Derivatives aminotriazole or their hydrates or their salts and pharmaceutical compositions on their basis

 

(57) Abstract:

Derivatives aminotriazole General formula I, where R1or R2is hydrogen; R3, R13- H, C1-6alkyl or hydroxy; R4and R14- H, C1-6alkyl, C1-6alkoxy, hydroxy, halogen, or R4and R14may together represent methylenedioxy; R5- H, C1-6alkyl, possibly substituted with halogen, amine, mono - or dialkylamino, morpholino, alkoxy or hydroxy, C1-6the stsyla; R6- phenylsulfonyl, possibly substituted by alkyl, alkoxy, halogenoalkane, hydroxy, nitro or halogen; a, b, and G is CH, N, N, N+-(R7)E-where R7- C1-6alkyl or benzyl; F - anion, Y -, and Z - ring, or their hydrates or salts have anti-cancer effect. 2 S. and 4 C.p. f-crystals, 4 PL.

The invention relates to applicable in medicine new derived aminotriazole or its hydrate and its pharmaceutically acceptable salts.

In cancer chemotherapy is currently applied to various anticancer drugs, such as alkiliruuchie agents, topoisomerase inhibitors, antimetabolites, inhibitors of cytoskeletal system, hormones, antihormones, antibiotics, and herbal products.

Antimicrotubular agents or agonists tubulin have high anticancer activity with broad antitumor spectrum and represent clinically important class of drugs.

Recently, the inhibition of polymerization of tubulin attracts attention as a mechanism of action of anticancer agents. Microtubules are ubiquitary intracellular structure, as a main component of the mitotic spindle plays an important role in cell division. Antimicrotubular agent binds to the protein tubulin microtubules and violates the dynamics of the orientation of microtubules or in the direction of Assembly or disassembly, showing thus their anticancer activity. Attract the attention of Vinca-alkaloids of plant origin, is known as a typical anti-cancer agents the inhibitors of polowanie polymerization of tubulin. Being a vegetable origin, these compounds can cause a number of problems. Such anti-cancer drugs that act on microtubules, which cannot be used in a conventional manner due to their side effects, applicable in injectable form that is not used in the mode of multiple doses. Recently it was discovered substance E7010 low molecular weight (Cancer and Chemoterapy, 1993, 20: 34-41, JP Kokai H5-39256), and is currently great interest in clinical trials.

It was reported that derivatives of stilbene represented by (Z)-3,4,5-trimetoksi-4'-methoxystilbene and derivatives dehydrosilybin that have stellanova the core, similar to the nucleus of the compounds according to the present invention have activity in inhibiting the polymerization of tubulin (J. Med. Chem. 1991, 34, 2579).

Meanwhile, it was reported that derivatives of hydroxamic acid, substituted phenylethenyl heterocyclic group, exhibit anti-allergic activity (Eur. J. Med. Chem. 1985, 20, 487-491). It was also reported about interaction between tetrahydrocarbazole and monoamine oxidase (J. Med. Chem. 1994, 37, 151-157).

The aim of the present invention is to develop a new compound that exhibits excellent contrast ratio, and hormones, currently available, and can be entered through the mouth.

To achieve this goal, the authors of the present invention have synthesized various compounds and evaluated them. In the research it was found that the compound of the following General formula [1] has a very strong anti-cancer activity with low toxicity and are the object of the present invention.

The present invention relates to a compound of the following General formula [I] , its salts and anti-cancer composition containing a specified compound or salt as an active ingredient:

< / BR>
where R1and R2are the same or different and each represent hydrogen, alkyl with 1-6 carbon atoms, acyl with 1 to 6 carbon atoms, cyano, or-COOR (R represents hydrogen or C1-6alkyl):

R3, R4, R13and R14are the same or different and each represent hydrogen, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, halogenoalkane with 1-6 carbon atoms, acyl with 1 to 6 carbon atoms, acyloxy with 1-6 carbon atoms, hydroxy, halogen, nitro, cyano, amino, acylamino with 1-6 carbon atoms, aminoacylase with 1-6 carbon atoms or Mohali to present methylendioxy:

R5represents (1) hydrogen, (2) alkyl with 1-6 carbon atoms, which is optionally substituted with halogen, amino, groups of monoalkylamines with 1-6 carbon atoms, dialkylamino with 1-6 carbon atoms, morpholino, alkoxy with 1-6 carbon atoms or hydroxy, (3) alkenyl with 2-6 carbon atoms, which is optionally substituted with halogen, (4) quinil with 2-6 carbon atoms or (5) acyl with 1 to 6 carbon atoms;

R6represents (1) a group aroyl with 7 to 11 carbon atoms, which is optionally substituted by alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms or halogen, or (2) arylsulfonyl with 6-10 carbon atoms, which is optionally substituted by alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, halogenoalkane with 1-6 carbon atoms, hydroxy, nitro or halogen,

A, B, G, Q and X may be the same or different and each represent N, CH, N--->O or N+-(R7)E-(R7represents alkyl with 1-6 carbon atoms or arylalkyl with 7-14 carbon atoms; E-represents an anion such as halogen ion, or nitrate ion), the Exceptions are cases when A, B and G simultaneously represent N, and in the case when A, B, G, Q and X in parallel represent CH;

Y and Z are the signs souveran [I]. The hallmark of the connection structure according to the invention is the substitution in anthopology phenyl in stilbazolium the core of the amino group.

Connection with the above-mentioned structural feature, not only is a new connection, never before documented, but also a connection with improved pharmacological properties, which will be described later, when a low toxicity.

In the context of this invention alkyl denotes a straight or branched alkyl group with 1-6 carbon atoms, including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. Especially preferred is alkyl with 1-3 carbon atoms. Alkoxy includes straight or branched alkoxygroup with 1-6 carbon atoms, such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentylamine, n-hexyloxy, etexilate. Especially preferred is alkyl with 1-3 carbon atoms. Alkenyl means any straight or branched alkenylphenol group with 2-6 carbon atoms, including, for example, vinyl, 1-propene preferred is alkenyl with 2-4 carbon atoms. Quinil includes straight or branched alkyline group with 2-6 carbon atoms, such as ethinyl, 1-PROPYNYL, 2-PROPYNYL, 2-butynyl, 3-butynyl and 3-methyl-2-butenyl. In particular, preferred are quinil with 2-4 carbon atoms. Acyl includes straight or branched Econoline group with 1-6 carbon atoms, such as, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl. Acyl may be substituted with halogen, as in the case of TRIFLUOROACETYL. Especially preferred is acyl with 2 to 4 carbon atoms. Aroyl includes, for example, a group of 7-11 carbon atoms, such as benzoyl, -naphtol and naphtol. Particularly preferred benzoyl. Aryl these arylsulfonyl includes groups with 6-10 carbon atoms, such as phenyl, naphthyl and naphthyl, to specify as few examples. In particular, preferred is phenyl. Aryl these Arola or arylsulfonyl may be substituted by at least one, and either the same or different groups of substituents, such as specified in the definition of R6. Halogen includes chlorine, fluorine, bromine and iodine.

Ring Y includes, for example, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and pyrazinyl. Suppose uchet phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl and 4-pyridazinyl. Preferred is pyridyl and, specifically, 4-pyridyl. It is preferable, in particular, unsubstituted or 3-substituted 4-pyridyl.

Preferred are compounds, in which in General formula [I] R1, R2, R3, R4, R13and R14all represent hydrogen, -NR5R6is 4-[(methoxyphenyl)sulfonyl]amino or N-(hydroxyethyl)-H-[(methoxyphenyl)sulfonyl]amino, ring Y is unsubstituted phenyl or hydroxy-or methoxsalen phenyl, and the ring Z represents either unsubstituted 4-pyridyl or 4-pyridyl, substituted hydroxy, acetoxy or fluorine, or N-oxide.

The salt of compound [I], which is included in the scope of the invention include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, Hydrobromic acid, etc. and organic acid salts, such as, for example, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonate acid, this is camphorsulfonic acid. When R1or R2represent COOH, corresponding salt includes salts with alkali metals or alkaline earth metals such as sodium, potassium, calcium, etc.

Compounds of the present invention can exist as CIS(Z) and TRANS(E) form. These representatives isomers and their mixtures are also included in the scope of the present invention.

In addition to the specific compounds synthesized in examples of the preparation, which are presented hereafter, the compounds of the present invention include, for example, the following specific compounds:

4-[1-Cyano-2-[2-[[(p-methoxyphenyl)sulfonyl]amino]-phenyl]ethynyl]pyridine,

4-[1,2-Dimethyl-2-[2-[[(p-methoxyphenyl)sulfonyl]amino]-phenyl]ethynyl] pyridine,

4-[1-Methoxycarbonyl-2-[2-[[(p-methoxyphenyl)sulfonyl] -amino] phenyl] ethynyl]pyridine,

2-Chloro-4-[2-[2-[[(p-methoxyphenyl)sulfonyl]amino]phenyl]-ethynyl] pyridine,

2-Methoxy-4-[2-[2-[[(p-methoxyphenyl)sulfonyl] amino] -phenyl]ethynyl] pyridine,

3-Methoxy-4-[2-[2-[[(p-methoxyphenyl)sulfonyl] amino] -phenyl]ethynyl] pyridine,

4-[2-[2-[[[(p-Methoxyphenyl)sulfonyl] amino] -5-methyl]-phenyl]ethynyl] pyridine,

4-[2-[[2-[[(p-Methoxyphenyl)sulfonyl] amino]-5-methoxy-phenyl]ethynyl] pyridine,

4-[2-[2-[[(2,4�Mino]-5-methoxyphenyl]ethynyl] pyridine,

4-[2-[[2-[[(3,4,5-Trimethoxyphenyl)sulfonyl] amino] -5-methoxy] phenyl] ethynyl]pyridine,

4-[2-Cyano-2-[2-[[(p-methoxyphenyl)sulfonyl] amino] -5-methoxyphenyl] ethynyl]pyridine,

4-[2-[2-[(p-Methoxybenzoyl)amino]phenyl]ethynyl]pyridine,

2-Fluoro-4-[2-[2-[[(p-methoxyphenyl)sulfonyl] amino]phenyl]-ethynyl] pyridine 1-oxide,

4-[2-[2-[N-Propionyl-N-[(p-methoxyphenyl)sulfonyl] -amino] phenyl]ethynyl] pyridine 1-oxide,

4-[2-[2-[N-Formyl-N-[(p-methoxyphenyl)sulfonyl] -amino] phenyl] ethynyl] pyridine 1-oxide,

4-[2-[2-[N-Butyryl-N-[(p-methoxyphenyl)sulfonyl] -amino] phenyl] ethynyl] pyridine 1-oxide,

3-Fluoro-4-[2-[2-[[(p-methoxyphenyl)sulfonyl]amino]phenyl]-ethynyl] pyridine,

2-Fluoro-4-[2-[2-[[(p-methoxyphenyl)sulfonyl]amino]phenyl]-ethynyl] pyridine,

4-[2-[2-[N-Acetyl-N-[(p-methoxyphenyl)sulfonyl] amino] -phenyl] ethynyl] pyridine,

2-Methoxy-4-[2-[2-[[(p-methoxyphenyl)sulfonyl] amino] -phenyl]ethynyl] pyridine 1-oxide.

Of the compounds of the present invention (E)-4-[2-[2-[[(p-methoxyphenyl) sulfonyl] amino] phenyl]ethynyl]pyridine and its hydrochloride (compound according to Example 3), (E)-4-[2-[2-[[(p-methoxyphenyl)sulfonyl]amino] phenyl]ethynyl]pyridine 1-oxide (compound in Example 20), (E)-4-[2-[2-[N-(2-hydroxyethyl)-N-[(p-methoxyphenyl)sulfonyl] amino] phenyl]ethynyl]pyridine 1-the Jn (connection Example 34) and (E)-4-[2-[2-[N-acetyl-N- [(p-methoxyphenyl)-sulfonyl] amino] phenyl] ethynyl] pyridine 1-oxide (compound according to Example 57) are preferred. Especially preferred are compounds according to Example 3, Example 34 and Example 49.

Compounds of the present invention can be achieved in the following ways:

Method 1.

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(In the above reaction scheme, R1, R2, R3, R4, R5, R6, R13, R14, A, B, G, Q and X have the meanings indicated above. E represents hydroxy or a leaving group).

This group includes, but is not limited to, chlorine, bromine, sulfoxy, imidazolyl and carboxy.

The amine of General formula [II] or interacts with the carboxylic acid or reactive derivative (E = leaving group) carboxylic acid or sulfonic acid, which has a General formula [III], in a suitable solvent with obtaining [I]. The reaction solvent may be any solvent type, which does not affect the reaction, including, therefore, ethers, such as tetrahydrofuran, dioxane and diethyl ether; hydrocarbons, such as benzene and toluene; halogenated hydrocarbons such as methylene chloride and chloroform; ketones, such as acetone and methyl ethyl ketone; Protanopia solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, pyridi the oil acid, which can be used includes the following types of reactive derivatives, which are commonly used, such as sulfonylmethane, carboxylated, the anhydride of sulfonic acid, carboxylic acid anhydride, N-sulfanilimide, activated amide, and the activated ester. Among the above, the most preferred sulfonyl-halide and carboxylate. Such halides of the acids include acid chloride acid and bromohydrin acid. The acid anhydride includes mixed anhydrides derived from monoalkylammonium acids and mixed anhydrides derived from aliphatic carboxylic acids (e.g. acetic acid, pivaloyloxy acid, valeric acid, isovalerianic acid, triperoxonane acid, and so on) and symmetric anhydrides. Activated amides include amides of acids, such as, for example, imidazole, pyrazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole and benzothiazole. Activated esters include such esters as methyl ether, methoxymethyl ether, propargilovyh ether, 4-nitrophenyloctyl ether, 2,4-dinitrophenoxy ether, trichloranisole ether, methanesulfonate ester and ether derivatives, such as, for example, N-Islami or carboxylic acid halide, the reaction is preferably conducted in the presence of a suitable removing the acid agent. Removes acid agent, which can be used include compounds of alkali metals such as sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and sodium methoxide, and organic Quaternary amines, such as, for example, triethylamine, triethylenediamine. As the reaction solvent, it is preferable to use the basic solvents such as pyridine, to ensure that it was not necessary to use to remove the acid agent. In many cases, the reaction proceeds at room temperature, but, when necessary, the reaction can be carried out with cooling or heating, usually in the range from -78oC to 150oC, or preferably at 0oC - 120oC. Preferred is a ratio of the compound [III] Amin [II] of 1 to 10 molar equivalents, better, 1 to 3 molar equivalents, when used to remove the acid agent. When removing the acid agent is not used, part [III] is less than equimolar, and is preferably from 0.5 to 0.1 molar equivalent. The reaction time, which depends on the input PR is. Obedinenie [Ia] (R6in the formula [I] represents aroyl) can also be obtained by reacting amine [II] with a carboxylic acid in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide (D), carbonyldiimidazole or diphenylphosphinite (D).

The compound of the present invention can also be obtained in accordance with the following methods.

Method 2.

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[In the above reaction scheme A, B, G, Q, X, R1, R2, R3, R4, R5, R6, R13and R14have the meanings given above. L represents a leaving group, such as-P(Ph)3Br, or-PO(OR0)2(R0is alkyl)].

Thus, the compound of General formula [I] can be obtained by reacting postnasal salt or diapir alkylphosphoric acid of General formula [IV] with a ketone or aldehyde of General formula [V] by a known method per se (Org. React., 14, 270) or any option.

Method 3:

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(In the above scheme, A, B, G, Q, X, R1, R2, R3, R4, R5, R6, R13and R14have the meanings defined above).

Thus, the compound [VI] EOI is ü conducted generally in accordance with the known method (J. Org. Chem. 41, 392). Thus, the compound [I] can be obtained by reacting compound [V] with the compound [VI] in the presence of low valent titanium obtained by using trichloride titanium or of titanium tetrachloride in combination with regenerating substance, such as lithium, potassium, n-utility, sociallyengaged or zinc.

Method 4.

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(In the above scheme, A, B, G, Q, X, R1, R2, R3, R4, R5, R6, R13and R14have the meanings given above. L1represents halogen, such as iodine).

Thus, the compound [I] can be obtained by reacting compound [VII] with a Grignard reagent [VIII], usually in accordance with a known method (Tetrahedron Letters, 30, 403). Thus, these compounds interact in a solvent inert to the reaction in the presence of complex compounds of metal, such as Nickel (Ni) or palladium (Pd), at from -78oC to 100oC and, preferably, from 0oC to 70oC. the Solvent which can be used include ethers, such as anhydrous diethyl ether and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene. The compound [VII] ASS="ptx2">

< / BR>
(In the above reaction scheme A, B, G, Q, X, R1, R2, R3, R4, R5, R6and R14have the meanings given above. L2represents a leaving group such as chloro, bromo, acetoxy, and so on).

The compound [I] can be obtained by heating compound [IX] with a mineral acid, such as sulfuric acid or phosphoric acid, an organic acid, such as oxalic acid or p-toluensulfonate acid, Lewis acid such as boron TRIFLUORIDE, or with a base, such as potassium hydrosulfate. The compound [I] can also be obtained by treating compound [IX] with a halogenation reagent, sulfonylureas agent or etherification agent with obtaining a reactive derivative [X] and then subjecting [X] interaction in alkaline conditions in the same way as in Method 1.

Method 6 (applicable when R1=R2=H in formula [I], only in the case when R3, R4, R13or R14are nitro or cyano, and when R5represents alkenyl, quinil or acyl)

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(In the above reaction scheme A, B, G, Q, X, R3, R4, R5, R6, R13and R14P> and R2is hydrogen) can be obtained by recovering the compound [XI] with sociallyengaged or by catalytic reduction.

Method 7.

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(In the above reaction scheme A, B, G, Q, X, R1, R2, R3, R4, R5, R6, R13and R14have the meanings defined above).

Thus, the compound [I] can be obtained by the condensation reaction of the compound [VI] and the compound [XII] (as described in JP Kokai H5-506857, J. Med. Chem., 1994, 37, 151).

Method 8.

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(In the above reaction scheme A, B, G, Q, X, R1, R2, R3, R4, R5, R6, R13and R14have the meanings defined above).

The compound [Ib] (compound of formula [I] , where B represents N--->0) can be obtained by reacting compound [XIII] with an organic peroxide in accordance with the known method [Jikken Called Koza (Experimental Chemistry Series) 21, Yukikagobutsu-no-Gosei (Synthesis of Organic Compounds) III (Part 2), page 295, 1958).

Method 9 (only in the case when R5in the General formula [I] represents the hydrogen).

< / BR>
(In the above reaction scheme A, B, G, Q, X, R1, R2, R3, R4, R6, R13and R14and R5).

Thus, the compound [Ie] (a compound of the formula [I], where R5different from hydrogen) can be obtained by treating [XIV] the alcohol of the formula R15-OH (cf. Synthesis 1981, 1).

Method 10 (only in the case when R5in the formula [I] is the hydrogen).

< / BR>
(In the above reaction scheme A, B, G, Q, X, R1, R2, R3, R4, R6, R13, R14and R15have the meanings given above. E represents a leaving group).

This group includes chlorine, bromine, iodine, carboxy, etc. [Ie] is produced by the interaction of the compounds of General formula [XIV] with the compound of the formula R15-E in a suitable solvent. This reaction can be carried out essentially in the same way as in Method 1.

When the compound obtained by any of the above methods, is alkilirovanny ether carboxylic acid (R1or R2is COOR where R is alkyl, it may be subjected, if desired, the alkaline hydrolysis of the derivatization of the free carboxylic acids (R= H). This hydrolysis reaction can be carried out by stirring the ester compounds 1-5% potassium hydroxide or hydroxide nattam by volume) at from room temperature to 100oC, preferably at the boiling point of the used solvent.

Alternatively, the hydrolysis reaction can be carried out using a large excess, preferably, 10-20 times the volume of acid (e.g., fuming sulfuric acid, sulfuric acid, hydrochloric acid, Hydrobromic acid, Hydrobromic acid/acetic acid, chlorosulfonic acid, polyphosphoric acid, etc.,) as solvent at from room temperature to 110oC.

The ester can be converted into another ester by stirring in 10-100-fold by volume of the alcohol corresponding to the desired ether, in the presence of catalytic amounts of sulfuric acid at 0oC to 150oC, preferably at from room temperature to 110oC.

When the target compound is a carboxylic acid (R1or R2are COOR, where R is hydrogen), it can be esterified, if desired, to obtain the ester (R1or R2are COOR, where R is alkyl). This esterification reaction can be carried out by known methods of esterification such as, for example, using thionyl chloride and alcohol, Gin and the alcoholate. Moreover, the carboxylic acid can be converted into pharmacologically acceptable salt (e.g. sodium salt, potassium, calcium and so on) by a known method per se.

When the functional group or groups, e.g. amino, hydroxy or carboxy, compounds obtained by any of the above methods, were protected, the protective group or groups may be removed by known methods, such as acid treatment, alkali treatment, catalytic reduction, etc.

Above the base or hydrate can be obtained by known methods.

The target compound [I] thus obtained can be isolated and purified by known methods, such as concentration, determination of pH, separation, extraction with solvent, crystallization, recrystallization, fractional distillation and chromatography.

The original compound [II] can be obtained in accordance with the known method (Eur. J. Med. Chem., 20, 487, 1985; J. Med. Chem., 37, 151, 1994). According to this method, mainly obtained E-derived. The mixture of E - and Z-derivatives can be obtained by known methods (Org. React. 14, 270). Z-derivative can be obtained by converting the sooma, as in the above-described Method 6.

The original compound [IV] can be obtained in a known manner (Org. React. 14, 270) or its modification.

The original compound [VI] can be obtained in accordance with the known method (JP Kokai H4-330057). The original compound [VII] can be obtained in accordance with the known method (Synthesis 1988, 236).

The original compound [X] can be synthesized in accordance with known methods (Org. Syn. Ill, 200).

The original compound [XII] can be synthesized in accordance with the known method (J. Org. Chem., 31, 4071).

For the introduction of compounds according to the invention as a drug, or compound, as such, a pharmaceutical composition containing it, in a medically acceptable non-toxic inert carrier, at a concentration of, for example, to 0.1% to 99.5%, preferably 0.5% to 90%, is introduced mammals, including humans.

Media that can be used include solid, semi-solid or liquid diluents, fillers and other adjuvants and at least one of them is selectively used. The pharmaceutical composition is preferably administered in a single dosage form. Pharmaceutical kompetizzjoni) or rectally. Undoubtedly, should be used in dosage forms appropriate for each route of administration. Oral administration, for example, is preferred.

The dose of a compound as an anti-cancer drug, preferably, should be selected with consideration of patient factors such as age, body weight, and so on, the nature and severity of the disease, and so on, as well as route of administration, but the usual oral dose as an active ingredient according to the invention, for an adult patient is between 0.1 mg to 500 mg per day, or, preferably, from 1 mg to 200 mg per day. In some cases, may be sufficient lower doses, while other cases require higher doses outside the above interval. The above daily dose is preferably administered at 1-3 divided doses.

Oral administration can be performed using solid or liquid unit dosage form such as coarse powders, powders, tablets, coated tablets, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets, and other forms.

Coarse powders prepared by grinding the active substance to particles of suitable size. Powders are prepared by and is lennemi pharmaceutical carriers, such as edible carbohydrates, such as starch, mannitol, etc., and other substances. When necessary, can be added flavors, preservatives, dispersing agents, dyes, perfumes, etc.

Capsules are prepared by granulating pounded coarse particles, powder or granules obtained as described below for tablets, and the filling of gelatin or other capsules. Before filling to the powder or the granules may be added to lubricating or giving a fluidity agent such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol, etc. in Addition, the efficiency of a drug after swallowing capsules may be increased by adding baking powder or solubilizer, for example, carboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropylcellulose with a low degree of substitution, sodium croscarmellose, sodium carboxymethyl, calcium carbonate and sodium carbonate.

Finely atomized powder can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin or a surface-active substance and Packed in a gelatin shell with obtaining soft capsules add baking powder or lubricants, and sieving the mixture. The powder composition can be obtained by mixing properly crushed substances with the specified diluent or base and may be supplemented, when necessary, a binder (for example, sodium carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, hypromellose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol and so on), dissolution retarders (for example, paraffin, gidrirovannoe castor oil, and so on), a stimulator of readable (for example, Quaternary salts), and the adsorbent (for example, bentonite, kaolin, ducally phosphate, and so on). The powder composition can be granulated by wetting material binder, such as syrup, starch paste, a solution of gum Arabic or cellulose or polymer solution and then jacking the wet mass through a sieve. Instead of granulating powder, it may be pressed using a tablet machine, and grinding the obtained casts, which are rough in the form of pellets.

Thus obtained granules can be protected from internal adhesion by addition of lubricants, such as stearic acid, salt stearin is ptx2">

Received uncoated tablets may be film-coated or coated with sugar.

Not exposing stage of the above-mentioned granulation or clumping, the drug may be first mixed with easy flowing inert carrier and immediately pressed. Can also be applied to a transparent or translucent protective coating comprising a hermetic lacquers, sugar or polymeric coating or wax glazurovka floor.

Other oral dosage forms such as solutions, syrups, elixirs, etc. can also be obtained in unit dosage forms, each of which contains a predetermined amount of medicine. The syrup can be obtained by dissolving the compound in a suitable palatable aqueous solvent, whereas the elixir can be obtained using non-toxic alcohol solvent. Suspension can be obtained by dispersing the compounds in a non-toxic solvent. When necessary, can also be added solubilization and emulsifying agents (e.g. ethoxylated isostearoyl alcohol, esters of polyoxyethylene-sorbitol, and so on), preservatives, flavoring agents (e.g., oil category is moralnego introduction can be microencapsulated. This drug may be covered or enclosed in a polymer, wax or a similar substance with the receipt of the delivery system for drugs extended action or slow release.

Parenteral administration can be effected using standard liquid dosage form, such as solution or suspension, for subcutaneous, intramuscular or intravenous injection. Such a standard dosage form can be prepared by suspension or dissolution of a predetermined number of compounds into non-toxic liquid solvent for injection such as an aqueous solvent or an oil solvent, and sterilizing the suspension or solution. An alternative method involves the preparation and distribution of a predetermined number of connections in each bubble, sterilized vial and the contents and sealing of the bubble. For unplanned dilution or mixing powdered or liofilizirovannoe active connection can be provided with a spare vial and solvent. To give isotonicity injectable form can be added non-toxic salt or salt solution. In addition, can also be associated tion can be produced by use of suppositories, which can be obtained by mixing the compounds with water-soluble or water-insoluble low-melting solid Foundation, such as polyethylene glycol, cacao butter or higher ester (for example, myristyl palmitate) or their mixture.

As will be described herein below, the toxicity of the compounds of the present invention is very low.

The following examples are presented to describe some characteristic types of the compounds according to the invention and should not be construed in any way as limiting the scope of invention.

The invention will be better understood from reference examples, working examples and case studies relevant to the connection according to the invention, which will be given below.

Referential example 1. Synthesis of (E)-3-(2-phenylethenyl)-2-aminopyridine.

In 35 ml of tetrahydrofuran (THF) was dissolved 1.28 g of 2-aminonicotinamide, then added 2.50 g determenirovana and of 2.08 g of potassium hydroxide, the mixture was heated under reflux at 80oC for 4.5 hours. This reaction mixture was filtered to remove insoluble matter and the filtrate is evaporated under reduced pressure. The residue was dissolved in 2 n hydrochloric acid and Raleigh dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was recrystallized from acetonitrile to obtain 0,83 g of compound indicated in the title, in the form of yellow prisms. This product was used as starting material without further purification.

Referential example 2. Synthesis of 2-[2-(4-pyridyl)ethynyl]aniline.

(1) Synthesis of 2-[2-(4-pyridyl)ethynyl]-1-nitrobenzene.

In 120 ml of benzene suspended 12.00 g of 2-nitro-benzyltriphenylphosphonium bromide and cautiously added dropwise in an argon atmosphere, 20 ml, 1.6 M n-utility/n-hexane under ice cooling, so that the internal temperature did not rise above 20oC. the Mixture was then stirred at room temperature for 2 hours, then added dropwise 3,05 g isonicotinamide under ice cooling and the mixture was stirred at room temperature over the next 4 hours. This reaction mixture was poured into ice water and was extracted with ether. This extract is evaporated under reduced pressure to remove solvent and the residue was diluted with chloroform and extracted with 2 n hydrochloric acid. The aqueous layer was podslushivaet by adding 30% aqueous hydroxide solution is tel evaporated. The residue was purified by column chromatography on silica gel (chloroform) to obtain 2,53 g of compound indicated in the heading in the form of a reddish-brown colored oil. This product was subjected to the subsequent reaction without further purification.

(2) Synthesis of 2-[2-(4-pyridyl)ethynyl]aniline.

In a mixture of concentrated hydrochloric acid (14 ml) and ethanol (14 ml) was dissolved 2,87 g 2-[2-(4-pyridyl)ethynyl]-1-nitrobenzene. To this solution was gradually dropwise added a solution of chloride dihydrate tin (8,59 g) in ethanol (25 ml) at ice cooling and the mixture was stirred at room temperature for 5 hours. After evaporation of the solvent under reduced pressure the residue was podslushivaet 30% aqueous sodium hydroxide solution and was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and the solution evaporated to obtain 2.2 g of the compound indicated in the title, in the form of a solid product. This product was used as source material without purification.

The following compounds were obtained by the same method as in referential example 2:

2-[2-(3-Pyridyl)ethynyl]aniline;

2-[2-(2-Pyridyl)ethynyl]aniline;

2-[2-(2-Methylpyridin-4-yl)ethynyl]aniline;

2-[2-MEA.

To a 15.1 g of 2-nitrobenzaldehyde was added 9.3 g of 4-picoline, then added 5 ml of acetic anhydride and the mixture was heated under reflux for 12 hours. This reaction mixture was poured into ice-cold water, podslushivaet 2 n NaOH and was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent evaporated to obtain 22,40 g (E)-2-[2-(4-pyridyl)ethynyl] -1-nitrobenzene. This product was treated as in reference example 2 (2), with the connection specified in the header.

Example 1. (E)-2-[[(p-Methoxyphenyl)sulfonyl]amino]-3-(2-phenylethenyl) - pyridine.

In 10 ml of pyridine was dissolved 0.8 g (E)-3-(2-phenylethenyl)-2-aminopyridine is obtained in referential example 1. To this solution was gradually added to 0.92 g of p-methoxyphenylacetonitrile under ice cooling and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent evaporated and the obtained residue was purified by chromatography on a column of silica gel (eluent: CHCl3/MeOH=9/1). Thus obtained crystalline mass was recrystallized from ethanol with the receipt of 0.77 g of the desired compound (yellow plates). So pl. 152-155oC.

Elemental analysis for C

Example 2. 3-[2-[2-[[(p-Methoxyphenyl)sulfonyl]amino]phenyl]ethynyl] pyridine.

Using 2.24 g of 2-[2-(3-pyridyl)ethynyl] aniline was obtained as in reference example 2, the reaction and procedure subsequent processing was carried out according to example 1 to obtain crystals of E - and Z-fractions. This crystalline mass respectively recrystallize from ethanol to obtain 1.51 g of Z-isomer (white vinyl) and 0.98 g of E-isomer (yellow prisms) of the connection specified in the header.

Z-isomer

so pl. 131-132oC

Elemental analysis for C20H18N2O3S:

Calculated (Percent): C - 65,55; H - 4,95; N - Of 7.64.

Found (Percent): C - 65,52; H - To 5.21; N - Of 7.64.

E-isomer

so pl. 153-154oC

Elemental analysis for C20H18N2O3S:

Calculated (Percent): C - 65,55; H - 4,95; N - Of 7.64.

Found (Percent): C - 65,35; H - 5,17; N - To 7.59.

Example 3A. (E)-4-[2-[2-[[(p-Methoxyphenyl)sulfonyl]amino]phenyl]ethynyl] -pyridine.

Using is 4.93 g of 2-[2-(4-pyridyl) ethynyl] aniline and 5,70 g p-methoxybenzenesulfonamide, the reaction and procedure for further processing as in example 1, was obtained crystalline mass. This crystalline mass was recrystallize from ethanol to obtain 1,94 g of compound indicated in the SUB>N2O3S:

Calculated (Percent): C - 65,55; H - 4,95; N - Of 7.64.

Found (Percent): C - 65,61; H - Is 5.06; N - Of 7.64.

Example 3B. Hydrochloride (E)-4-[2-[2-[[(p-methoxyphenyl)sulfonyl]amino]- phenyl]ethynyl]pyridine.

to 1.00 g of the compound obtained in Example 3A, was dissolved in 100 ml of methanol was then added while cooling with ice, saturated with gaseous hydrogen chloride ether solution, a 5-fold excess by volume. The solvent is then evaporated to obtain 1.07 g of the compound indicated in the title, in the form of a yellow powder. So pl. 258-261oC (decomposition).

Elemental analysis for C20H18N2O3SHCl:

Calculated (Percent): C - 59,62; H - 4,75; N - 6,95.

Found (Percent): C - 59,36; H - To 4.81; N - 6,90.

The following compounds synthesized in the same manner as in Example 1.

Example 4. (E)-2-[2-[2-[[(p-Methoxyphenyl)sulfonyl]amino]phenyl]ethynyl]- pyridine.

Light yellowish-white prisms (ethanol), so pl. 137-142oC.

Elemental analysis for C20H18N2O3S:

Calculated (Percent): C - 65,55; H - 4,95; N - Of 7.64.

Found (Percent): C - 65,54; H - 5,13; N - 7,60.

Example 5. (E)-4-[2-[2-[[(p-Were)sulfonyl]amino]phenyl]ethynyl]- 1 pyridine.

Yellowish-white needles, so pl. 244 - 246- 7,99,

Found (Percent): C - 68,41; H - 5,32; N - Of 7.96.

Example 6. (E)-4-[2-[2-[[[(p-Floratone)phenyl] sulfonyl] amino]phenyl]- ethynyl]pyridine.

Colorless needles, so pl. 174-176oC.

Elemental analysis for C21H19FH2O3S;

Calculated (Percent): C - 63,30; H - To 4.81; N - 7,03.

Found (Percent): C - 63,40; H - A 4.86; N - 7,07.

Example 7. (E)-4-[2-[2-[[(p-Ethoxyphenyl)sulfonyl]amino]phenyl] ethynyl]-pyridine.

Light yellow prisms, so pl. 201-203oC,

Elemental analysis for C21H20N2O3S:

Calculated (Percent): C - To 66.30; H - And 5.30; N And 7.36.

Found (Percent): C - 66,18; H - 5,18; N - 7,39.

Example 8. (E)-4-[2-[2-[[(p-Hydroxyphenyl)sulfonyl]amino] phenyl]ethynyl] -pyridine.

In DMF was dissolved 2.00 g (E)-4-[2-[2-[[(p-methoxyphenyl)-sulfonyl] amino] phenyl] ethynyl] pyridine obtained in example 3 was then added at 1.91 g of methanolate sodium and the mixture was stirred at 100oC overnight and then processed. The obtained crystals are recrystallized from methanol to obtain 0,19 g of compound indicated in heading (white powder).

So pl. 293 - 296oC (decomposition).

Elemental analysis for C19H16N2O3S:

Calculated (Percent): C - 64,76; H - 4,58; N - 7,95.

l]amino]phenyl] ethynyl]pyridine.

In 100 ml of acetone was dissolved 0,80 g (E)-4-[2-[2-[[(p-methoxyphenyl) sulfonyl] amino] phenyl] ethynyl] pyridine as much as possible. Then was added 1.19 g of 1-bromo-2-floridana and of 0.60 g of potassium carbonate and spent the reaction mixture in a sealed reaction tube at 80oC during the night. After cooling, the solvent is evaporated under reduced pressure and the residue was dissolved with water and was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified by chromatography on a column of silica gel (chloroform-methanol=99:1) to obtain the 0,86 g of a light yellow oil. Then this oil was dissolved in ether, was added ether saturated with hydrogen chloride while cooling with ice and the resulting yellow powder was isolated by filtration to obtain the connection specified in the header. So pl. 218-220oC (decomposition).

Elemental analysis for C22H21FN2O3SHCl.

Calculated (%): - Of 60.50; H - 5,08; N - 6,72.

Found (Percent): C - 60,36; H Of 4.83; N - 6.75 In.

The following compounds are obtained in the same manner as described in example 1.

Example 11. (4-[1-Methyl-2-[2-[[(p-methoxyphenyl)sulfonyl] amino]phenyl]- ethynyl]pyridine.

Colorless ylitalo (%): - 65,55; H - 4,95; N - OF 7.64.

Found (Percent): C - 65,69; H - 4,95; N - 7,69.

Example 12. (E)-4-[2-[2-[[(p-Nitrophenyl)sulfonyl]amino]phenyl] ethynyl]-pyridine.

Yellowish-white powder (ethanol), so pl. 281-284oC (decomposition).

Elemental analysis for C19H15N3O4S:

Calculated (Percent): C - 59,83; H - 3,96; N - 11,02.

Found (Percent): C - 59,72; H - 3,86; N - 10,75.

Example 13. (E)-4-[2-[2-[[(p-Forfinal)sulfonyl] amino] phenyl]ethynyl]- pyridine.

Yellow needles (ethanol), so pl. 272-276oC (decomposition).

Elemental analysis for C19H15N3O4FS:

Calculated (Percent): C - 64,39; H - 4,27; N - Of 7.90.

Found (Percent): C - 64,43; H - 4,18; N - 7,65.

The following compounds were obtained in the same manner as in example 10.

Example 14. (Hydrochloride (E)-3-chloro-4-[2-[2-[[(p-methoxyphenyl)sulfonyl]- amino]phenyl]ethynyl]pyridine.

Light yellow prisms (ethanol), so pl. 208-211oC.

Elemental analysis for C20H17ClN2O3SHCl:

Calculated (Percent): C - 56,50; H - 4,49; N Is The 10.40.

Found (Percent): C - 56,64; H - 4,49; N - 10,37.

Example 16. Hydrochloride (E)-2-[2-[2-[[(p-methoxyphenyl)sulfonyl] amino] -phenyl]ethynyl]pyrazine.

Orange colored prisms (ethanol), so pl. 216-218

Found (%): 56,31; H - 4,55; N - 10,29.

Example 17. (Hydrochloride (E)-2,6-dimethyl-4-[2-[2-[[(p-methoxyphenyl)- sulfonyl]amino]phenyl]ethynyl]pyridine.

Yellow powder, so pl. 227-230oC (decomposition).

Elemental analysis for C22H22N2O3SHCl:

Calculated (Percent): C - 61,32; H Is 5.38; N - 6,50.

Found (Percent): C - 60,79; H Of 5.39; N - 6,50.

The following compounds were synthesized in the same manner as in example 1.

Example 18. (E)-2-Methyl-4-[2-[2-[(p-methoxybenzoyl)amino]phenyl]ethynyl]- pyridine.

Colorless needles (ethanol), so pl. 183-184oC.

Elemental analysis for C22H20N2O2:

Calculated (Percent): C - 76,72; H - 5,85; N - 8,14.

Found (Percent): C - 76,65; H - 5,97; N - 8,12.

Example 19. ((E)-2-Methyl-4-[2-[4-chloro-2-[[(p-methoxyphenyl)sulfonyl] amino]-phenyl]ethynyl]pyridine.

Colorless needles, so pl. 174-175oC.

Elemental analysis for C21H19ClN2O3S:

Calculated (Percent): C - 60,79; H - To 4.62; N - 6.75 In.

Found (Percent): C - 60,80; H - To 4.68; N - Of 6.71.

Example 20. (E)-4-[2-[2-[[(p-Methoxyphenyl)sulfonyl]amino]phenyl]ethynyl] -pyridine 1-oxide.

In 10 ml of acetic acid was dissolved 1,83 g connection, pauchari 70oC during the night. To the reaction mixture were added saturated aqueous solution of one-deputizing sodium carbonate, followed by extraction with chloroform. The chloroform layer was obezvozhivani over anhydrous magnesium sulfate, and the solvent evaporated. The residue was purified by column chromatography on silica gel (chloroform-methanol=9:1). The crystalline mass was recrystallized from ethanol with the receipt of 0.48 g of compound indicated in heading (white needles). So pl. 224-226oC (decomposition).

Elemental analysis for C20H18N2O4S:

Calculated (Percent): C - 62,81; H - 4,74; N - 7,32.

Found (Percent): C - 62,71; H - 4,72; N - 7,32.

The following compounds were obtained in the same manner as in example 1.

Example 21. (E)-3-Methyl-4-[2-[2-[[(p-methoxyphenyl)sulfonyl] amino]-phenyl]ethynyl]pyridine.

Yellow-brown prisms (ethanol), so pl. 183-185oC.

Elemental analysis for C20H18N2O4S:

Calculated (%): - To 66.30; H - And 5.30; N And 7.36.

Found (Percent): C - 66,21; H Lower Than The 5.37; N - 7,38.

Example 22. (E)-4-[2-[2-[[(p-Methoxyphenyl)sulfonyl]amino]-3-methoxyphenyl]ethynyl] pyridine.

Colorless needles (methanol), so pl. 205-206oC.

Elemental analysis for C21

Example 23. (E)-4-[2-[2-[[(p-Chlorophenyl)sulfonyl]amino]phenyl] ethynyl]pyridine.

Light yellow needles (ethanol), so pl. 218-220oC.

Elemental analysis for C19H15ClN2O2S:

Calculated (Percent): C - 61,54; H - 4,08; N - 7,55.

Found (%): 61,74; H - Was 4.02; N - 7,55.

Example 24. (E)-4-[2-[2-[[(2,5-Acid)sulfonyl]amino] phenyl]-ethynyl]pyridine.

Light yellow plate (ethanol), so pl. 193-195oC.

Elemental analysis for C21H20N2O4S:

Calculated (Percent): C - 63,62; H - 5,08; N - 7,07.

Found (Percent): C - 63,38; H Is 5.07; N? 7.04 Baby Mortality.

Example 25. (E)-4-[2-[2-[[(3,4-Acid)sulfonyl]amino] phenyl]-ethynyl]pyridine.

Light yellow needles (ethanol), so pl. 181 - 183oC.

Elemental analysis for C21H20N2O4S:

Calculated (Percent): C - 63,62; H - 5,08; N - 7,07.

Found (Percent): C - 63,56; H - 5,08; N - 7,07.

Example 26. (E)-4-[2-[2-[[(p-Hydroxyphenyl)sulfonyl]amino]phenyl]-ethynyl] pyridine 1-oxide.

Using 1.50 g of the compound obtained in example 8, the reaction and post-treatment was carried out according to example 20, but the resulting crystalline mass was recrystallize from methanol to obtain the compound indicated in heading (b4S:

Calculated (Percent): C - 61,94; H - To 4.38; N - 7,60.

Found (Percent): C - 61,96; H Is 4.36; N - 7,58.

The following compounds were obtained in the same manner as in example 1.

Example 27. (E)-4-[2-[4-Chloro-2-[[(p-methoxyphenyl)sulfonyl]amino]phenyl]- ethynyl]pyridine.

Colorless needles (methanol), so pl. 190-193oC.

Elemental analysis for C20H17ClN2O3S:

Calculated (%): 59,92; H - 4,27; N - 6,99.

Found (%): - To 59.82; H, 4.26 Deaths; N - 7,01.

Example 28. (E)-4-[2-[5-Chloro-2-[[(p-methoxyphenyl)sulfonyl] amino]phenyl] -ethynyl]pyridine.

Colorless prisms (ethanol), so pl. 175-176oC.

Elemental analysis for C20H17ClN2O3S:

Calculated (%): 59,92; H - 4,27; N - 6,99.

Found (%): 59,87; H - 4,29; N - 6,97.

Example 29. (E)-4-[2-[2-[N-(3,4,4-Cryptor-3-butenyl)-N-[(p-methoxyphenyl)-sulfonyl] amino]phenyl]-ethynyl]pyridine.

In tetrahydrofuran was dissolved to 1.83 g of the compound obtained according to example 3. To this solution was added 1.89 g of 3,4,4-Cryptor-3-butenyl bromide and 1.38 g of potassium carbonate and spent the reaction mixture in zapasaemoi reaction tube at 80oC overnight and then subjected to subsequent processing. The crystalline mass of PerekrestoC.

Elemental analysis for C24H21F3N2O3S:

Calculated (%): 60,75; H - 4,46; N - 5,90.

Found (Percent): C - 60,82; H - 4,43; N - 5,97.

Example 30. (E)-4-[2-[2-[N-(3,3,4,4-Tetrafluoroethyl)-N-[(p-methoxyphenyl) -sulfonyl]amino]phenyl]-ethynyl]pyridine.

Using of 1.00 g of the compound obtained according to example 3, the reaction and the subsequent procedure in example 9, was obtained crystalline mass. This crystalline mass was recrystallized from ethanol-ether to obtain and 0.61 g of compound indicated in heading (light yellow prisms). So pl. 124-126oC.

Elemental analysis for C24H22F4N2O3S:

Calculated (%): 58,29; H - 4,48; N - 5,66.

Found (Percent): C - 58,29; H - To 4.41; N - 5,55.

Example 31. (E)-4-[2-[2-[N-(3,3,3-Trifloromethyl)-N-[(p-methoxyphenyl)- sulfonyl]amino]phenyl]-ethynyl]pyridine.

Using of 1.00 g of the compound obtained according to example 3, the reaction and the subsequent procedure in example 9, was obtained crystalline mass. This crystalline mass was recrystallized from ethanol to obtain 0.39 g of the compound indicated in heading (light yellow prisms). So pl. 124-126oC.

Elemental analysis for C23

The following compounds were obtained in the same manner as in example 1.

Example 32. (E)-4-[2-[2-[[(p-Methoxyphenyl)sulfonyl] amino] -4,5 - methylenedioxyphenyl]ethynyl]pyridine.

Yellow prisms (ethanol), so pl. 163-165oC.

Elemental analysis for C21H18N2O5S1/4H2O:

Calculated (Percent): C - 60,79; H - 4,49; N - 6.75 In.

Found (%): Comparison With 60.87; H - 4,95; N - 6,44.

Example 33. (E)-4-[2-[2-[[(p-Methoxyphenyl)sulfonyl] amino] -4,5 - acid]ethynyl]pyridine.

Light yellow needles (ethanol), so pl. 209-211oC (decomposition).

Elemental analysis for C22H22N2O5S:

Calculated (Percent): C - 61,96; H - 5,20; N - 6,57.

Found (Percent): C - 61,78; H And 5.36; N - 6,58.

Example 34. (E)-4-[2-[2-[N-(2-Hydroxyethyl)-N-[(p-methoxyphenyl)-sulfonyl]amino] phenyl]ethynyl]pyridine.

Using of 1.00 g of the compound obtained according to example 3, the reaction and the subsequent procedure in example 9, was obtained crystalline mass. This crystalline mass was recrystallized from ethanol to obtain 0,57 g of compound indicated in heading (white needles). So pl. 198-200oC.

Elemental analysis for C22H22N2O4S:

Calculated (Illuminati)-N- [(p-methoxyphenyl)sulfonyl]amino]phenyl]ethynyl]pyridine.

To 1.00 g of the compound obtained according to example 3, was added 1.07 g of triphenylphosphine, and tetrahydrofuran. Then added to 0.30 g dimethylaminoethanol and 0.72 g of diethylazodicarboxylate, in that order. The reaction was carried out at room temperature overnight and the reaction mixture was processed and converted into the hydrochloride. In this way there was obtained a 0.23 g of compound indicated in heading (white powder). So pl. 259-261oC (decomposition).

Elemental analysis for C24H27N3O3S2HClH2O.

Calculated (%): 54,54; H - Of 5.53; N - 7,95.

Found (Percent): C - 54,54; H - 5,85; N - 7,94.

Example 36. Hydrochloride (E)-4-[2-[2-[N-(2-amino-ethyl)-N-[(p-methoxyphenyl)-sulfonyl] amino]phenyl]ethynyl]pyridine.

Using of 1.00 g of the compound obtained according to example 3, the reaction and post-treatment was carried out according to example 35. Then aminosidine group was removed by acidification. Then the connection with the removed protection was converted to hydrochloride to obtain 0.21 g of the compound indicated in heading (light yellow powder). So pl. 233-235oC (decomposition).

Elemental analysis for C22H23N3O3S2HCl3/2H2O:

Calculated (%): 51,86; H - Of 5.53; N Is 8.25.

Example 37. (E)-4-[2-[2-[[(p-Trifloromethyl)sulfonyl]amino]phenyl]- ethynyl]pyridine.

Bright yellowish-white needles (2-propanol), so pl. 151-153oC.

Elemental analysis for C20H15F3N2O3S:

Calculated (%): 57,14; H - 3,60; N - 6,66.

Found (Percent): C - 57,17; H - 3,74; N - 6,72.

Example 38. (E)-4-[2-[2-[[(p-Ethylphenyl)sulfonyl] amino] phenyl]-ethynyl] pyridine.

Yellow prisms (ethanol), so pl. 232-234oC.

Elemental analysis for C21H20N2O2S:

Calculated (Percent): C - 69,21; H - Of 5.53; N - 7,69.

Found (Percent): C - 69,08; H - 5,63; N - 7,68.

Example 39.(E)-4-[2-[3-[[(p-Methoxyphenyl)sulfonyl]amino] -2-pyridyl]-ethynyl]phenol.

Using of 0.90 g of 3-amino-2-[2-(4-hydroxyphenyl)ethynyl]-pyridine, the reaction and post-treatment was carried out according to example 1 and the crystalline mass preregistration from ethanol to obtain 0.16 g of the compound indicated in heading (yellow flakes). So pl. 217-219oC.

Elemental analysis for C20H18N2O4S:

Calculated (Percent): C - 62,81; H - 4,74; N - 7,32.

Found (Percent): C - 62,62; H - 4,79; N - 7,42.

Example 40. Hydrochloride (E)-4-[2-[3-[[(p-methoxyphenyl)sulfonyl]amino]- 2-pyridyl]ethynyl]phenol.

Elemental analysis for C20H18N2O4SHCl:

Calculated (%): 57,35; H - Of 4.57; N - 6,69.

Found (%): 56,93; H - 4,66; N - 6,68.

The following compounds were obtained by the same method as in Example 1.

Example 41. (E)-4-[2-[6-Chloro-2-[[(p-methoxyphenyl)sulfonyl]amino]phenyl]- ethynyl]pyridine.

Light yellow plate (ethanol), so pl. 188-190oC.

Elemental analysis for C20H17ClN2O3S:

Calculated (%): 59,92; H - 4,27; N - 6,99.

Found (%): - To 59.82; H, 4.26 Deaths; N - 6,95.

Example 42. (E)-4-[2-[[2-[(p-Methoxyphenyl)sulfonyl]amino]-3,4 - methylenedioxyphenyl]ethynyl]pyridine.

Orange colored needles (ethanol), so pl. 279-281oC (decomposition).

Elemental analysis for C21H18N2O5S2H2O:

Calculated (%): 56,49; H Is Equal To 4.97; N - 6,27.

Found (%): 56,21; H - 4,63; N - 6,36.

Example 43. (E)-4-[2-[6-fluoro-2-[[(p-methoxyphenyl)sulfonyl] amino]phenyl] -ethynyl]pyridine.

Colorless prisms (ethanol), so pl. 177-178oC.

Elemental analysis for C20H17N2FN2O3S:

Calculated (Percent): C - 62,47; H - 4,46; N - 7,29.

Found (percent): C - 62,48; H - 4,49; N

By the same methods as in example 1 and example 3B, got orange colored needles. So pl. 250oC.

IR ((Kbr) cm-1: 1622, 1593, 1499, 1323, 1262, 1148, 1094, 941, 814, 669, 583, 550.

Elemental analysis for C21H20N2O3SHCl:

Calculated (%): - Of 60.50; H - 5,08; N - 6,72.

Found (Percent): C - 60,44; H - 5,10; N - 6,68.

Example 45. (E)-4-[2-[2-[[[4-(2-Floratone)phenyl]sulfonyl] amino]phenyl] -ethynyl]pyridine 1-oxide.

Using 3,18 g of the compound obtained in example 6, reaction and subsequent processing was carried out according to example 20 to obtain a crystalline mass. This crystalline mass was recrystallized from methanol to obtain 1,21 g of compound indicated in heading (colorless prisms). So pl. 214-215oC.

Elemental analysis for C21H19F2N2O4S:

Calculated (Percent): C - 60,86; H - To 4.62; N - 6,76.

Found (Percent): C - 60,84; H - 4,55; N - 6,86.

Example 46. (E)-4-[2-[2-[[(p-Ethoxyphenyl)sulfonyl]amino]phenyl]- ethynyl] pyridine 1-oxide.

Using 3,18 g of the compound obtained in example 6, reaction and subsequent processing was carried out according to example 20 to obtain a crystalline mass. This crystalline mass was recrystallized from methanol to sing the analysis for C21H20N2O4S;

Calculated (Percent): C - 63,62; H - 5,08; N - 7,07.

Found (Percent): C - 63,58; H Is 5.07; N - 7,11.

Example 47. (E)-4-[2-[2-[[(p-Methoxyphenyl)sulfonyl] amino]-3 - methoxyphenyl]-ethynyl]pyridine 1-oxide.

Using 3,17 g of the compound obtained in example 22, the reaction and post-treatment was carried out according to example 20 to obtain a crystalline mass. This crystalline mass was recrystallized from ethanol to obtain 2.10 g of the compound indicated in heading (colorless prisms). So pl. 233-234oC (decomposition).

Elemental analysis for C21H20N2O5S:

Calculated (Percent): C - 61,15; H - 4,89; N - 6,79.

Found (Percent): C - 61,04; H - 4,85; N - 6,86.

Example 48. (E)-4-[2-[2-[N-(2-Hydroxyethyl)-N-[(p-ethoxyphenyl)sulfonyl]- amino]phenyl]ethynyl]pyridine.

Using of 1.00 g of the compound obtained in example 7, reaction and subsequent processing was carried out according to example 9 to obtain a crystalline mass. This crystalline mass was recrystallized from ethanol to obtain 0.56 g of the compound indicated in heading (light yellow prisms). So pl. 167-169oC.

Elemental analysis for C23H24N2O4S:

Calculated (percent): C - 65,07; H - 5,70; N is Lionel]-amino]phenyl]ethynyl]pyridine 1-oxide.

Using of 1.00 g of the compound obtained in example 20, the reaction and post-treatment was carried out according to example 9 to obtain a crystalline mass. This crystalline mass was recrystallized from ethanol to obtain 0.17 g of the compound indicated in heading (yellow plastic). So pl. 219-221oC.

Elemental analysis for C22H22N2O5S:

Calculated (Percent): C - 61,96; H - 5,20; N - 6,57.

Found (Percent): C - 61,77; H - 5,32; N - 6,57.

Example 50. (E)-4-[2-[2-[N-(2-Hydroxyethyl)-N-[p-[(2-floratone)phenyl]- sulfonyl]amino]phenyl]ethynyl]pyridine.

Using of 1.00 g of the compound obtained in example 6, reaction and subsequent processing was carried out according to example 9 to obtain a crystalline mass. This crystalline mass was recrystallized from ethanol to obtain 0,59 g of compound indicated in heading (light yellow fine needles). So pl. 180 - 182oC.

Elemental analysis for C23H23FN2O4S:

Calculated (Percent): C - 62,43; H - 5,24; N - 6,33.

Found (Percent): C - 62,36; H At 5.27; N - 6,29.

Example 51. (E)-4-[2-[2-[N-[2-(4-Morpholino)ethyl]-N-[(p-methoxy)phenyl] -sulfonyl]amino]phenyl]ethynyl]pyridine.

Using of 1.00 g of the compound obtained according to example 3, the reactions the mass was recrystallized from ethanol to obtain 0.75 g of the compound, specified in the header (white prisms). So pl. 142-144oC.

Elemental analysis for C26H29N3O4S:

Calculated (Percent): C - 65,11; H - 6,09; N - 8,76.

Found (Percent): C - 64,93; H - The 6.06; N - 8,71.

Example 52. (E)-4-[2-[6-fluoro-2-[N-(2-hydroxyethyl)-N-[p-methoxyphenyl)- sulfonyl]amino]phenyl]ethynyl]pyridine.

In tetrahydrofuran was dissolved 1.92 g of the compound obtained in example 43 was then added 1,72 g of 2-idechannel and 0.69 g of potassium carbonate. The mixture was heated under reflux during the night and after processed with obtaining crystals. This crystalline mass was recrystallized from ethanol to obtain and 0.46 g of compound indicated in heading (light yellow needles). So pl. 152-153oC.

Elemental analysis for C22H21FN2O4S:

Calculated (Percent): C - 61,67; H Is Equal To 4.97; N - 6,54.

Found (Percent): C - 61,51; H - Is 4.93; N - 6,62.

The following compounds were obtained in the same manner as in example 1.

Example 53. (E)-4-[2-[2-[[(p-Methoxyphenyl)sulfonyl] amino] -3-hydroxyphenyl]ethynyl]pyridine.

Yellow needles (methanol), so pl. 204-205oC (decomposition).

Elemental analysis for C22H21FN2O4S:

Calculated (percent): C - 62,81; H - 4]-5-hydroxyphenyl] ethynyl]pyridine.

Yellow fine needles (ethanol), so pl. 244-246oC (decomposition).

Elemental analysis for C20H18N2O4S:

Calculated (Percent): C - 62,81; H - 4,74; N - 7,32.

Found (Percent): C - 62,62; H - 4,58; N - 7,38.

Example 55. Hydrochloride (E)-4-[2-[2-[N-(2-Methoxyethyl)-N-[(p-methoxyphenyl) -sulfonyl]amino]phenyl]ethynyl]pyridine.

Using of 1.00 g of the compound obtained according to example 3A and 1-bromo-2-methoxyethane, conduct the reaction and post-treatment in example 9, and the product is converted into the hydrochloride. According to this method was obtained 0.45 g of the compound (amorphous) specified in the header.

IR (KBr) cm-1: 1662, 1595, 1499, 1343, 1262, 1157, 1020, 806, 722, 586, 552,

Elemental analysis for C23H24N3O4SHCl1/2H2O:

Calculated (%): 58,77; H - To 5.58; N - 5,96.

Found (Percent): C - 58,55; H - 5,62; N - 6,22.

Example 56. (E)-4-[2-[2-[[N-(2-Hydroxyethyl)-N-[(p-methoxyphenyl)- sulfonyl] amino]-3-methoxy]phenyl]ethynyl]pyridine.

Using of 1.00 g of the compound obtained in example 22, conduct the reaction and post-treatment in example 9 to obtain a crystalline mass. This crystalline mass was recrystallized from ethanol to obtain 0.50 g of the compound indicated in heading (
Calculated (%): 62,71; H - 5,49; N - 6,36.

Found (Percent): C - 62,64; H - 5,41; N - 6,60.

Example 57. (E)-4-[2-[2-[N-Acetyl-N-[(p-methoxyphenyl)sulfonyl] amino]-phenyl]ethynyl]pyridine 1-oxide.

Using 1.54 g of the compound obtained in example 20, the reaction was carried out in the presence of acetic anhydride at 140oC for 10 minutes and then processed. The crystalline mass was recrystallized from ethanol with the receipt of 0.62 g of compound indicated in heading (white granules). So pl. 235-237oC (decomposition).

Elemental analysis for C22H20N3O5S:

Calculated (Percent): C - 64,37; H - Of 5.40; N - 6,82.

Found (Percent): C - 64,11; H - 5,12; N - 6,85.

Example 58. (E)-4-[2-[2-[N-(3-Hydroxypropyl)-N-[(p-methoxyphenyl)- sulfonyl]amino]phenyl]ethynyl]pyridine.

Using 1,89 g of the compound obtained according to example 3, the reaction and post-treatment was carried out according to example 9 to obtain 1.89 g of the compound indicated in heading (white granules). So pl. 164-167oC.

Elemental analysis for C23H24N3O4S:

Calculated (Percent): C - 65,07; H - 5,70; N - 6,60.

Found (%): Compared With 65.38; H - Of 5.53; N - 6,80.

Example 59. (E)-1-Benzyl-4-[2-[2-[[(p-methoxyphenyl)sulfonyl] amino]-phenyl]ethynyl]pyridine and at 120oC during the night. The reaction mixture was processed and the crystals are recrystallized from methanol to obtain and 0.62 g of compound indicated in heading (yellow fine needles). So pl. 280oC.

IR (KBr) cm-1: 1620, 1597, 1518, 1327, 1266, 1156, 1092, 598, 571.

Elemental analysis for C27H25BrN3O3S:

Calculated (Percent): C - 60,34; H - 4,69; N - To 5.21.

Found (Percent): C - 60,18; H - 4,55; N - 5,39.

Anticancer activity of the compounds of the present invention can be confirmed by further research. Used the research methods that are most widely represented in the estimates in vitro and in vivo in real time [in vitro method: European Journal of Cancer 1980, 17, 129; in vivo method: Cancer Research 1988, 48, 589-601].

A case study 1. Antitumor activity in vitro cell line KB (carcinoma of the nasopharynx person), Colon 38 (colon cancer mouse) and WiDr (colon and rectum of a person).

Each cell line KB, Colon 38 and WiDr, respectively, were cultured using medium D-MEM (Nissui Pharmaceutical) supplemented with 10% fetal calf serum. Each monolayer cell layers were treated with a mixture of 50:50 (vol/vol) of 0.25% trypsin and 0.02% ethylenediaminetetraacetic was cilingiroglu in the same environment, above. The number of cells in the suspension was counted using hemocytometer. The suspension was dissolved by environment up to 5104cells/ml and distributed in 100 μl into the plate with 96 cells with a flat bottom.

The study drugs were first dissolved in dimethyl sulfoxide at a concentration of 2 mg/ml and was diluted in the above environment, up to 20 mcg/ml Using this solution for higher concentrations, received a series of twofold dilutions, 100 μl of each dilution was added to the above cell suspension.

Then the plate was incubated in a 5% atmosphere of CO2at 37oC for 72 hours. Then the dice solution was added 5 mg/ml MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] to 30 μl of the cell and the reaction was performed in a 5% atmosphere of CO2at 37oC for 4 hours. After completion of the reaction solution from each cell was aspirated and added to 100 μl of dimethyl sulfoxide on the cell. After 5 minutes of shaking was measured by the absorption at 540 nm on the device Multiscan (Titertek) and determine the 50% inhibition concentration (IC50) cell growth. Certain values thus IC50presented in table 1.

A case study 2. Inhibiting activity of polymerization migratr is his) was purified from the crude extract of brain pigs in accordance with the method of allocation Williams et al. [Method in Enzymology, 85, 36, 1982] investigated the inhibitory activity of compounds on the inhibition of the polymerization of microtubules. The protein solution of microtubules was diluted in reaction buffer to 4 mg/ml in the calculation of the purified protein of microtubules with the addition GFT (guanosin-5'-triphosphate) (pH 6,8) (100 mm MES [2-(N-morpholino)econsultancy acid] , 0.5 mm MgCl2-1 mm EGTA (ethylene glycol bis - aminoethylamino)-N, N, N', N'-tetraoxane acid, 1 mm GTP) under cooling with ice, and after degassing in ice was added investigational drugs. Curve polymerization was measured absorption in the system at 350 nm through a two-minute intervals for 30 minutes, using maintained at 37oC spectrophotometer, and calculates the concentration corresponding to 50% inhibition of the polymerization of microtubules. As a comparison, used the compound from example 3A.

As determined by the above method, the 50% inhibitory concentration of the compound from example 3A, with respect to the polymerization of microtubules, were 11.2 ám.

A case study 3. The activity of growth inhibition against tumor cells WiDr, transplantirovannam naked mice.

Took subcultural g tumor, tumor mass was cut for removal of a Central necrotic tissue, then cut into cubes with a side of 2 mm, One cube was placed in the needle for transplantation and transplanted subcutaneously in the left pectoral region of hairless mice. With the help of caliper measured greater and lesser diameters of the tumor, and calculated tumor volume according to equation 1. Since when tumor volume reaches about 100 mm3mice were divided to 6 individuals into groups, and the test drug suspended in 0.5% solution of methylcellulose was administered orally using a stomach probe once a day.

Equation 1:

Volume = 1/2 larger diameter (smaller diameter)2.

Tumor volume was determined by the above method at the scheduled intervals. Thus, from the calculation of the tumor volume was calculated growth rate using equation 2. Thus, using equation 3, the expected degree of inhibition of growth in each of the processed drug group compared to the control group.

Equation 2:

Growth rate = tumor volume at day n / tumor volume at the beginning of the introduction.

Equation 3.

The degree of growth inhibition (%) = (1 - rate of growth was lucasportugal connection example 3A.

The results are presented in Table 2.

In these experiments, the compound from example 3A was introduced through the mouth once a day 100 mg/kg for 14 days, but the deaths were not observed until the end of the period of introduction.

A case study 4. Anticancer activity against cell transplant Colon-26 (colon cancer mice) in mice.

Using the injection syringe, the cells of the Colon-26 in vitro, were transplanted to BALB/c mice (5 weeks of age, males) subcutaneously at a dose of 5105/animal in the area right of the sternum. As in case study 3, mice were divided into groups of 6, when tumor volume reached about 150 mm3. Starting from the next day, the drug suspended in 0.5% solution of methylcellulose was administered orally using a stomach probe once a day for 8 days. Tumor volume was measured at scheduled intervals using the same method as example studies 3 and used to calculate the degree of inhibition of tumor growth in each treated group compared to the control group. As connections comparisons used the compound from example 3A. The results are presented in table 3.

A case study 5. Anticancer Akti the peritoneal transplanted a suspension of tumor cells in a dose of 106cells/animal. The investigational drug suspended in 0.5% solution of methylcellulose was administered through the mouth the next day and after 5 days, or twice. The experiment was carried out in 8-12 mice for each control group, and 6 mice for each group treated with the drug.

To estimate the time of polovesiane in days for each group treated with the drug was determined (T), and for the control group (C), and calculated T/C. the Results are presented in table 4.

A case study 6. Acute toxicity.

Used male mice CDF1by 5 weeks of age. Investigated the extent of mortality after 2 weeks and hoped LD50by probit method after a single injection through the mouth of the compound from example 3B or 34. As a result, it was found that LD50connection example 3B is 510 mg/kg, and it was found that the compounds according to example 34 is 754 mg/kg Evident high security compounds according to the invention.

The results of the above examples of research from example 1 to 6 clearly noted that the connection of the present invention has a remarkable high antitumor efficacy and is exclusively labotek is the Rimera 3 - 10 mg

Lactose 100 mg

Corn starch - 55 mg

Hydroxypropylcellulose with a low degree of substitution - 9 mg

Polyvinyl alcohol (partially hydrolyzed), 5 mg

Magnesium stearate is 1 mg.

The above-mentioned components, with the exception of polyvinyl alcohol, and magnesium stearate were uniformly mixed, and by wet granulation were obtained pellets, using an aqueous solution of polyvinyl alcohol as a binder. To the obtained granules was added magnesium stearate and the mixture is extruded on a tablet machine to obtain oral tablets for reception through the mouth, measuring 8 mm in diameter and each weighing 180 mg.

Example composition 2.

Hard capsules 220 mg capsule

The compound from example 3A 10 mg

Lactose - 187 mg

Microcrystalline cellulose 20 mg

Magnesium stearate 3 mg

The above components were uniformly mixed and the mixture is filled in the shell of the capsules N 2, 220 mg per capsule, using filling capsule machine, provide hard capsules.

Example of compound 3.

Granules - 1 g pellet

The compound from example 3A 10 mg

Lactose - 880 mg

Hydroxypropylcellulose with a low article is echani with subsequent mixing, kneaded mass was granulated to a diameter of 0.7 mm using a granulator, to obtain granules.

The compound of the present invention has a strong inhibiting the polymerization of tubulin activity and anticancer activity with low toxicity and can be administered orally. Therefore, the connection can be safely used for long treatment of various malignant tumors, such as lung cancer, breast cancer, cancer of the gastrointestinal tract, prostate cancer, and blood cancer, among other malignant cancers.

1. Derivatives aminotriazole General formula I

< / BR>
where R1and R2is hydrogen,

R3and R13- same or different is hydrogen, alkyl with 1 to 6 carbon atoms, hydroxy or halogen;

R4and R14- same or different and each is hydrogen, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, hydroxy, halogen, or R4and R14may together represent methylenedioxy;

R5represents (1) hydrogen, (2) alkyl of 1 to 6 carbon atoms, which is optionally substituted with halogen, amino, groups of monoalkylamines with 1 to 6 carbon atoms, dialkylamino with 1 to 6 carbon atoms, Morfelden halogen, (4) acyl with 1 to 6 carbon atoms;

R6represents (1) phenylsulfonyl, which is optionally substituted by alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, halogenoalkane with 1 to 6 carbon atoms, hydroxy, nitro or halogen, (2) aroyl with 7 to 11 carbon atoms, which is optionally substituted by alkoxy with 1 to 6 carbon atoms;

A, B, and G each is CH, N, N ->O or N+-(R7) E-where R7is alkyl with 1 to 6 carbon atoms or benzyl, E - anion such as halogen ion, chlorate or nitrate, except for the case when A, B and G are both N;

Q and X are each CH, or one of them is CH and the other is N;

Y and Z independently represent a ring, except for the case when A, B, G, Q and X are both CH,

or their hydrates or their salts.

2. Connection on p. 1, where R1and R2is hydrogen, R3and R13each is hydrogen, alkyl, halogen or hydroxy; R4and R14each is hydrogen, halogen, hydroxy or alkoxy; R5is hydrogen, replacement alkyl with 1 to 3 carbon atoms or acyl with 2 to 4 carbon atoms, R6- benzazolyl, substituted alkoxy with 1 to 3 carbon atoms, ring Y is phenyl, ring Z is 4-pyridyl or its oxide.

3. Connection on p. 1, is d, fluorine or hydroxy, R5is hydrogen, replacement ethyl or acetyl, R6- methoxsalen benzazolyl, ring Y is phenyl, ring Z is 4-pyridyl or 1-oxido-4-pyridyl.

4. Connection on p. 1, which is selected from the group consisting of (E)-4-[2-[[(p-methoxyphenyl)sulfonyl] amino] phenyl]ethynyl]pyridine, (E)-4-[2-[2-[[(p-methoxyphenyl)sulfonyl] amino]phenyl]ethynyl]pyridine-1-oxide, (E)-4-[2-[2-[N-(2-hydroxyethyl)-N-[(p-methoxyphenyl) sulfonyl]amino]phenyl]ethynyl]pyridine-1-oxide, (E)-4-[2-[2-[N-(2-hydroxyethyl)-N-[(p-methoxyphenyl) sulfonyl] amino] phenyl] ethynyl] pyridine or (E)-4-[2-[2-[N-acetyl-N-[(p-methoxyphenyl)sulfonyl] amino] phenyl]ethynyl]pyridine-1-oxide, including their salts or hydrates.

5. Connection on p. 1, which is selected from the group comprising (E)-4-[2-[2-[[(p-methoxyphenyl)sulfonyl] amino]phenyl]ethynyl]pyridine, (E)-4-[2-[2-[N-(2-hydroxyethyl)-N-[(p-methoxyphenyl) sulfonyl]amino]phenyl]ethynyl]pyridine-1-oxide, (E)-4-[2-[2-[N-(2-hydroxyethyl)-N-[(p-methoxyphenyl) sulfonyl] amino] phenyl] ethynyl] pyridine or E-4-[2-[2-[N-acetyl-N-[(p-methoxyphenyl)sulfonyl] amino] phenyl]ethynyl]pyridine-1-oxide, including their salts or hydrates.

6. Pharmaceutical composition having anti-cancer activity comprising an effective amount of the compounds on l is

 

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