d, (= central benzene kr uh) spin system C: δ 6.18 (s) (= isoxazole circle). spin system D: δ 7.21 (d) (= ethend i y bridge), spin system E: δ 2.33 (with) (= methyl group u p i n a).

³ (a) (process for the preparation of the ethanol solvate of 2-hydroxy-5-2-methyl-2-pyrimide 1) aminosulfenyl / phenyl ether ethers 1] hen43

This compound was synthesized in analogy to Example 15e. Yield: 38%.

1 H-NMR spectrum:

switching system A: δ 7.02 (d), 7.84 (dd), 8.03 (d):

(= salicylate ring), spin system B: δ 7.76 (d, 2H), 7.97 (d, 2H):

(= central benzene ring),

switching system C: δ 7,20 (d) , 7.40 (dd): (= pyrimidine ring), switching system D: δ 7,20 (d) , 7.40 (d): ethendiyl bridge) switching system E: δ 2,30 (s): (- methyl), switching system F: δ 1,05 (t, 0.5x3H ), 3.42 (d, 0.5Χ2Η)

(= ethanol).

Example 20

Process for the preparation of 2-hydroxy-5- [2- [4 - [(2-pyridazinyl aminosulfonyl) phenyl] ethenyl] benzoic acid

This compound was synthesized in analogy to Example 15e. Yield 67%.

1 H-NMR Spectrum:

switching system A: δ 7.02 (d), 7.84 (dd), 3.03 (d):

(= salicylate ring), spin system B: δ 7.73 (d, 2H), 7.93 (d, 2H):

(= central benzene ring), spin system C: δ 8.24 (s, 2H), 8.40 (s):

(= pyridazine ring), spin system D: S. 7.20 (d), 7.41 (d):

(= ethendiyl bridge).

Example 21

Process for the preparation of 2-hydroxy-5- [2- [4 - [[6-fluoro- (2-benzo [d] thiazolyl)] aminosulfonyl] phenyl] ethenyl] benzoic acid

This compound was synthesized in analogy to Example 15e. Yield: 27%.

1 H-NMR spectrum:

switching system A: δ 7.0 (d), 7.35 (dd), 8.02 (d):

(= salicylate ring), spin system B: δ 7.76 (d, 2H), 7.83 (d, 2H):

(= central benzene ring), spin system C: δ 7.77 (dcl), 7.25 (ddd), 7.30 (dd):

(= benzothiazole ring), spin system D: δ 7.20 (d), 7.38 (d):

(= ethendiyl bridge).

Example 22

Process for the preparation of 2-hydroxy-5- [2- [4- (N-methyl- (2-pyridyl) aminosulfonyl) phenyl] ethenyl] benzoic acid

This compound was synthesized by the anal in Example 15e. Yield -81% of theory.

¹ H-N1TR spectrum:

switching system A: δ 7,02 (d), /, 8 / (dd), (= salicylate k : ruh) switching system B: δ 7,56 (d, from H), /,: ( (= central benzene k ruh), switching system C: δ 7,50 kx j y /, 67 - ξ Cx kx ki · (dd): (= pyramid ring 7n), with a new world D: δ 7,20 (d) 7.42 (d):

(= ethendiyl bridge), spin system E: δ 3,2 (s): (= methyl group).

Example 23

Process for preparing 2-hydroxy-5- [2- [4 - [(2-pyridyl) aminosulfonyl / phenyl] ethenyl] benzoic acid

Example 23a

Process for the preparation of isobutyl [2-hydroxy-5- [2- (4-sulfophenyl) ethenyl] benzoate, dipotassium salt]

Dissolve 55.2 g (0.15 mol) of tributylammonium 4-ethenylbenzenesulfonate, 47.8 g (0.36 mol) of isobutyl (2-hydroxy-5-iodobenzoate) and 41,4 g (0,15 mol) of tributylamine in 150 ml of dimethylacetamide. To the solution was added 0.33 g (0.0015 mol) of palladium acetate and heated with stirring to 85 ^° C for 7 hours. After about 3 hours, 23.9 g (0.13 mol) of isobutyl (2-hydroxy-5-iodobenzoate) was added as an additional portion and the reaction mixture was evaporated to dryness. the residue is dissolved in 750 ml of dichloromethane. The solution was stirred vigorously and 600 ml of 0.5M KOH was added rapidly. The precipitated dipotassium salt was filtered off and washed with dichloromethane. Yield: 42 g (68%).

Example 23b

Process for the preparation of isobutyl-2,3-cetyloxy-5- [2- (4-sulfophenyl) ethenyl] benzoate potassium salt]

37.2 g (0.09 mmol) of diphenylhydroxy-5- [2- (4-sulfophenyl) ethenyl] benzacetate are added to the boiling solution of 20 ml of acetic acid and 80 ml of acetic anhydride. 8 ml of sulfuric acid are carefully added to the reaction mixture and the mixture is refluxed until the bulk of the solid has dissolved. An additional 80 mL of acetic anhydride was added. Boil for 1 hour and then cool to room temperature. 350 ml of diethyl ether are added to the mixture, the suspension is filtered and the filter cake is washed with diethyl ether. Yield: 36.1 g (88%).

Example 23c

Process for preparing isobutyl 1- [2-acetyloxy-5- [2- / 4- (chlorosulfonyl) phenyl] ethenyl] benzoate]

36.1 g (0.08 mol) of the isobutyl [2-acetyloxy-5- [2- (4-sulfophenyl) ethenyl] benzoate potassium salt is suspended in dichloromethane. 20 ml of dimethylformamide and 20 ml of thionyl chloride are added to the suspension, and the resulting mixture is refluxed under stirring for 3 hours. After cooling to room temperature, 15 ml of water are added to the reaction mixture. A 5 molar solution of sodium hydroxide was then carefully added to the mixture and the pH of the aqueous phase was adjusted to about 7. The phases were separated and the organic phase was washed with water. The residue is dried over magnesium sulphate, treated with activated carbon and filtered. After evaporation of the solvent, the residue is recrystallized from toluene / petroleum ether. Yield 19.5 g (57%).

Example 2 3 d

Process for the preparation of 2-hydroxy-5- [2- [4 - [(2-pyridyl amino) sulfonyl] phenyl] ethenyl] benzoic acid

1.99 g (0.0046 mol) of isobutyl- [2-acetyloxy-5- [2- / 447]

- (chlorosulfonyl) phenyl / ethenyl] benzoate] and 1.3 g (0.0138 mol) of 2-pyridinamine are stirred in 10 ml of dichloromethane at 45 ° C for 1 hour. After cooling to room temperature, 20 ml of dichloromethane and 20 ml of 2M sulfuric acid were added to the reaction mixture. The precipitated solid, 1.3 g, was collected and washed with water. The organic phase is dried and the residue is treated with boiling methanol containing 2 ml of ammonia for 20 minutes. After cooling, 0.6 g of material was collected and combined with its first crop. 1.9 g of the combined substances are refluxed with 1 g of potassium hydroxide in 50 ml of water. After acidification and filtration, the solid residue is dissolved in 70% ethanol containing approximately 3 equivalents of potassium hydroxide at boiling and acidified with boiling hydrochloric acid. After filtration and drying, the yield was 1.25 g, which corresponds to 70% of theory.

The NMR spectrum shows identity with the compound of Example 3

Example 24

Process for the preparation of 2-hydroxy-5- [2- [4 - [(6-methyl-2-pyridylamino) sulfonyl] phenyl] ethenyl] benzoic acid

This compound was synthesized in analogy to Example 23d. Yield: 69%.

1 H-NMR Spectrum:

switching system A: δ 7.0 (d), 7.82 (dd), 8.02 (d):

(= salicylate ring), spin system B: δ 7.71 (d, 2H), 7.83 (d, 2H):

(= central benzene ring), spin system C: δ 7.04 (d), 7.61 (dd), 6.66 (d):

(= pyridine ring), · spin system D: δ 7.17 (d), 7.36 (d):

(= ethendiyl bridge),

- 4 O - * switch system E: & 2.30 (s):

(= methyl).

Example 25

Method for producing (2: 1) ethanol solvate of 2-hydroxy-5- [2- [4 - [(4-methyl-2-pyridylamino) sulfonyl / phenyl] ethenyl] benzoic acid

This compound was synthesized analogously to ⁷ as in Example 23d. Yield: 69%.

-R-NMR spectrum:

spin system A: δ 7.0 (d), (= salicylate ring), spin system B: δ 7.72 (d, (= central benzene ring) spin system C: δ 7.04 (d) (- pyridine ring) )

7.83 (dd), 8.02 (d):

2H), 7.84 (d, 2H):

6.69 (dd), 7.83 (d):

spin system D: & 7.18 (d), (= ethendiyl bridge), spin system E: S 2.25 (s):

(= methyl).

Example 26

Process for the preparation of 2-hydroxy-5- [2- [4 - [(2-pyridylamino) sulfonyl] phenyl] ethyl] benzoic acid

A solution of 3 g (7.5 mmol) of 2-hydroxy-5- [2- [4- (2-pyridylamino) sulfonyl] phenyl] ethenyl] benzoic acid in 100 ml of tetrahydrofuran and 100 ml of acetic acid is hydrogenated to 0.3 g of 10% palladium- on carbon at atmospheric pressure at room temperature for 27 hours. The catalyst was filtered off and the solvent was evaporated. The residue is dissolved

(....

in a solution of 0.3 g of sodium hydroxide in 30 ml of acetone and 30 ml of water. The solution is acidified with hydrochloric acid at a temperature of approximately 50 ° C. After cooling, the substance crystallizes. Yield: 1.6 g (52%).

1 H-NMR spectrum:

Switch system A: 8 6.31 (d), 7.29 (dd), 7.61 (d):

(= salicylate ring), spin system B: δ 7.35 (d, 2H), 7.76 (d, 2H):

(= central benzene ring), spin system C: δ 7.13 (d), 7.67 (ddd), 6.84 (ddd),

7.93 (d):

(= pyridine ring), spin system D: δ 2,7 to 2,9 (m, 4H):

(= ethendiyl bridge).

Example 27

Process for preparing 2-hydroxy-5 - [[4 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] acetyl] benzoic acid

A solution of 4.1 g (0.01 mmol) of 2-hydroxy-5 - [[4 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethenyl] benzoic acid in 100 ml of formic acid is refluxed for 3 hours. for 30 hours. Water (200 ml) was added to the reaction mixture and the product crystallized out. Yield: 3.0 g (71%).

1 H-NMR Spectrum:

switching system A: 8 7.08 (d), 8.20 (dd), 8.48 (d):

(= salicylate ring), spin system B: δ 7.42 (d, 2H), 7.90 (d, 2H):

(= central benzene ring), Cr. 8 7.62 (d), 6.78 (broad signal)). '', 22 (wide signal):

(= pyridine ring), spin system D: δ 4.45 (s): (= methylene bridge), spin system E: 3 2.15 (s): (= methyl group).

Example 28

Process for the preparation of 2-hydroxy-5- [14 - [(2-pyridylamino) sulfonyl] phenylacetyl] benzoic acid

The compound was prepared from 2-hydroxy-5 - [[4 - [(2-pyridylamino) sulfonyl] phenyl] ethynyl] benzoic acid according to the method of Example 27.

H-NMR Spectrum:

Switch system A: S 7.05 (d), 8.14 (dd), 8.44 (d):

(= salicylate ring), spin system B: δ 7.38 (d, 2H), 7.81 (d, 2H):

(= central benzene ring), spin system C: 3 7.16 (from), 7.65 (dcd), 6.84 (ddd),

7, op:

pyridine ring), new system D: δ 4p 4 (s):

methylene bridge).

k 1 a d 2 9 Production of 2-hydroxy-5- [1-oxo-3- [4 - [(2-pyridylno) sulfonyl] phenyl] -2-propenyl] benzoic acid

5.7 g (0.022 mol) of 4-formyl-N- (2-pyridyl) benzenesulfonic acid and 6.64 q (0.0-4 mol) of 5-acetyl-2-hyrinoxybon zoo acid ^; e 20 ml of a 5 molar sodium hydroxide solution was stirred from the room for 3 days. The resulting anger from maturing years

ml of water and acetic acid are added dropwise in excess. The precipitate was collected by filtration and washed with water. After drying, the material is recrystallized from acetic acid and dried at 120 ° C under reduced pressure. Yield: 6.4 g (66%).

¹ H-NMR spectrum:

switching system A: δ 7.12 (d), 8.35 (dd), 8.58 (d):

(= salicylate ring), spin system B: δ 7.93 (d, 2H), 8.05 (d, 2H):

(= central benzene ring), spin system C: δ 7.23 (d), 7.76 (ddd), 6.88 (ddd),

8.02 (m):

(= pyridine ring), spin system D: δ 7.77 (d), 8.02 (d):

(= oxopropenediyl bridge).

Example 30

Process for preparing 2-hydroxy-5 - [[4 - [(3-methyl-2-pyridyl-amino) sulfonyl] phenyl] ethynyl] benzoic acid

Example 30a

Process for preparing 4-methylphenyl-4-iodobenzenesulfonate

604 g (2 mol) of 4-iodobenzenesulfonyl chloride are added with stirring to a solution of 227 g (2.1 mol) of 4-methylphenol and 222 g (2.2 mol) of triethylamine in 1.5 liters of toluene. The suspension was stirred at 60 ° C for 2 hours. The reaction mixture was added to an excess of dilute hydrochloric acid. The precipitate was filtered off and washed with ethanol. A second crop of product is obtained by evaporating the mother liquors containing toluene and collecting the solid in the same manner. The combined fractions were recrystallized from 2.5 liters of 2-propanol. Yield: 680 g (91%).

Example 30b

4-Methylphenyl- [4- (2-trimethylsilylethynyl) benzenesulfonate]

374 g (1 mol) of 4-methylphenyl iodobenzenesulfonate are dissolved in 1 liter of tetrahydrofuran. 200 g (2 mol) of triethylamine, 1.1 g (1.6 mmol) of dichlorobis (triphenylphosphine) palladium and 1.9 g (10 mmol) of copper (I) iodide are added to the solution. The solution was heated to 40 ° C and trimethylsilylethine (108 g, 1.1 mol) was added over 15 minutes with stirring and the reaction mixture was cooled to keep the reaction temperature below 55 ^° C. Just before the end of the addition, the color of the reaction mixture turns from yellow to green with a shade to brown. The reaction mixture is maintained at about 40 ° C for 30 minutes, the particulate matter is filtered off and the solvent is evaporated. The residue was dissolved in toluene and washed with dilute hydrochloric acid. After drying and treatment with activated carbon, the solution was evaporated. 392 g of an oily substance are obtained which contains some toluene. This material was used directly in the next step without purification.

Example 30c

Process for preparing 4-methylphenyl (4-ethynylbenzenesulfonate)

The crude oily 4-methylphenyl- [4- (2-trimethylsilylethynyl) benzenesulfonate] weighing 392 g from the preceding step was dissolved in 800 ml of dimethylformamide and 20 ml of water and 50 g (0.36 mol) of potassium fluoride were added. The solution, which darkens, is diluted with water after 20 minutes and the precipitated oily product is sounded tomorrow. The substance is collected and dissolved in 4 liters of boiling heptane. ha solution

The solution was treated with activated carbon and then dried over magnesium sulfate. After filtering the solution through a 1 cm thick alumina layer, the crystalline material is obtained in three portions, after crystallization and evaporation. The total yield was 242 g, corresponding to 89% of theory in two steps, based on 4-methylphenyl (4-iodobenzenesulfonate).

Example 30d

Process for the preparation of ethyl [2-hydroxy-5 - [[4 - [(4-methylphenoxysulfonyl) phenyl] ethynyl] benzoate]

58.5 g (0.2 mol) of ethyl (2-hydroxy-5-iodobenzoate),

54.4 g (0.2 mol) of 4-methylphenyl (4-ethynylbenzenesulfonate) and 40 g (0.4 mol) of triethylamine are dissolved in 100 g of tetrahydrofuran.

The solution is heated to 50 ^DEG C. and 0.5 g (0.72 mmol) of dichlorobis (triphenylphosphine) palladium and 1 g (5.2 mmol) of copper (I) iodide are added simultaneously with stirring. The reaction mixture darkens and after about 10 minutes triethylamine hydroiodide begins to precipitate. The reaction mixture is maintained at 45 ° C for 45 minutes, the suspension is poured into dilute hydrochloric acid and the mixture is extracted with toluene. The toluene solution was evaporated to dryness. The residue is treated with acetonitrile, the solid is filtered off and dried. Yield: 73 g (84%). The combined material from several batches weighing 270 g was recrystallized from 1.2 liters of acetonitrile. 250 g of compound are obtained.

Example 30e

Process for preparing the ethyl salt of ethyl [2-hydroxy-5 - [(4-sulfophenyl) ethynyl] benzoate]

500 ml of ethanol are mixed together with 100 ml of toluene, 200 ml of this mixture are distilled off and then 11.5 g (0.5 mol) of sodium metal are added in one portion to the rest of the original mixture. The resulting sodium ethoxide solution was heated to boiling and 43.6 g (0.1 mol) of ethyl [2-hydroxy-5 - [[4 - [(4-methylphenoxysulfonyl) phenyl] ethynyl] benzoate] was added. The solution is refluxed for 30 minutes. The solution was then neutralized with acetic acid and cooled. A thick paste is formed. This solid was filtered off and washed with ethanol. Dissolve the substance in boiling water and add 90 g of potassium acetate to the resulting solution. The solution is cooled to room temperature, the crystalline material is filtered off, washed with acetone and dried at 100 ^DEG C. The yield is practically quantitative. The product contains certain inorganic salts.

Example 30f

Process for the preparation of ethyl [2-hydroxy-5 - [(4-chlorosulfonyiphenyl) ethynyl] benzoate 1 g (50 mmol) of ethyl 2-hydroxy-5 - [(4-sulfophenyl) ethynyl] benzoate potassium salt 1 is suspended in 100 ml of oluene. 1 ml of dimethylformamide and 12 thionyl chloride are added to the suspension, and the suspension is refluxed for 1 hour. The reaction mixture was added to an almost saturated sodium chloride solution and the precipitated oil was extracted with luene. The solution was dried and evaporated to dryness. The resulting product is sufficiently pure for the next step. Yield: 6 g (88%).

Process 1 for the preparation of ethyl [2-acetyloxy-5 - [(4-chlorosulfonylphenyl) hvinyl]], starting from ethyl [2-hydroxy-5 - [(4-chlorosulfonylphenyl) phenyl] phenyl] -benzyl] -benzyl Ethylene / benzoate] is dissolved in 40 ml of acetic anhydride at 120 ^DEG C. and about 0.4 ml of sulfuric acid is added dropwise. After 5 minutes, the solution was diluted with approximately 100 mL of toluene and added with saturated sodium chloride solution with vigorous stirring. The phases are separated, the toluene solution is dried and evaporated. Additional toluene was added to the residue and the evaporation was repeated. Then the oily substance crystallizes. The compound obtained is sufficiently pure for the next step. Yield: 17.0 g (95%).

Example 30h

Process for the preparation of 2-hydroxy-5 - [[4 - [(3-methyl-2-pyridyl-4-amino) sulfonyl] phenyl] ethynyl] benzoic acid

1.3 g (12 mmol) of 3-methyl-2-pyridinamine are dissolved in 20 ml of dry pyridine and 4.1 g (10 mmol) of ethyl [2-acetyloxy-5 - [(4-chlorosulfonylphenyl) ethynyl] is added. / benzoate]. The solution was kept at room temperature for 13 hours. The solvent was evaporated and the residue dissolved in a small amount of tetrahydrofuran. The above solution was added to a solution of 6 g of potassium hydroxide in 100 ml of water and 50 ml of ethanol maintained at reflux. After 15 minutes, the resulting solution was acidified with formic acid to precipitate a precipitate. The solid was collected by filtration, washed with water and dried. Yield: 1.2 g (29%).

The NKR spectrum shows identity to the compound of Example 2.

Example 31

Process for the preparation of 2-hydroxy-5 - [(4 - ([3- (phenylmethoxy) -2-pyridylamino / sulfonyl) phenyl] ethinyl]] benzoic acid

This compound was synthesized in analogy to Example 30h. The material was recrystallized from acetic acid and then from nitromethane. Yield 58%.

1 H-NMR spectrum:

switching system A: δ 7,06 (d), 7,7 (dd, overlaps with other signals), 8,0 (d):

(= salicylate ring), spin system B: δ 7.7 (d, 2H, overlaps with other signals), 8.02 (d, 2H):

(= central benzene ring), spin system C: δ 7.40 (d, broad signal), 6.97 (t, broad signal), 7.7 (overlaps with other signals):

(- pyridine ring), spin system D: δ 7.53 (d, 2H), 7.43 (t, 2H), 7.36 (t):

(= phenyl), spin system F: δ 5.10 (s):

methylene group).

Example 32

Process for the preparation of 5 - [[4 - [(5-chloro-2-pyridylamino) sulfonyl] phenylethynyl] -2-hydroxybenzoic acid

This compound was synthesized in analogy to Example 30h. The material was recrystallized twice from a mixture of dimethoxyethane and methylcyclohexane. Yield 58%.

1 H-NMR Spectrum:

spin system A: 8 7.04 (d), (= - salicylate ring), spin system B: 8 7.73 (d, (= central benzene ring),

7, 0 (dd), 7

b), 7.94 (d, spin system C: δ 7.12 (d), 7.82 (dd), 8.23 (d): (= pyridine ring).

Example 33

Process for the preparation of 2-hydroxy-5 - [[4 - [(4-methyl-2-pyridyl) aminosulfonyl] phenyl] ethinyl] benzoic acid

These compounds were prepared synthetically in a similar manner to Example 30h. The obtained material was dissolved in potassium hydroxide at a pH of approximately 9. Potassium acetate was added to the solution, and the precipitated potassium salt was filtered off. The salt was dissolved in 100 ml of water and 50 ml of ethanol and the compound was precipitated by acidification with formic acid. Hydrochloric acid was then added to reduce the pH to less than 2. The solid was filtered off, washed with water and dried. The yield is

2.5 g, which corresponds to 61% of theory.

spectrum:

spin system A: 8 7.04 (d), 7.7 (= salicylate ring), spin system B: 8 7.68 íd, 2H), (= central benzene ring), spin system C: 8 6.70 ( dd), 7, (= pyridine ring), spin system D: δ 2.24 (s):

(= methyl).

Example 34 (dd), 7.98 (d):

7.89 (d, 2 H):

(broad signal), 7.82 (d)?

Process for the preparation of 2-hydroxy-5- [4 - [[5-fluoro- (2-benzodol) thiazolyl] aminosulfonyl] phenyl] ethinyl] benzoic acid

This compound was synthesized in an ethically similar manner to Example 30h. The obtained lacquer is dissolved in dilute sodium hydroxide and carefully neutralized to about 7. Some solid material is filtered off and a solid is repeatedly precipitated from the solution by the addition of formic acid and hydrochloric acid as described above. Yield: 2.2 g (47%).

1 H-NMR Spectrum:

switching system A: δ 7.03 (d), 7.70 (dd), 7.99 (d):

(= salicylate ring), spin system B: δ 7.74 (d, 2H), 7.90 (d, 2H):

(= central benzene ring), spin system C: δ 7.79 (dd), 7.27 (ddd), 7.33 (dd):

(= benzothiazole ring).

Example 35

Process for the preparation of 2-hydroxy-5 - [[4- / N-methyl- (2-pyridyl) aminosulfonyl] phenyl] ethynylbenzoic acid

This compound was synthesized in analogy to Example 30h. Yield: 2.6 g (64%).

spectrum:

switching system A: δ 7.05 (d), 7.7 signals), 8.01 (d):

(= salicylate ring), spin system B: δ 7.63 (d, 2H), (== central benzene ring), spin system C: S 7.58 (ddd), 7 (ddd):

(dd, overlaps with others, 71 (d, 2H):

9 (ddd), 7.25 (ddd), 8.32 (= pyridine ring), spin system E: δ 3.2 (s): (= methyl group).

Process for preparing 2-hydroxy-5 - [[4 - [(5-methyl-3-isoxazolyl aminosulfonyl) phenyl] ethynyl] benzoic acid Example 36a

Process for the preparation of ethyl [2-hydroxy-5 - [[4 - [(5-methyl-3-isoxazolyl) -1-aminosulfonyl] phenyl] ethynyl] benzoate

1.2 g (12 mmol) of 5-methyl-2-isoxazolamine are dissolved in 20 ml of dry pyridine and 4.1 g (10 mmol) of ethyl [2-acetyloxy-5 - [(4-chlorosulfonylphenyl) ethynyl] is added. / benzoátuj. The solution was kept at room temperature for 72 hours. The solvent was evaporated and the residue dissolved in a small amount of tetrahydrofuran. To a solution of 2.5 g (38 mmol) of potassium hydroxide in 100 ml of refluxing water was added the above solution. After 5 minutes, the resulting solution was acidified with formic acid to precipitate a precipitate. The solid was collected by filtration, washed with water and dried. The material was recrystallized three times from ethanol. Yield: 1.5 g (35%).

Example 36b

Process for preparing 2-hydroxy-5- [4 - [(5-methyl-3-isoxazolyl) aminosulfonyl] phenyl] ethynylbenzoic acid

1.5 g of ethyl [2-hydroxy-5 - [[4 - [(5-methyl-3-isoxazolyl) aminosulfonyl] phenyl] ethynyl] benzoate is added to a boiling solution of 6 g (92 mmol) of potassium hydroxide in 100 ml of water. After 5 minutes, 25 ml of ethanol were added and the resulting solution was acidified with formic acid. The precipitate was collected by filtration, washed with water and dried. Yield 1.4 g is quantitative.

1 H-NMR Spectrum:

Switch system A: & 7.02 (d), 7.68 (dd), 7.97 (d):

(= salicylate ring), spin system B: δ 7.74 (d, 2H), 7.87 (d, 2H):

(= central benzene ring), spinning system C: δ 6.14 (s):

(isoxazole ring), spin system E: δ 2,2 5 (s):

(= methyl).

Example 37

Process for preparing 4-fluoro-2-hydroxy-5- [2- [4 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethynyl] benzoic acid

Example 37a

Process for the preparation of ethyl 4-fluoro-2-hydroxybenzoate

A mixture of 10.8 g (0.07 mol) of 4-fluoro-2-hydroxybenzoic acid, 6.9 g (0.084 mol) of sodium acetate, 55 g (0.35 mol) of ethyl iodide and dimethylformamide is stirred at room temperature for 48 hours. hours. The mixture was poured into water and extracted with n-hexane. The solution was filtered through a pad of silica gel and evaporated. The residue is an almost pure compound which is used directly in the next step. Yield: 10.2 g (80%).

Example 37b

Process for the preparation of ethyl (4-fluoro-2-hydroxy-5-iodobenzoate)

10.2 g (55 mmol) of ethyl 4-fluoro-2-hydroxybenzoate) are dissolved in n-heptane and 12 g (74 mmol) of iodmonochloride are added dropwise to the solution while stirring. After 1 hour, water was added to the reaction mixture, and then solid sulfur was added.

sodium tin in small portions until the suspension becomes discolored. More n-heptane was added to the clear solution and the phases were separated. The organic phase was dried and evaporated. The product crystallizes by cooling. The crystals obtained are filtered off and washed with cold n-heptane. The crude material is obtained in a yield of 10 g. The product is a mixture of ethyl (4-fluoro-2-hydroxy-5-iodobenzoate) (about 80%) and 5 chlorinated analogues (about 20%).

Example 37c

Process for the preparation of ethyl [4-fluoro-2-hydroxy-5 - [[4 - [(3-methyl-2-pyridinyl) sulfonyl] phenyl] ethynyl] benzoate]

3.6 g (10 mmol) of 80% ethyl (4-fluoro-2-hydroxy-5-iodobenzoate) 2.7 g (10 mmol) of 4-ethynyl-N- (3-methyl-2-pyridyl) benzenesulfonamide and 5 g (50 mmol) of triethylamine are suspended in 20 ml of tetrahydrofuran and the mixture is heated to 50 ° C. To the reaction mixture was added 45 g (0.06 mol) of dichlorobis (triphenylphosphine) palladium and 76 mg (0.4 mmol) of copper (I) iodide with stirring. After 15 minutes a partially clear solution formed. After 3 hours 50 minutes, the solution was evaporated to dryness and triturated with isobutyl methyl ketone and dilute hydrochloric acid. The organic phase was separated and the solvent was evaporated. The oily residue was triturated with a small amount of acetonitrile to give crystals. The crystals are recrystallized from acetic acid. Dissolve the substance in a small amount of chloroform and load the solution into the top of a short column packed with silica gel and elute with 25% isobutylmethylketone in toluene. Evaporation of the solvent gave the pure compound. Yield: 2.0 g (44%).

Example 37d

Process for preparing 4-fluoro-2-hydroxy-5 - [[4 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethinyl (benzoic acid)

2.0 g (4.4 mmol) of ethyl [4-fluoro-2-hydroxy-5 - [[4 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethynyl] benzoate is added to boiling solution of 2.0 g of potassium hydroxide. in 50 ml of water. After 15 minutes, 50 ml of water and 50 ml of ethanol were added and the solution was acidified with formic acid and hydrochloric acid. After cooling, the precipitate was filtered off and dried. The yield is quantitative.

¹ H-NMR spectrum (solvent: trifluoroacetic acid): spin system A: δ 6.80 (d), 8.21 (d):

(= salicylate ring), spin system B: δ 7.72 (d, 2H), 7.91 (d, 2H):

(= central benzene ring), spin system C: 8 7.64 (dd), 8.31 (d), 8.45 (d):

(pyridine ring), spin system D: δ 2,35 (s):

(= methyl).

Example 38

A process for the preparation of 4-fluoro-2-hydroxy-5- {2- [4 / (3-methyl-2-pyridinyl) sulfonyl] phenyl] ethinylbenzoic acid, example 38a

A process for the preparation of ethyl [4-fluoro-2-hydroxy-5- [2- [4 - [(3-methyl-2-pyrimidinoyl) sulfonyl] phenylethyl] benzoate].

2. g (10 mmol) of 4-ethenyl-N- (3-methyl-2-pyridyl) benzenesulfonamide, 3.6 g of hydroxy-5-iodobenzoate), d of N-dimethylacetamide with C. keeps behind

8.0% (10 mmol) of ethyl (4-fluoro) 5 ml of triethylamine and 5 ml were mixed and heated to a temperature of 4 mg of palladium acetate over 18 hours.

Pour into water and dissolve the precipitate in chloroform. The solution was then dried, loaded on top of a short column packed with silica gel and eluted with 30% isobutylmethylketone in toluene. Pure fractions were collected and evaporated to dryness. The title compound crystallizes after trituration with acetonitrile. Yield 1.1 g.

Example 38b

4-Fluoro-2-hydroxy-5- [2- [4 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethenyl] benzoic acid

1.1 g (2.4 mmol) of ethyl [4-fluoro-2-hydroxy-5- [2- [4 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethynyl] benzoate] is added to boiling solution 2.0 g of potassium hydroxide in 50 ml · water. Ethanol (10 ml) was added to obtain a clear solution. After 15 minutes, an additional 25 mL of ethanol was added and the solution was neutralized to about pH 7 with formic acid. The slightly opalescent solution is treated with decolorizing charcoal and acidified with formic acid. After cooling, the precipitate was filtered off and dried. Yield 0.8 g.

1 H-NMR spectrum (solvent: acid: trifluoroacetic acid):

switching system A: δ 6,79 (d) , 8.29 (d): (= salicylate ring) spin system B: δ 7.72 (d, 2H), 7.90 (d, 2H): (= central benzene kr uh) switching system C: δ 7,62 (dd) , 8.29 (d), 8.44 (d (pyridine ring), switching system D: δ 7.21 (d) 7.35 (d): (= ethendiyl bridge), switching system E: δ 2,36 (s):

(= methyl).

Example 39

Process for the preparation of 2-hydroxy-5- [3 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethinyl] benzoic acid

Example 39a

3-Iodo-N- (3-methyl-2-pyridyl) benzenesulfonamide * 32.4 g (0.3 mol) of 3-methyl-2-pyridinamine are dissolved in 200 ml of isobutylmethyl ketone and the resulting solution is added with stirring. 2 g (0.1 mol) of 3-iodobenzenesulfonyl chloride. The solution was maintained at 40 ° C for 8 hours and then diluted hydrochloric acid was added. The precipitate is filtered off and the organic phase is separated and evaporated. The residue was combined with the first solid and recrystallized from ethanol. The crystals are dissolved in approximately 200 ml of 1M sodium hydroxide solution and extracted three times with 100 ml of isobutyl methyl ketone each. The aqueous phase is partially evaporated to remove isobutylmethylketone residues. 100 ml of ethanol are then added to the reaction mixture and the solution is acidified with acetic acid. The precipitate was filtered off, washed with water and dried. Yield: 23 g (61%).

Example 39b * Process for the preparation of ethyl [2-hydroxy-5 - [[3 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethynyl] benzoate

A mixture of 18.7 g (50 mmol) of 3-iodo-N- (3-methyl-2-pyridyl) benzenesulfonamide, 9.5 g (50 mmol) of ethyl (5-ethynyl-2-hydroxybenzoate), 65 ml of triethylamine and 65 ml of tetrahydrofuran are stirred at 60 ° C. To the reaction mixture were added 250 mg (0.36 mmol) of dichlorobis (triphenylphosphine) palladium and 140 mg (0.7 mmol) of copper (I) iodide with stirring. After 1 hour, the solution was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried, treated with charcoal and the solvent was evaporated. The residue is recrystallized from methanol, then from toluene and finally from acetic acid. Yield: 12.7 g (58%).

Example 39c

Process for the preparation of 2-hydroxy-5 - [[3 - [(3-methyl-2-pyridylamino) sulfonyl] phenyl] ethynyl] benzoic acid g (9.2 mmol) ethyl [2-hydroxy-5 - [[3 - / ( 3-Methyl-2-pyridylamino) sulfonyl / phenyl] ethinyl] benzate] was added to a boiling solution of 6 g (90 mmol) of potassium hydroxide in 100 ml of water. After 15 minutes, 50 ml of ethanol are added and the solution is acidified with hydrochloric acid. The compound was collected by filtration and dried at 110 ° C. Yield: 3.5 g (93%).

¹ H-NMR spectrum:

switching system A: δ 7.0 (d), 7.68 (dd), 7.97 (d):

(= salicylate ring), spin system B: δ 7.55 (t), 7.69 (d), 7.90 (d), 8.06 (s): (= central benzene ring), spin system C: δ 7.62 (d, broad signal), 6.78 (t, broad signal), 7.81 (s, broad signal):

(= pyridine ring), spin system D: δ 2,10 (s):

(= methyl).

Signal extension in the pyridine ring by methyl substituted derivatives in the 3-position.

is typical for

Example 40

Effect of compounds on human lymphocyte proliferation

Peripheral blood mononuclear cells are isolated from heparinized blood of healthy volunteers by density gradient centrifugation as reported by Bain and Pshyk, Transplantation Proc. 4, 1 * 53-164 (1972). Cell proliferation induced by Concanavalinen A is measured in a standard assay as described by Soderstrom et al. in Scand. J. Immunol. 3, 503-516 (1990) using 5% fetal bovine serum in culture medium. The reaction mixture (final concentration) consists of 200,000 cells stimulated with 2.5 µg / ml Concanavalin A and test compound in a total volume of 0.2 ml. Test compounds are added at the beginning of the 3-day test with the addition of ofradioactive [ ³ H] -thymidine over the last 18 hours. Cell bound radioactivity is measured in a liquid scintillation counter.

Table

Inhibitory effects of 250 μπιοί of test compounds on Concanavalin A-induced proliferation in human lymphocytes. Data are from two experiments and are given as percent inhibition from proliferation in the absence of test compounds

Test Compound Inhibition,% Standard Example Mean Deviation

asalazine 53.7 5 1 95.6 2 2 99.5 0 3 73.6 21 4 92.3 4 15 Dec 93.9 2 16 95.4 0 17 99.5 0 18 4 3,8 26 19 Dec 10.3 11 20 May 34.8 10 21 99.8 0 22nd 99.8 0 26 16.0 11 27 Mar: 37, 3 23 28 15.0 13 29 66.0 4 31 100 ALIGN! 0 32 100 ALIGN! 0 34 9 8 T of 35 About Ί- of 37 100 ALIGN! 0 3 3 100 ALIGN! 0 39 -: • 100 0

Example 41

Effects of test compounds on hyperoxide production from human granulocytes

Granulocytes are isolated from heparinized blood from healthy volunteers. The hyperoxide assay is essentially the same as that of J. M. McCord and I. Fridovich in J. Biol. Chem. 244, 6049-6055 (1969), according to a modification made by G. Carlin et al. (Pharmacol. Toxicol. 6 5, 121-127 (1989)). The reaction mixture containing (final concentration) 125 pmol of cytochrome C in Dulbeccos's phosphate buffer containing magnesium and calcium, 10 pmol of test compound and 400,000 granulocytes was treated with 5 pm / ml cytochalasin B immediately prior to the experiment. The reaction mixture is pre-incubated at 37 ° C for 10 minutes, then 10 nmol of N-formyl-L-methionyl-L-leucyl-L-phenylalanine is added to start the reaction and the mixture is brought to a final volume of 1 ml. After 10 minutes, the tubes were centrifuged and the absorbance of the supernatant was measured at 540-550 nm. Hyperoxide production is expressed as the difference in absorbance at these wavelengths.

Table

Inhibitory effects of 10 μτηοΐ of the test compound on N-formyl-L-methionyl-L-leucyl-L-phenylalanine induced hyperoxide production. Data are reported as a percentage of inhibition of hyperoxide production in the absence of test compounds

Test compound Inhibition, % Authoritative Number from example no. center deviation experiments Sulfasalazine 63.5 11.8 19 Dec 1 71.0 13.6 4 2 86.0 7.3 Λ 3 55.7 17.0 4 4 76.9 10.6 4 5 25.8 10.1 3 16 94.6 1.1 3 17 71.9 5.9 3 18 44, 2 6.4 3 19 Dec 6 5.9 2.9 3 20 May 35.1 7.9 3 21 93.0 4, 2 3 22nd 85.5 8, 2 4 25 4 5,5 4, 1 j 26 26.3 16.2 4 27 Mar: 32.7 17.1 /, 28 17.9 8.7 4 29 33.4 11.9 5

Example 42

Effects of test compounds on hyperoxide production from human granulocytes at 100 μη

Granulocytes are isolated from heparinized blood from healthy volunteers. The hyperoxide assay is essentially identical to that reported by JM McCord and I. Fridovich in J. Biol. Chem. 244, 6049-6055 (1969), according to a modification made by G. Carlin et al. (Pharmacol. Toxicol. 65: 121-127 (1989)). The reaction mixture containing (final concentration) 125 pmol of cytochrome C in Dulbeccos's phosphate buffer containing magnesium and calcium, 100 pmol of test compound and 600,000 granulocytes is treated with 5 μπι / ml cytochalasin B immediately before. experimentem. The reaction mixture is pre-incubated at 37 ^° C for 10 minutes, then 100 nmol of N-formyl-L-methionyl-L-leucyl-L-phenylalanine is added to start the reaction and the mixture is brought to a final volume of 1 ml. ⁵ to 10 minutes, the tubes were centrifuged and the supernatant absorbance was measured at a wavelength of 540-550 nm. Hyperoxide production is expressed as the difference in absorbance at these wavelengths.

Table

Inhibitory effects of 100 μιηοΐ of the test compound on the production of hyperoxide induced by 100 nmol of N-formyl-L-methionyl-L-leucyl-L-phenylalanine. Data are shown as percent inhibition from hyperoxide production in the absence of test compounds

Test Compound Inhibition,% Standard Number of Example No. Mean Deviation of Experiments

asalazine 65.4 9.0 3 2 94.1 4.2 3 33 92.1 3.7 3 37 97.5 3.2 3 38 98.7 1.7 3 39 93.5 1,8 3

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JUDr. Ivan

Attorneys? plio CO Prdia 1, kouecek cr /. office] un £ ú.iirnova 16

Claims (22)

PATENT CLAIMS A compound of formula Het-NR-SO ₂ -Ph ¹ -A-Ph ² (COOH) (OH) and tautomeric forms, salt, solvate, C 1 -C 6 alkyl and a pharmaceutical composition comprising the compound, wherein Ph ¹ and Ph ² are optionally substituted benzene rings, with the proviso that the carboxy and hydroxy groups are ortho to each other, A represents a bridge and Het- includes an optionally substituted heterocyclic ring containing conjugated double bonds and is bound to NR, wherein A is a bridge that is stable against reduction because it is not an azo group, and R is a hydrogen atom or a lower alkyl group. A compound according to claim 1, wherein A and SO ₂ are bonded to each other in the para or meta position on Ph ¹ and the hydroxy group and A are bonded to each other in the ph ^{2 position} . A compound according to any one of claims 1 and 2, wherein it represents a straight carbon chain containing at most three carbon atoms, comprising a C-C, C = C or C ^C bond, or iromads with a carbonyl of the formula C = O. A compound according to any one of claims 1 to 3, wherein it is selected from the groups -C = C-, -CH = CH-, -CH ₂ -CH ₂ -, -CH = CH-, -CH = CH-CO- and -CH ₂ -CO-, if they are useful in the trans form. A compound according to any one of claims 1 to 4, wherein? selected from the groups -CsC- and -CH = CH-. A compound according to any one of claims 1 to 5, wherein R is hydrogen. A compound according to any one of claims 1 to 5, wherein R is lower alkyl, preferably methyl. A compound according to any one of claims 1 to 7, wherein the heterocyclic ring is a five or six membered ring containing two or three conjugated double bonds. A compound according to claim 8, wherein Het represents a group of formula (R ₁ , R ₂ , R ₃ ) -Het · -, wherein Het 1 - represents a group of formula wherein the free valence in this group is bound to NR and X represents a group of the formula i) 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 (ii) -CH = CH-CH = CH-, -CH = CH-CH = N-, -CH = N-CH = CH-, -CH = CH-N = CH-, -N = CH-CH = CH-, in which adjacent hydrogen atoms represented in bold (H) can be replaced in pairs group of formula -CH = CH — CH = CH-- to form a bicyclic structure (condensed ring) a R 1, R ₂ and are substituents on carbon atoms in Het 1 and are selected from the group consisting of hydrogen, lower alkyl, halogen, hydroxy, cyano, carboxy, lower alkoxy, benzyloxy, lower acyl, including acetyl and benzoyl, phenyl and benzyl groups, some of which. the benzene rings present may be substituted. - ¹ The compound of claim 9, wherein X is -O-CH = CH-, -NH-CH = CH-, -CH = CH-NH-, and -CH = CH-S-. The compound of claim 9, wherein X is -CH = CH-CH = CH-, -CH = N-CH = CH-, -CH = CH-N = CH-, and -N = CH-CH-CH -. A compound according to any one of claims 9 to 11, wherein, Het 1 is a monocyclic structure. A compound according to any one of claims 9 to 11, wherein Het 1 is a bicyclic structure. A compound according to any one of claims 9 to 13, wherein R ₁ and R ₂ are hydrogen and R ₃ is selected from the remaining substituents. t A compound according to claim 14, wherein it is hydrogen. A compound according to any one of claims 12, 14 and 15, wherein Het ¹ is a pyridine residue. A compound according to claim 16, wherein A represents a group of formula -CsC- or · - <3H = CH- and R 6 is not a hydrogen atom, but is preferably methyl. The compound of claim 17, wherein R is hydrogen. The compound of claim 17, wherein R ₃ is ortho to the -NRSO ₂ -substituted in the pyridine ring. A process for producing a compound according to any one of claims 1 to 19, characterized in that (I) a compound of the general formula Het-NR-SO ₂ -Ph ¹ -X is chemically reacted with a compound of formula Y-Ph ² (COOR ₅ ) (OH) to form a bond between X and Y to form a compound according to any one of claims 1 to 16, and wherein Het, R, Ph and Ph have the same meanings as set forth in claim 1, R ₅ represents a hydrogen atom or a lower alkyl group and X and Y are a pair, meaning a group of formula -C? CH and Z ₁ -, -Z ₁ and HCsC-, -CH = CH ₂ and Zj-, -Zj_ and -CH = CH _2, -CO-CH ₃ and HCO-, -CHO and CH ₃ -CO-, -CH ₂ CO ₂ and H-, -CHO and Z ₃ CH ₂ -, —CH ₂ Z ₃ and HCO-, wherein Z ₁ is bromine or iodine, Z ₂ is a halogen atom, preferably a chlorine atom, and is a Wittig-type organophosphorus compound, for example a triphenylphosphonium group or a dialkylphosphonate radical, and then, if R 6 is not a hydrogen atom, the resulting compound, if desired, undergoes a base catalyzed hydrolysis process replacing the group R ₅ with a hydrogen atom or a suitable metal ion, or (II) a compound of the formula Het-NRH is reacted chemically in the presence of a basic condensing agent in a solvent with a lower alkyl ester of a compound of formula ClSO ₂ -Ph ¹ -A-Ph ² (COOH) (OR ₆ ), in which compounds Het, R, Ph ¹ , Ph ² and A have the same meanings as in claim 1 a R ₆ represents a lower acyl group, preferably acetyl, such that coupling occurs at the NRH and C 1 SO ₂ groups to give a compound which by subsequent hydrolysis of the ester groups present provides a compound according to any one of claims 1 to 16, or (III) a bridge in the compound formulas Het-NR-SO ₂ -Ph ¹ -A'-Ph ² (COOR ₇ ) (OR _g ) in which Het, R, Ph · ¹ · and Ph ^ have the same meanings as set forth in claim 1, R ₇ represents a hydrogen atom or R _g , Rg is hydrogen or _Rg, A 'represents a group which can be transformed by an addition or elimination reaction or optionally by an oxidation or reduction reaction to A as defined in claim 1, is chemically transformed to A with one of the above reactions and thereafter when R ₇ and / or _Rg are not hydrogen, the resulting compound, if desired, to an alkali-Catalysed hydrolysis to replace R ₇ and / or R _{g is} hydrogen or a suitable metal ion. A compound according to any of the uses as a drug substance. A compound according to any one of for the manufacture of a medicament for nitrous diseases.