Triazole derivative

FIELD: chemistry.

SUBSTANCE: described are novel triazole derivatives with general formula where values of radicals are given in the formula of invention, a pharmaceutical composition containing said derivatives, and a method of treating autoimmune diseases. Compounds with general formula (1) and their pharmaceutically acceptable salts have inhibition effect on S1P and its Edg-1 receptor (S1P1).

EFFECT: possibility of use as a pharmaceutical product.

43 cl, 10 ex, 1 tbl

 

The technical field to which the invention relates.

This invention relates to new derivatives of triazole, having the effect of inhibiting the binding sphingosine-1-phosphate, involved in various physiological functions, and Edg-1 (endothelial receptor gene differentiation type-1, S1P1), which is one of its receptors, and pharmaceutical products containing them as active ingredients.

The level of technology

Sphingosine-1-phosphate (in the following called S1P) is a physiologically active lipid that is produced in cells during metabolism of sphingolipids, representative of which is sphingomyelin. It is known that S1P has a wide range of activities, including inducing effect on cell differentiation, stimulating effect on cell growth, regulation of cell motility and anti-apoptotic action, and manifests physiological action, such as angiogenesis, induction of bradycardia, activation of inflammatory cells and platelet activation (non-patent document 1).

Reported 5 subtypes, Edg-1 (S1P1), Edg-3 (S1P3), Edg-5 (S1P2), Edg-6 (S1P4and Edg-8 (S1P5as S1P receptors (non-patent document 2).

One of them, Edg-1 (S1P1), is expressed in large quantities in immune cells such as T cells and dend is the ITA, and vascular endothelial cells, and it is assumed that he is making an active contribution to the associated with S1P migration of T cells (non-patent document 3), the migration of mast cells (non-patent document 4), the emigration of T cells and b cells of the organs of the lymphatic system (non-patent document 5) and angiogenesis (non-patent document 6), and are involved in autoimmune diseases such as Crohn's disease, syndrome of irritated bowel syndrome, Sjogren's syndrome, multiple sclerosis and systemic lupus erythematosus, and diseases such as rheumatoid arthritis, asthma, atopic dermatitis, the rejection reaction after organ transplantation, malignant disease, retinopathy, psoriasis, osteoarthritis and age-related macular degeneration of the retina.

Thus, ligands Edg-1 (S1P1) are considered as effective for the treatment or prevention of these diseases.

Still, it was reported that some types of derivatives of thiophene (non-patent document 7), derivative of complex phosphate esters (patent document 1, patent document 2, non-patent document 8), and derivatives of thiazolidine (patent document 3) are ligands Edg-1 (S1P1). However, it is not known inhibitors having the structure similar to the structure of the compounds of the present invention.

Compounds similar in structure to the connection nastasemarian, come to the market as reagents company Bionet, but their pharmaceutical use are completely unknown.

Patent document 1: WO 02/18395.

Patent document 2: publication is not passing the examination, the Japan patent No. 2003-137894.

Patent document 3: publication is not passing the examination, the Japan patent No. 2002-332278.

Non-patent document 1: J. Biol. Chem., 2004, 279: 20555, FASEB j 2002, 16: 625, Proceedings of Japanese Society of Immunology 2003, 33: 2-J-W30-20-P.

Non-patent document 2: Pharmacol. Res. 2003, 47: 401.

Non-patent document 3: FASEB j 2002, 16: 1874.

Non-patent document 4: J. Exp. Med. 2004, 199: 959.

Non-patent document 5: Nature 2004, 427: 355.

Non-patent document 6: J. Clin. Inves. 2000, 106: 951, Biochim. Biophys. Acta 2002, 1582: 222.

Non-patent document 7: J. Biol. Chem. 2004, 279: 13839.

Non-patent document 8: Bioorg. Med. Chem. Lett. 2003, 13: 3401.

Detailed description of the invention

Objectives of the invention

The purpose of this invention is the provision of a compound that has the property to inhibit the binding of S1P and its receptor Edg-1 (S1P1) and is useful as a pharmaceutical product.

Resolving problems

The inventors conducted thorough research to try to find connections ligands for Edg-1 (S1P1). In the result it was found that by using certain types of derivatives, triazole or Pharma is efticiency acceptable salts can achieve this goal. The establishment of this fact has led to the implementation of the present invention.

That is, the present invention is a compound having the formula (I)below, or its pharmaceutically acceptable salt

{where a represents a sulfur atom, an oxygen atom, a group having the formula-SO-, or a group having the formula-SO2-,

R1represents a hydrogen atom, alkyl containing 1 to 16 carbon atoms, alkenyl containing 2-8 carbon atoms, quinil containing 2-8 carbon atoms, [alkyl containing 1-6 carbon atoms, which is substituted by phenyl, phenyl substituted by 1-5 groups selected from phenyl, cyano, halogen atom, alkyl containing 1-6 carbon atoms, trifloromethyl, methoxycarbonyl, alkylthio containing 1-6 carbon atoms, dimethylamino, nitro, acetamido, cycloalkyl containing 3-8 carbon atoms, hydroxyl, alkylthio containing 1-6 carbon atoms, alkoxy containing 1-6 carbon atoms, benzyloxy, phenoxy, trifluoromethyl, deformation, benzosulfimide, naphthyl, tricyclohexyl containing 7-10 carbon atoms, carbomethoxy(phenyl)stands, diphenylmethyl, 1-venilation, imidazolium, indolium, pyridium, oxetanyl, akaranam, methylpiperidino, benzylpiperidine, morpholino, 2-oxopyrrolidin-1-yl, 2-Oxymetazoline-1-yl,

group having the formula

-CO2R11,

where R11represents a hydrogen atom or alkyl containing 1-6 carbon atoms,

group having the formula

where R12and R13each represents a hydrogen atom or alkyl containing 1-6 carbon atoms,

group having the formula

where R14and R15each represents a hydrogen atom, alkyl containing 1-6 carbon atoms, phenyl or 4-pyridylcarbonyl,

or a group having the formula

-COR16,

where R16represents alkyl containing 1-6 carbon atoms or phenyl],

alkenyl containing 2-8 carbon atoms, which is substituted by phenyl or benzyloxy, quinil containing 2-8 carbon atoms, which is substituted by phenyl, cycloalkyl containing 3-8 carbon atoms, cycloalkyl containing 3-8 carbon atoms, condensed with a benzene ring, oxiranyl, methylpiperidine or a group having the formula

;

R2represents alkyl containing 1-6 carbon atoms, cycloalkyl containing 3-8 carbon atoms, phenyl or [alkyl containing 1-6 carbon atoms, which is substituted by phenyl, alkoxy containing 1-6 carbon atoms, morpholino, piperidino, a group having the formula

where R21represents the t atom of hydrogen or alkyl, containing 1-6 carbon atoms,

or a group having the formula

where R22and R23each represents a hydrogen atom or alkyl containing 1-6 carbon atoms],

R3represents a hydrogen atom or alkyl containing 1-6 carbon atoms,

R4represents a hydrogen atom, alkyl containing 1-6 carbon atoms, benzyl, substituted benzyl, phenethyl, alkyl containing 1-6 carbon atoms, which is substituted by alkoxygroup containing 1-6 carbon atoms, a halogen atom or a hydroxyl or phenyl, or

R3and R4together they form a 3 - to 6-membered saturated hydrocarbon ring,

R5represents a hydrogen atom or alkyl containing 1-6 carbon atoms, and

Y represents a group having the formula

where R6represents alkyl containing 1-10 carbon atoms, alkenyl containing 2-8 carbon atoms, alkyl containing 1-10 carbon atoms, which is substituted by 1-5 groups selected from phenyl, substituted phenyl, cycloalkyl containing 3-8 carbon atoms, halogen atom, naphthyl, heterocyclic group and substituted heterocyclic group", "alkenyl containing 2-8 carbon atoms, which is substituted by 1-5 groups selected from phenyl, substituted phenyl, cycloalkyl containing 3-8 carbon atoms, atom ha is ogena, naphthyl, heterocyclic group and substituted heterocyclic group, phenyl, substituted phenyl, naphthyl, naphthyl, substituted by dimethylamino, heterocyclic group or substituted heterocyclic group,

except for [connection, where a represents an oxygen atom and R1is a hydrogen atom], [join, where a represents a sulfur atom, and R1is a hydrogen atom], [join, where a represents a sulfur atom, and R3and R4each is simultaneously a hydrogen atom], [join, where a represents a sulfur atom, and R2is a phenyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal and R1is 3-methoxybenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal and R1is 3-terbisil], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal and R1is 2-propenyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R 5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal and R1is 4-tert-butylbenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal and R1represents methyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6is 4-chlorophenyl and R1represents methyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6is 4-chlorophenyl and R1is 2-propenyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6is 4-chlorophenyl and R1is 4-methoxybenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6is 4-chlorophenyl and R1is 4-tert-butylbenzyl], [join, where a represents a sulfur atom, R2is ethyl, R 3and R5each represents a hydrogen atom, R4is stands, R6is 4-chlorophenyl and R1is 3,4-dichlorobenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6is 4-chlorophenyl and R1is 2-Chlorobenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6is 4-chlorophenyl and R1is 3-terbisil], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-chlorophenyl and R1is 2-methyl-2-propenyl], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-chlorophenyl and R1is 2-propenyl], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-chlorophenyl and R1is methoxycarbonylmethyl], [the compound where a is the atom series is, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-chlorophenyl and R1is 4-trifloromethyl], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-chlorophenyl and R1is 3,4-dichlorobenzyl], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-chlorophenyl and R1is 4-bromobenzyl] and [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal and R1is 4-methylbenzyl]}.

Another aspect of the present invention is a pharmaceutical product containing the compound having the formula (I)below, or its pharmaceutically acceptable salt as an active ingredient:

{where a represents a sulfur atom, an oxygen atom, a group having the formula-SO-, or a group having the formula-SO2-,

R1represents a hydrogen atom, alkyl containing 1 to 16 carbon atoms,alkenyl, containing 2-8 carbon atoms, quinil containing 2-8 carbon atoms, [alkyl containing 1-6 carbon atoms, which is substituted by phenyl, phenyl substituted by 1-5 groups selected from phenyl, cyano, halogen atom, alkyl containing 1-6 carbon atoms, trifloromethyl, methoxycarbonyl, alkylthio containing 1-6 carbon atoms, dimethylamino, nitro, acetamido, cycloalkyl containing 3-8 carbon atoms, hydroxyl, alkylthio containing 1-6 carbon atoms, alkoxy containing 1-6 carbon atoms, benzyloxy, phenoxy, trifluoromethyl, deformation, benzosulfimide, naphthyl, tricyclohexyl containing 7-10 carbon atoms, carbomethoxy(phenyl)stands, diphenylmethyl, 1-venilation, imidazolium, indolium, pyridium, oxetanyl, akaranam, methylpiperidino, benzylpiperidine, morpholino, 2-oxopyrrolidin-1-yl, 2-Oxymetazoline-1-yl group having the formula

-CO2R11,

where R11represents a hydrogen atom or alkyl containing 1-6 carbon atoms,

group having the formula

where R12and R13each represents a hydrogen atom or alkyl containing 1-6 carbon atoms,

group having the formula

where R14and R15each represents a hydrogen atom, alkyl containing 1-6 atoms of plastics technology : turning & the Yes, phenyl or 4-pyridylcarbonyl,

or a group having the formula

-COR16,

where R16represents alkyl containing 1-6 carbon atoms or phenyl],

alkenyl containing 2-8 carbon atoms, which is substituted by phenyl or benzyloxy, quinil containing 2-8 carbon atoms, which is substituted by phenyl, cycloalkyl containing 3-8 carbon atoms, cycloalkyl containing 3-8 carbon atoms, condensed with a benzene ring, oxiranyl, methylpiperidine or a group having the formula

;

R2represents alkyl containing 1-6 carbon atoms, cycloalkyl containing 3-8 carbon atoms, phenyl or [alkyl containing 1-6 carbon atoms, which is substituted by phenyl, alkoxy containing 1-6 carbon atoms, morpholino, piperidino,

group having the formula

where R21represents a hydrogen atom or alkyl containing 1-6 carbon atoms,

or a group having the formula

where R22and R23each represents a hydrogen atom or alkyl containing 1-6 carbon atoms],

R3represents a hydrogen atom or alkyl containing 1-6 carbon atoms,

R4represents a hydrogen atom, alkyl containing 1-6 carbon atoms, benzyl, substituted benzyl, phenethyl, alkyl containing 1-6 carbon atoms, is which is substituted by alkoxygroup, containing 1-6 carbon atoms, a halogen atom or a hydroxyl or phenyl, or

R3and R4together they form a 3 - to 6-membered saturated hydrocarbon ring,

R5represents a hydrogen atom or alkyl containing 1-6 carbon atoms, and

Y represents a group having the formula

where R6represents alkyl containing 1-10 carbon atoms, alkenyl containing 2-8 carbon atoms, alkyl containing 1-10 carbon atoms, which is substituted by 1-5 groups selected from phenyl, substituted phenyl, cycloalkyl containing 3-8 carbon atoms, halogen atom, naphthyl, heterocyclic group and substituted heterocyclic group", "alkenyl containing 2-8 carbon atoms, which is substituted by 1-5 groups selected from phenyl, substituted phenyl, cycloalkyl containing 3-8 carbon atoms, halogen atom, naphthyl, heterocyclic group and substituted heterocyclic group, phenyl, substituted phenyl, naphthyl, naphthyl, substituted by dimethylamino, heterocyclic group or substituted heterocyclic group}.

Another aspect of the present invention is a compound of formula (I) or its pharmaceutically acceptable salt according to claim 1, where the fragment corresponding to Y represents a hydrogen atom, a represents an oxygen atom and R5is a hydrogen atom is, and it is an intermediate connection, suitable for obtaining compounds of formula (I).

In the present invention, the alkyl containing 1 to 16 carbon atoms, refers to alkyl, normal or branched chain containing 1 to 16 carbon atoms. His examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, secondary butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl and n-hexadecyl.

Alkyl containing 1-6 carbon atoms, refers to alkyl, normal or branched chain containing 1-6 carbon atoms. His examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, secondary butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and n-hexyl.

Alkyl containing 1-4 carbon atoms, refers to alkyl, normal or branched chain containing 1-4 carbon atoms. His examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, secondary butyl.

Alkenyl containing 2-8 carbon atoms, refers to alkenyl with normal or branched chain, containing 2-8 carbon atoms. His examples are vinyl, allyl, 1-propenyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 2-methylallyl, 2-methylpropenyl, 2-pentenyl and 3-methylbut-2-enyl.

Alkenyl containing 3-5 carbon atoms refers to alkenyl is a normal or branched chain, containing 3-5 carbon atoms. His examples are allyl, 1-propenyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 2-methylallyl, 2-methylpropenyl and 4-pentenyl.

Quinil containing 2-8 carbon atoms, refers to the quinil with normal or branched chain, containing 2-8 carbon atoms. His examples are ethinyl, 2-PROPYNYL, 2-butynyl, 1-methylprop-2-inyl, 2-pentenyl and 4-pentenyl.

Cycloalkyl containing 3-8 carbon atoms, refers to cycloalkyl containing 3-8 carbon atoms, and its examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Cycloalkyl containing 3-6 carbon atoms, refers to cycloalkyl containing 3-6 carbon atoms, and its examples are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Halogen atom refers to a fluorine atom, chlorine atom, bromine atom or iodine atom.

Alkylthio containing 1-6 carbon atoms, refers to alkylthio with normal or branched chain containing 1-6 carbon atoms. His examples are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, pentylthio, hexylthio, allylthio.

Alkoxy containing 1-6 carbon atoms, refers to alkoxy, normal or branched chain containing 1-6 carbon atoms. His examples are methoxy, ethoxy, propoxy, ISO is robaxi, butoxy, isobutoxy, secondary butoxy, tert-butoxy, pentyloxy, hexyloxy, allyloxy.

Cycloalkyl containing 3-8 carbon atoms, refers to cycloalkyl containing 3-8 carbon atoms, and its examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Tricyclohexyl containing 7-10 carbon atoms, refers to tricyclohexyl containing 7-10 carbon atoms and includes, for example, substituted.

Cycloalkyl containing 3-8 carbon atoms, condensed with a benzene ring include, for example, 1,2,3,4-tetrahydronaphthalene and indanyl.

Substituted benzyl refers to benzyl, substituted with 1-2 groups selected from phenyl, halogen atom, methyl, methoxy, trifloromethyl or hydroxyl). His examples are 4-phenylbenzyl, 3,4-dichlorobenzyl, 4-methylbenzyl and 4-methoxybenzyl.

As a 3-6-membered saturated hydrocarbon ring can be called cyclopropane, CYCLOBUTANE, cyclopentane and cyclohexane.

Alkyl containing 1-10 carbon atoms, refers to alkyl, normal or branched chain containing 1-10 carbon atoms. His examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, secondary butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, n-heptyl and n-decyl.

Substituted phenyl refers to phenyl, samisen the mu 1-5 groups, selected from, for example, phenyl, methoxy, phenyl, substituted acetyl, oxazolyl, pyrazolyl, methylpyrimidine, cyano, halogen atom, alkyl containing 1-6 carbon atoms, trifloromethyl, hydroxyl, alkoxy containing 1-6 carbon atoms, cyanoethoxy, phenoxy, phenoxy, substituted methoxy, pyridyloxy, acetyl, benzoyl, pyridylcarbonyl, methoxycarbonyl, methoxycarbonylethyl, alkylthio containing 1-6 carbon atoms, dimethylamino, nitro, acetamido, sulfamoyl, methanesulfonyl, benzosulfimide, pyrrolidinecarbonyl, morpholinoethyl, macilwraith, butylurea, methoxyethylamine, trimethylurea, morpholinylcarbonyl, pyridinedicarboxylate.

Heterocyclic group refers to saturated or unsaturated monocyclic or polycyclic heterocyclic group containing 1-6 heteroatoms, such as oxygen atom, sulfur atom and nitrogen atom. Her examples are imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, furyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, hinely, ethanolic, benzofuranyl, benzothiazol, dihydrobenzofuranyl, coumarinyl, 2,3-dihydrobenzo[1,4]dioxines, 3,4-dihydro-2H-benzo[b][1,4]doxepin, benzo[1,3]dioxole, 2-oxo-2,3-dihydroisoxazole, benzo[1,2,5]thiadiazolyl, 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazinyl, phthalimido.

Sames the fair heterocyclic group refers to the above-mentioned heterocyclic group, substituted by 1-5 substituents selected from a halogen atom, alkyl containing 1-6 carbon atoms, methoxycarbonyl, benzosulfimide and oxazolyl.

Pharmaceutically acceptable salt refers to a salt of an alkali metal, alkaline earth metal, ammonium, alkylamine or the like, or salts of mineral acids or organic acids. Her examples are sodium salt, potassium salt, calcium salt, ammonium salt, an aluminium salt, salt of triethylamine, acetate, propionate, butyrate, formate, triptorelin, maleate, tartrate, citrate, stearate, succinate, ethylsuccinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, aconsultant, 2-hydroxyethanesulfonic, bansilalpet, p-toluensulfonate, lauryl, malate, aspartate, glutamate, adipat, salt cysteine, salt of N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodic, nicotinate, oxalate, picrate, thiocyanate undecanoate, salt of acrylic polymer and salt carboxyvinyl polymer.

The compound of the present invention may be in the form of a stereoisomer, such as optical isomer, diastereoisomer or geometric isomer. All of these stereoisomers and mixtures thereof are included in the compounds of the present invention.

The compound of the present invention can be synthesized, for example, by the methods provided below.

1) a Compound having the following formula (a)

where R3and R4have the meanings given above, is subjected to the interaction with the compound having the formula R OH (where R' represents alkyl containing 1-6 carbon atoms), in the presence of reagent such as trimethylsilane. Then the product is subjected to interaction with the compound having the following formula (b)

where R6has the values defined above,

in a solvent or without solvent, in the presence of a base to obtain the compounds having the following formula (C)

where R3, R4, R6and R' have the meanings given above.

2) Compound having the formula (C), is subjected to the interaction with hydrazine in a solvent or without solvent to obtain compounds having the following formula (d)

where R3, R4and R6have the meanings given above.

3) the compound Obtained in (d) is subjected to interaction with the compound having the following formula (e)

R2-N=C=S (e)

where R2has the values defined above,

in a solvent or without solvent to obtain compounds having the following formula (f)

where R2, R3, R4and R6have the meanings given above.

4) the compound Obtained in (f) is subjected to cyclization with base in a solvent or without solvent to obtain compounds having the following formula (g)

where R2, R3, R4and R6have the meanings given above.

5) the Obtained compound (g) is subjected to interaction with the compound having the following formula (h)

R18-L (h)

where R18has the same meaning as given for the above R1with the exception of the hydrogen atom, and L represents a leaving group, which, for example, represents a halogen atom such as chlorine atom, bromine atom or iodine atom, or alkylsulfonates or arylsulfonate, such as methanesulfonamido or p-toluensulfonate,

in a solvent or without solvent, in the presence of a base, whereby it is possible to obtain the compound of the present invention, having the following formula (i)

where R18, R2, R3, R4and R6have the meanings given above.

6) the compound of the present invention, having the above formula (i), is subjected to the interaction with the connection with pursuing the th formula (j)

R51-L (j)

where R51represents alkyl containing 1-6 carbon atoms, and L have the meanings given above,

in a solvent or without solvent, in the presence of a base, whereby it is possible to synthesize another connection of the present invention, having the following formula (k)

where R18, R2, R3, R4, R51and R6have the meanings given above.

7) Next, the compound having the formula (i) or (k), is subjected to the interaction with the oxidant in a solvent, whereby it is possible to synthesize another compound of the present invention, having the following formula (l)

where R18, R2, R3, R4, R5and R6have the meanings given above.

8) Then, the compound having the above formula (l), is subjected to the interaction with the compound having the formula (m)

where a1represents a sulfur atom or an oxygen atom, and

R18has the values defined above,

in a solvent or without solvent, in the presence of a base, whereby it is possible to synthesize another compound of the present invention, having the following formula (n)

where a1, R18, R 2, R3, R4, R5and R6have the meanings given above.

The alternate connection of the present invention can be synthesized by the method shown below.

(2-1), the Compound having the following formula (o)

where R” represents a protective group for the amino group, such as tert-butoxycarbonyl or benzyloxycarbonyl, and R3, R4and R' have the meanings given above,

subjected to interaction with hydrazine in a solvent or without solvent to obtain compounds having the following formula (p)

where R3, R4and R” have the meanings given above.

(2-2) the compound Obtained of the formula (R) is subjected to interaction with the compound having the following formula (e)

where R2has the values defined above,

in a solvent or without solvent to obtain compounds having the following formula (q)

where R2, R3, R4and R” have the meanings given above.

(2-3) the compound Obtained of the formula (q) is subjected to cyclization in a solvent or without solvent to obtain compounds having the formula (r)

where R2, R3, Rsup> 4and R” have the meanings given above.

(2-4) the compound Obtained of the formula (r) is subjected to interaction with the compound having the following formula (h)

where R18and L have the meanings given above,

in a solvent or without solvent, in the presence of a base to obtain the compounds having the following formula (s)

where R18, R2, R3, R4and R” have the meanings given above.

(2-5) the compound Obtained of the formula (s) is subjected to interaction with the oxidant in a solvent to obtain compounds having the formula (t)

where R18, R2, R3, R4and R” have the meanings given above.

(2-6) the resulting compound of formula (t) is subjected to removal of the protection of the amino group in normal conditions, such as interaction with acid, in a solvent to obtain compounds having the following formula (u)

where R18, R2, R3and R4have the meanings given above,

or salts of the compounds.

(2-7) the resulting compound of formula (u) is subjected to interaction with the compound having the following formula (m)

where a1and R18have the meanings given above,

in RA is the solvent or without solvent in the presence of a base to obtain the salt in there, where it is appropriate, thereby obtaining compounds having the following formula (v)

where a1, R18, X, R2, R3and R4have the meanings given above,

or its pharmaceutically acceptable salt.

(2-8) the compound Obtained of the formula (v) is subjected to interaction with the compound having the following formula (b)

where R6has the values defined above,

in a solvent or without solvent in the presence of a base to obtain thereby the connection of the present invention, having the following formula (w)

where a1, R18, R2, R3, R4and R6have the meanings given above.

(2-9) the compound Obtained according to the present invention having the formula (w), is subjected to the interaction with the compound having the following formula (j)

where R51and L have the meanings given above,

in a solvent or without solvent, in the presence of a base to obtain thereby the connection of the present invention, having the following formula (x)

where a1, R18, R2, R3, R4, R51and R6have the meanings given above.

Primarymeasure, used in the above reaction, are alkali metal salts, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, diminati, sodium hydride, sodium amide and tert-butyl potassium, amines, such as triethylamine, Diisopropylamine, pyrrolidine and piperidine, sodium acetate and potassium acetate.

Examples of the acid are inorganic acids (e.g. hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid and nitric acid) and organic acids (for example, triperoxonane acid, p-toluensulfonate acid and methanesulfonamide acid).

As the oxidizing agent can be used, for example, organic percolate, such as m-perchlorobenzene acid, moreperfect magnesium uranyl, peracetic acid and paranavitana acid, inorganic and organic peroxides, such as hydrogen peroxide, urea adduct with hydrogen peroxide/phthalic anhydride, tert-butylhydroperoxide and the hydroperoxide cumene, periodate sodium, Oxon (registered trademark), N-bromosuccinimide, N-chlorosuccinimide, chloramine-T, tert-butylhypochlorite, identitetet and compound bromo-1,4-diazabicyclo[2,2,2,]octane.

As the reaction solvent can be used, for example the EP, water, alcohols, such as methanol, ethanol, isopropyl alcohol and tert-butyl alcohol, ethers such as dioxane and tetrahydrofuran, and inert solvents for reactions, such as dimethylformamide, N,N'-dimethylacetamide, N,N'-dimethylpropyleneurea (DMPU), hexamethylphosphoramide (NMRA), dimethylsulfoxide, pyridine, methylene chloride, chloroform, acetone, acetic acid and benzene.

The reaction can be conducted at atmospheric pressure, under pressure, under microwave irradiation, etc. at the appropriate temperature selected in the range from -78°C to the boiling temperature of the solvent for the reaction.

When the compound of the present invention used as a pharmaceutical product, as a rule, to the compound of the present invention add carriers, fillers, pH regulators, soljubilizatory etc. obtained mixture is formed into tablets, granules, pills, capsules, powders, liquids, solutions, suspensions, injectables, etc. using conventional methods of preparation of pharmaceutical preparations, and the resulting preparations can be administered orally or inject funds or funds for local use.

The compound of the present invention it is possible to enter an adult patient in a daily dose of from 1 to 1000 mg once or in several divided doses. This dose m is tenderly to increase or decrease, respectively, depending on the type of disease, age, body weight, symptoms of the patient, etc.

The effects of the invention

It was found that the compound of the present invention is an effective ligand Edg-1 (S1P1as shown in the experimental examples described below.

The best option of carrying out the invention

The present invention will be further described in the subsequent examples and experimental examples.

Example 1

4-Chloro-N-[1-(5-mercapto-4-methyl-4H-1,2,4-triazole-3-yl)butyl]benzosulfimide (compound 128)

1) Trimethylchlorosilane (12,4 ml) was added at room temperature to a suspension of DL-Norvaline (2,157 g) in methanol (37 ml), the mixture was stirred for 2 days at room temperature and then boiled under reflux for 3 hours

The reaction mixture was cooled to room temperature and then the solvent is evaporated under reduced pressure. The obtained light yellow solid was dissolved in chloroform (37 ml) was added triethylamine (10.3 ml) and 4-chlorobenzenesulfonamide (3,886 g) at 0°C., followed by stirring the mixture for 2 h at room temperature. The reaction mixture was added to aqueous solution (120 ml) of hydrochloric acid (2 mol/l) and the mixture was extracted with ethyl acetate (200 ml) followed by washing of the extract rich in denim solution of sodium chloride (100 ml×2). The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure to obtain methyl ester 2-{[(4-chlorophenyl)sulfonyl]amino}pentanol acid (4,592 g) as a pale yellow oily substance.

1H NMR (300 MHz, CDCl3) δ ppm: to 0.89 (t, J=7,3 Hz, 3H), 1,20-1,80 (m, 4H), 3,52 (s, 3H), a 3.87-3,98 (m, 1H), 5,11 (d, J=9.5 Hz, 1H), 7,47 (d, J=8,9 Hz, 2H), to 7.77 (d, J=8,9 Hz, 2H).

2) To a solution of methyl ester 2-{[(4-chlorophenyl)sulfonyl]amino}pentanol acid (4,590 g)obtained in example 1-(1)in methanol (50 ml) was added hydrazine monohydrate (21,8 ml) at room temperature and the mixture was stirred for 14 h at room temperature. From the reaction mixture the solvent evaporated under reduced pressure and to the residue was added water (150 ml). The mixture was extracted with ethyl acetate (200 ml) and washed with saturated aqueous sodium chloride (100 ml×2).

The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure to obtain 4-chloro-N-[1-(hydrazinophenyl)butyl]benzosulfimide (4,368 g). TPL 120,0 is 120.5°C.

1H NMR (300 MHz, DMSO-d6) δ ppm: 0,74 (t, J=7,3 Hz, 3H), 0,98-of 1.52 (m, 4H), 3,63 (t, J=7.2 Hz, 1H), 3,94-4,10 (m, 2H), 7,63 (d, J=8,9 Hz, 2H), of 7.75 (d, J=8,9 Hz, 2H), 8,08 (s, 1H), 9,10 (s, 1H).

3) Methylisothiocyanate (683 mg) was added at room temperature to a solution of 4-chloro-N-[1-(hydrazinophenyl)butyl]is encasulated (2,596 g), obtained in example 1-(2), in ethanol (85 ml). The mixture was stirred for 30 min and then was stirred for 2 h at boiling under reflux. The solvent is evaporated from the reaction mixture to obtain a solid substance. The solid is washed with chloroform (100 ml) and then dried to obtain thioamide group by forming 2-(2-{[(4-chlorophenyl)sulfonyl]amino}pentanoyl)-N-methylhydrazine (2,868 g). TPL 191,0-195,0°C.

1H NMR (300 MHz, DMSO-d6) δ ppm: 0,71 (t, J=7,3 Hz, 3H), 1.00 and-of 1.64 (m, 4H), 2,88 (d, J=4,2 Hz, 3H), 3,56 of 3.75 (m, 1H), 7,26-7,46 (m, 1H), 7,66 (d, J=8.7 Hz, 2H), 7,83 (d, J=8.7 Hz, 2H), 9,29 (s, 1H), 10,00 (s, 1H).

4) Aqueous solution (8.5 ml) of sodium hydroxide (1 mol/l) was added at room temperature to a solution of thioamide group by forming 2-(2-{[(4-chlorophenyl)sulfonyl]amino}pentanoyl)-N-methylhydrazine (2,157 g)obtained in example 1-(3), in a mixture of methanol (9.5 ml) and dioxane (19 ml). The mixture was stirred for 30 min and then stirred for 30 min at 85°C. the Solvent is evaporated from the reaction mixture and to the residue was added aqueous hydrochloric acid solution (0.5 mol/l). The mixture was extracted with ethyl acetate (100 ml) and washed with saturated aqueous solution (100 ml) of sodium chloride.

The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure to obtain compound 128 (2,177 g).

1H NMR (300 MHz, CDCl3) δ ppm: to 0.89 (t, J=7,3 Hz, 3H), 1,20-of 1.95 (m, 4H), to 3.58 (s, 3H), of 4.44-of 4.57 (m, 1H), 6,59-6,76 (m, 1H), 7,45 (d, J=8.5 Hz, 2H), 7,69 (d, J=8.5 Hz, 2H), 11,41 (s, 1H).

Example 2

N-{1-[(5-Allylthio)-4-methyl-4H-1,2,4-triazole-3-yl]butyl}-4-chlorobenzenesulfonamide (compound 125)

Diisopropylamine (0,407 ml) and allylbromide (0,218 ml) was added at room temperature to a solution of 4-chloro-N-[1-(5-mercapto-4-methyl-4H-1,2,4-triazole-3-yl)butyl]benzosulfimide (compound 128) (698 mg)obtained in example 1-(4), in tetrahydrofuran (9.7 ml), and the mixture was stirred over night at room temperature. The solvent is evaporated from the reaction mixture under reduced pressure. The obtained residue was dissolved in ethyl acetate (100 ml) and the solution was sequentially washed with an aqueous solution (50 ml) of hydrochloric acid (1 mol/l) and saturated aqueous solution (100 ml) of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The residue was recrystallized from a solvent mixture of hexane (20 ml) and ethyl acetate (15 ml) for purification to obtain compound 125 (590 mg). TPL 161,5-162,0°C.

1H NMR (300 MHz, CDCl3) δ ppm: 0,86 (t, J=7,3 Hz, 3H), 1,15-1,35 (m, 2H), 1,65 is 1.96 (m, 2H), 3,39 (s, 3H), of 3.73-of 3.80 (m, 2H), 4,37 figure-4.49 (m, 1H), 5,07 at 5.27 (m, 2H), 5,85-6,01 (m, 2H), 7,40 (d, J=8,9 Hz, 2H), of 7.70 (d, J=8,9 Hz, 2H).

Example 3

N-{(1R)-1-[5-(Benzylthio)-4-ethyl-4H-1,2,4-triazole-3-yl]ethyl}-4-chlorobenzenesulfonamide (with the Association 5)

Methylchloride (from 25.8 mg) and triethylamine (by 0.055 ml) was added to a solution of benzyl alcohol (16.2 mg) in chloroform (0.9 ml) and the mixture was stirred for 3 h at room temperature. The reaction mixture was subjected to column chromatography on silica gel NH-type (Chromatorex, Fuji Silysia Chemical Ltd.) using tetrahydrofuran as a solvent to obtain benzyl ether methanesulfonate acid. To a solution of benzyl ether methanesulfonate acid in tetrahydrofuran (0.9 ml) was added 4-chloro-N-[(1R)-1-(4-ethyl-5-mercapto-4H-1,2,4-triazole-3-yl)ethyl]benzosulfimide (compound 90) (17.3 mg)obtained by the method similar to that applied in example 1 using appropriate starting compounds, and tert-butyl potassium (8,4 mg), followed by stirring the mixture for 20 h at 40°C. was Added PSA (Amin on a polymeric substrate) (0.15 ml) in the reaction mixture and the resulting mixture was stirred for 4 h at room temperature. The reaction mixture was suirable a mixture of ethyl acetate-tetrahydrofuran and the solvent evaporated. The obtained residue was subjected to column chromatography on silica gel NH-type using tetrahydrofuran as solvent and the eluate was purified column chromatography on silica gel to obtain compound 5 (2.3 mg).

1H NMR (300 MHz, DMSO-d6) δ ppm: 1,10 (who, J=7,1 Hz, 3H), 1,25 (d, J=6.8 Hz, 3H), 3,62-of 3.96 (m, 2H), 4,36 (s, 2H), 4,55-4,78 (m, 1H), 7,15-7,47 (m, 5H), to 7.64 (d, J=8.6 Hz, 2H), to 7.77 (d, J=8.6 Hz, 2H), charged 8.52 (d, J=8.6 Hz, 1H).

Example 4

4-Chloro-N-{(1R)-1-[4-ethyl-5-(methylsulfonyl)-4H-1,2,4-triazole-3-yl]ethyl}benzosulfimide (compound 180, the connection 181)

To a solution of 4-chloro-N-{(1R)-1-[4-ethyl-5-(methylthio)-4H-1,2,4-triazole-3-yl]ethyl}benzosulfimide (compound 1) (329 mg)obtained by the method similar to those used in examples 1 and 2 using the appropriate starting substances in chloroform (18 ml) was added m-perchlorobenzene acid (157 mg) under cooling on ice. The mixture was stirred for 30 min at 0°C and then stirred overnight at room temperature. The reaction solution was washed with saturated aqueous sodium bicarbonate solution (20 ml). The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel using a mixture of acetone-ethyl acetate. The eluate was twice divided preparative TLC (Merck, analytical TLC plate placed, 20×20 cm Silicagel plates 60F254×4) using ethyl acetate as solvent. Then the divided connection was suirable using a mixture of 5% methanol/chloroform to obtain compound 180 (14 mg) with low Polarnet the Yu and connections 181 (21 mg) with high polarity (compound 180 and the connection 181: diastereoisomer).

Connection 180 with a low polarity:1H NMR (300 MHz, CDCl3) δ ppm: 1,47 (t, J=7.2 Hz, 3H), and 1.54 (d, J=6.8 Hz, 3H), 3,26 (s, 3H), 4,18-to 4.46 (m, 2H), 4.63 to-4,78 (m, 1H), 5,95 (d, J=9.6 Hz, 1H), 7,45 (d, J=8.5 Hz, 2H), of 7.70 (d, J=8.5 Hz, 2H).

Compound 181 with high polarity:1H NMR (300 MHz, CDCl3) δ ppm: 1,47 (t, J=7,3 Hz, 3H), of 1.55 (d, J=6.8 Hz, 3H), 3,24 (s, 3H), 4,18 figure-4.49 (m, 2H), 4.63 to-4,80 (m, 1H), 6,00 (d, J=9,3 Hz, 1H), 7,46 (d, J=8,8 Hz, 2H), 7,72 (d, J=8,8 Hz, 2H).

Example 5

4-Chloro-N-{(1R)-1-[4-ethyl-5-(methylsulphonyl)-4H-1,2,4-triazole-3-yl]ethyl}benzosulfimide (compound 182)

To a solution of 4-chloro-N-{(1R)-1-[4-ethyl-5-(methylthio)-4H-1,2,4-triazole-3-yl]ethyl}benzosulfimide (compound 1) (520 mg)obtained by the method similar to those used in examples 1 and 2 using the appropriate starting substances in chloroform (30 ml) was added m-perchlorobenzene acid (746 mg) under cooling on ice, followed by stirring the mixture for 1 h at 0°C. To the reaction mixture was added saturated aqueous sodium bicarbonate solution (100 ml) and the resulting mixture was extracted with chloroform (50 ml). The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was column purified flash chromatography on silica gel using a solvent mixture of ethyl acetate-chloroform to obtain compound 182 (481 mg).

1H NMR (300 MHz, DCl 3) δ ppm: of 1.46 (t, J=7,3 Hz, 3H), 1,54-to 1.60 (m, 3H), 3,49 (s, 3H), 4,25-and 4.40 (m, 2H), 4,65-4,78 (m, 1H), 5,44 (d, J=9.8 Hz, 1H), 7,45 (d, J=8,9 Hz, 2H), 7,68 (d, J=8,9 Hz, 2H).

Example 6

N-{(1R)-1-[5-(Allylthio)-4-ethyl-4H-1,2,4-triazole-3-yl]ethyl}-4-chloro-N-methylbenzenesulfonamide (compound 99)

To a solution of N-{(1R)-1-[5-(allylthio)-4-ethyl-4H-1,2,4-triazole-3-yl]ethyl}-4-chlorobenzenesulfonamide (compound 3) (200 mg)obtained by the method, similarly used in examples 1 and 2 using the appropriate starting substances in dimethylformamide (2 ml) was added potassium carbonate (120 mg) and methyliodide (0,040 ml) at room temperature, followed by stirring the mixture for 3 h at room temperature. To the reaction mixture were added ethyl acetate and the resulting mixture was sequentially washed with an aqueous solution of hydrochloric acid 1 mol/l) and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was column purified flash chromatography on silica gel using a solvent mixture of ethyl acetate-hexane. Then the eluate was recrystallized using a solvent mixture of ethyl acetate-hexane to clean with obtaining compound 98 (112 mg). TPL 142,0-143,0°C.

1H NMR (200 MHz, DMSO-d6) δ ppm: 1,13 (d, J=6.8 Hz, 3H), of 1.27 (t, J=7,1 is C, 3H), of 2.56 (s, 3H), 3,82 (d, J=7,1 Hz, 2H), 3,90-of 4.25 (m, 2H), 5,04 at 5.27 (m, 2H), 5,43 (kV, J=6,8 Hz, 1H), of 5.82-the 6.06 (m, 1H), 7,74 (d, J=8,8 Hz, 2H), of 7.90 (d, J=8,8 Hz, 2H).

Example 7

4-Chloro-N-[(1R)-1-(4-ethyl-5-propoxy-4H-1,2,4-triazole-3-yl)ethyl]benzosulfimide (compound 183)

Sodium hydride (12 mg) was added while cooled on ice to a solution of 4-chloro-N-{(1R)-1-[4-ethyl-5-(methylsulphonyl)-4H-1,2,4-triazole-3-yl]ethyl}benzosulfimide (compound 182) (47 mg)obtained in example 5 in dimethylformamide (1.2 ml) and n-propanol (0,027 ml). The mixture was stirred for 30 min at room temperature and then was stirred for 2 h at 100°C. After cooling the reaction mixture to room temperature, it was added to the saturated aqueous solution of ammonium chloride (5 ml). The mixture was extracted with ethyl acetate (20 ml×2) and washed with saturated aqueous sodium chloride (20 ml). The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was column purified flash chromatography on silica gel using a solvent mixture of methanol-chloroform to obtain compound 183 (35 mg).

1H NMR (300 MHz, CDCl3) δ ppm: 1,02 (t, J=7.5 Hz, 3H), 1,24 (t, J=7.2 Hz, 3H), 1,47 (d, J=6.8 Hz, 3H), 1,75 is 1.91 (m, 2H), 3,68-of 3.80 (m, 2H), 4,37 (t, J=6.5 Hz, 2H), 4,45-4,58 (m, 1H), ceiling of 5.60 (users, 1H), 7,45 (d, J=8.6 Hz, 2H), to 7.77 (d, J=8.6 Hz, 2H).

Example 8

(1R)-1-(4-Ethyl-5-methoxy-4H-[1,2,4]triazole-3-yl)ethylamine (compound 519)

1) hydrazine Monohydrate (30 ml) was added to a solution of methyl ester of N-(tert-butoxycarbonyl)-D-alanine (41.8 g) in methanol (180 ml) and the mixture was stirred for 12 h at room temperature. The reaction mixture was concentrated and the obtained crude crystals were washed with a mixture solvent of hexane-ethyl eilatin (1:1, 300 ml). Then the washed crystals were dried to obtain tert-butyl ether (R)-(1-hydrazinophenyl-2-ethyl) - carbamino acid as a colourless powder (32,6 g).

1H NMR (300 MHz, DMSO-d6) δ ppm: 1.14 in (d, J=7.2 Hz, 3H), of 1.37 (s, 9H), 3,30-4.09 to (m, 3H), 6,70-of 6.90 (m, 1H), 8,96 (users, 1H).

2) Ethylisothiocyanate (14.6 ml) was added to a solution of tert-butyl methyl ether (R)-(1-hydrazinophenyl-2-ethyl) - carbamino acid (30,8 g)obtained in example 8-(1)in EtOH (152 ml) and the mixture was heated for 2 hours at the boil under reflux. After cooling the mixture to room temperature, the precipitated crystals were filtered. The filtrate was concentrated and the obtained residue was purified by chromatography on silica gel using a solvent mixture of ethyl acetate-chloroform, obtaining (R)-2-(N-(tert-butoxycarbonyl)amino)propionyl)-N-ethylhydrocupreine in the form of a colorless amorphous substance (43,2 g).

1H NMR (300 MHz, DMSO-d6) δ ppm: 0,98 of 1.28 (m, 6H), of 1.40 (s, 9H), 3.25 to the 3.65 (m, 2H), of 3.77-3,95 (m, 1H), 7,20-7,39 (m, 1H), 7,45-of 7.60 (m, H), the 9.25 (s, 1H), 10,00 (s, 1H).

3) Aqueous solution (218 ml) of sodium hydroxide (1 mol/l) was added to a solution of (R)-2-(N-(tert-butoxycarbonyl)amino)propionyl)-N-ethylhydrocupreine (42,1 g)obtained in example 8-(2), in a solvent mixture of methanol (120 ml) and dioxane (240 ml) followed by heating the mixture for 3 h at boiling under reflux. The reaction mixture was concentrated and added an aqueous solution (100 ml) of hydrochloric acid (2 mol/l). The mixture was extracted with a mixture solvent ethyl acetate-CHCl3-MeOH (10:10:1, 500 ml) and the organic layer was dried over anhydrous magnesium sulfate. The solvent is then evaporated under reduced pressure and the obtained residue was washed with a mixture solvent of hexane-ethyl acetate (1:1, 300 ml) followed by drying to obtain tert-butyl ester [(R)-1-(4-ethyl-5-mercapto-4H-[1,2,4]triazole-3-yl)ethyl]carbamino acid as a white solid (29,22 g).

1H NMR (300 MHz, DMSO-d6) δ ppm: to 1.21 (t, J=7,1 Hz, 3H), 1,30-1,50 (m, 3H), of 1.39 (s, 9H), 3,82-of 4.05 (m, 2H), 4.72 in-4,88 (m, 1H), 7,58 (d, J=8.5 Hz, 1H), 13,60 (users, 1H).

4) Diisopropylamine a (17.4 ml) and iodomethane (7.7 ml) was added to a solution of tert-butyl ester [(R)-1-(4-ethyl-5-mercapto-4H-[1,2,4]triazole-3-yl)ethyl]carbamino acid (28,12 g)obtained in example 8-(3), in tetrahydrofuran (200 ml). The mixture was stirred for 1 h at room temperature and then the precipitated crystal is filtered. The filtrate was concentrated and the obtained crude crystals were washed with a mixture solvent of hexane-ethyl acetate (3:1, 200 ml) followed by drying to obtain tert-butyl ester [(R)-1-(4-ethyl-5-methylsulfanyl-4H-[1,2,4]triazole-3-yl)ethyl]carbamino acid as a white powder (29.5 g).

1H NMR (300 MHz, DMSO-d6) δ ppm: to 1.21 (t, J=7.0 Hz, 3H), of 1.38 (s, 9H), of 1.45 (t, J=7.0 Hz, 3H), 2,62 (s, 3H), of 3.80-4.00 points (m, 2H), 4,85 to 4.92 (m, 1H), 7,52 (d, J=8.5 Hz, 1H).

5) To a solution of tert-butyl ester [(R)-1-(4-ethyl-5-methylsulfanyl-4H-[1,2,4]triazole-3-yl)ethyl]carbamino acid (21,0 g)obtained in example 8-(4), in chloroform (293 ml) was added m-perchlorobenzene acid (43,0 g) four portions while cooling on ice. The mixture was stirred for 3 h at room temperature and then was stirred for 1 h at 40°C. To the reaction mixture was added Na2S2O3(12.9 g) and an aqueous solution (300 ml) of sodium hydroxide (1 mol/l). The organic layer was separated and washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The obtained residue was column purified flash chromatography on silica gel using a solvent mixture of hexane-ethyl acetate. Then the purified substance was recrystallized using a mixture of hexane-chloroform to obtain tert-bout the business ester [(R)-1-(4-ethyl-5-methanesulfonyl-4H-[1,2,4]triazole-3-yl)ethyl]carbamino acid as a white powder (17,2 g).

1H NMR (300 MHz, CDCl3) δ ppm: the 1.44 (s, 9H), for 1.49 (t, J=7,1 Hz, 3H), 1,67 (t, J=6.8 Hz, 3H), 3,53 (s, 3H), 4,25-4,59 (m, 2H), 4.92 in-5,20 (m, 2H).

6) Triperoxonane acid (121 ml) was added to tert-butyl ether [(R)-1-(4-ethyl-5-methanesulfonyl-4H-[1,2,4]triazole-3-yl)ethyl]carbamino acid (100.0 g)obtained in example 8-(5), and the mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated under reduced pressure to obtain (R)-1-(4-ethyl-5-methanesulfonyl-4H-[1,2,4]triazole-3-yl)ethylamine of triptoreline in the form of a white powder (to 103.8 g).

1H NMR (300 MHz, DMSO-d6) δ ppm: to 1.37 (t, J=7.2 Hz, 3H), 1.59 CI (t, J=6.8 Hz, 3H), of 3.65 (s, 3H), 4,21-4,50 (m, 2H), 4.72 in-the 4.90 (m, 1H), 8,69 (users, 3H).

7) NaOMe (18 ml of 2.0 n solution in Meon) was added to trifenatate (R)-1-(4-ethyl-5-methanesulfonyl-4H-[1,2,4]triazole-3-yl)ethylamine (3.0 g)obtained in example 8-(6), and the mixture was heated for 1 h at boiling under reflux. The reaction mixture was cooled to room temperature and was added Et2O (100 ml). After cooling the mixture to 0°C. the precipitated crystals were filtered. The filtrate was concentrated and the crude product was purified by chromatography on NH-silica gel using a solvent mixture of Et2O-Meon obtaining specified in the title compound (compound 519) as a colorless oily substance (1.55 g).

1H NMR (300 MHz, CDCl3) δ ppm: 1.32 to(t, J=7.2 Hz, 3H), and 1.54 (t, J=6,7 Hz, 3H), 3,78-3,95 (m, 2H), was 4.02-4,20 (m, 1H), 4,13 (s, 3H).

Example 9

[(1R)-1-(4-Ethyl-5-methoxy-4H-[1,2,4]triazole-3-yl)ethyl]benzosulfimide (compound 376)

The solution benzosulfimide (31 mg) in tetrahydrofuran (0.9 ml) was added at room temperature to the compound (20 mg)obtained in example 8-(7). Then was added triethylamine (0,040 ml) and the mixture was stirred for 3 h at room temperature. The reaction mixture was subjected to column chromatography on silica gel NH-type using tetrahydrofuran as a solvent, and then the eluate was concentrated to obtain specified in the connection header (to 36.5 mg).

1H NMR (200 MHz, CDCl3) δ ppm: 1,24 (t, J=7,1 Hz, 3H), of 1.41 (t, J=7.0 Hz, 3H), 3,79 (kV, J=7,1 Hz, 3H), 4.09 to (s, 3H), 4,40-of 4.67 (m, 1H), 6,20-6,60 (m, 1H), 7,40 to 7.62 (m, 3H), 7,80-7,98 (m, 2H).

Example 10

Used methods similar to those used in examples 1-9, received salts where appropriate, to obtain the compounds shown in the table below. As connections 89, 104, 136 and 137, used compounds production Bionet.

The compound obtained in the above examples 1-9, also presented in the table along with other compounds.

The test example 1 (test binding with the cellular system)

Using a cell line SOME 293 transferred the human genome Edg-1 (S1P1) (show is her linking K d=6,4±2,1 nmmax=160±94 fmol/105cells with [3H]-S1P), which was obtained using the method described in the literature (Science 1998, 279-1552), investigated the inhibitory against binding Edg-1 (S1P1action of the compounds of the present invention according to the method described in the literature. Cells (1×105cells/well)obtained as described above were sown in 96-well plates, coated with poly-L-lysine (Corning Incorporated) and then incubated in an incubator in an atmosphere of 5% carbon dioxide in air for 12 h at 37°C by using the MEM (Invitrogen Corporation)containing 100 u/ml penicillin, 100 μg/ml streptomycin, 1% solution of essential amino acids MEM and 10% FCS. The cultured cells were twice washed with buffer (20 mm Tris-HCl, pH 7.4, 100 mm NaCl, 15 mm NaF, 2 mm deoxypyridoxine, 4 mg/ml does not contain fatty acid BSA) and then was treated with 100 μl of buffer containing [3H]-S1P (produced by ARC, final concentration 10 nm), and a solution of test compound in DMSO (final concentration is 10-5M, final concentration of DMSO 0.1%) for 1 h at 4°C. After washing the cells twice with buffer they were solubilizers 100 ál Opti Phase Supermix (produced by Perkin-Elmer) and radioactivity was determined using a counter Micro Beta (produced by Perkin-Elmer). Based on the data on radioactivity counted the number of (a) is connected is of [ 3H]-S1P adding connections.

The same test was performed in the absence of the test compound and counted the number of (In) associated with [3H]-S1P. In addition, the same test was performed in the absence of test compounds using cells SOME 293, in which the gene Edg-1 (S1P1) was not migrated, and expected background number (S) associated

[3H]-S1P.

The ratio of inhibition of binding of Edg-1 (S1P1under the action of the compounds was calculated by the following equation presented in the table.

The ratio of inhibition (%)=[1-(a-C)/(b-C)]×100.

Sample test 2 (test binding with the membrane system)

Using the membrane fraction of the cell line SOME 293, transferred the human genome Edg-1 (S1P1) investigated the inhibitory against binding Edg-1 (S1P1action of the compounds of the present invention according to the method described in the literature (Science 2002, 296-346) (showing the binding of Kd=0,15 nmmax=2.5 fmol/μg with [33R]-S1P). The membrane fraction was obtained by treating the cells with solubilization buffer (1 mm Tris-HCl, pH to 7.2) for 10 min on ice, centrifugation system (1000×g, 5 min) to remove insoluble fractions and then by centrifugation system (40000×g, 30 min, 4°C). The obtained membrane fraction was dissolved in the buffer for binding (20 mm Tris-HCl, pH 4, 100 mm NaCl, 15 mm NaF, 2 mm deoxypyridoxine, 4 mg/ml does not contain fatty acid BSA) and then added a [33R]-S1P (produced by ARC, final concentration 0.1 nm) and a solution of test compound in DMSO (final concentration is 10-5M, final concentration of DMSO of 0.1%), followed by stirring of the mixture and processed within 1 h at 30°C. With the use of a header cell membrane fraction was collected on unifilter-96GF/filter (manufactured by Perkin-Elmer). Then the filter with the membrane fraction was washed 4 times with buffer for binding and the filter was dried. The filter was applied 25 μl of scintillation fluid Microscint (produced by Perkin-Elmer) and determined the radioactivity of the analytical system using counter Top Count NXT (Packard). Based on the data on radioactivity counted number (S) associated with the membrane fraction [33R]-S1P adding connections.

The same methodology was applied in the absence of the test compound and counted the number of (In) associated with [33R]-S1P. In addition, the same methodology was applied in the absence of test compounds using cells SOME 293, in which the gene Edg-1 (S1P1) was not migrated, and expected background number (S) associated with [33R]-S1P.

The ratio of inhibition of binding of Edg-1 (S1P1under the action of the compounds, calculated after the ith equation, presented in the table.

The ratio of inhibition (%)=[1-(a-C)/(b-C)]×100.

Industrial applicability

The compound of the present invention is an effective ligand EDG-1(S1P1). Therefore, it is suitable as a means for the treatment or prevention of autoimmune diseases, such as Crohn's disease, irritable bowel syndrome, Sjogren syndrome, multiple sclerosis and systemic lupus erythematosus, and diseases, such as rheumatoid arthritis, asthma, atopic dermatitis, rejection reaction after organ transplantation, malignant disease, retinopathy, psoriasis, osteoarthritis and age-related macular degeneration of the retina.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-78

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-88

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

1. The compound having the following formula (I)or its pharmaceutically acceptable salt

where a represents a sulfur atom, an oxygen atom, a group having the formula-SO-, or a group having the formula-SO2-,
R1represents a hydrogen atom, alkyl containing 1 to 16 carbon atoms, alkenyl containing 2-8 carbon atoms, quinil containing 2-8 carbon atoms, [alkyl containing 1-6 carbon atoms, which is substituted phenyl groups, phenyl, substituted by 1-5 groups selected from phenyl, cyano, halogen atom, alkyl containing 1-6 carbon atoms, trifloromethyl, methoxycarbonyl, alkylthio containing 1-6 carbon atoms, dimethylamino, nitro, acetamido, cycloalkyl containing 3-8 carbon atoms, hydroxyl, alkylthio containing 1-6 carbon atoms, alkoxy containing 1-6 atoms carbon, benzyloxy, phenoxy, trifluoromethyl, deformation, benzosulfimide, naphthyl, tricyclohexyl containing 7-10 carbon atoms, 1-venilation, imidazolium, indolium, pyridium, oxetanyl, akaranam, methylpiperidino, benzylpiperidine, morpholino, 2-oxopyrrolidin-1-yl, 2-Oxymetazoline-1-yl group having the formula
-CO2R11,
where R11represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
group having the formula

where R12and R13each represents a hydrogen atom or alkyl containing 1-6 carbon atoms, a group having the formula

where R14and R15each represents a hydrogen atom, alkyl containing 1-6 carbon atoms, phenyl or 4-pyridylcarbonyl, or a group having the formula
-COR16,
where R16represents alkyl containing 1-6 carbon atoms, or phenyl], alkenyl containing 2-8 carbon atoms, which is substituted by phenyl or benzyloxycarbonyl, quinil containing 2-8 carbon atoms, which is substituted by phenyl, cycloalkyl containing 3-8 carbon atoms, cycloalkyl containing 3-8 carbon atoms, condensed with a benzene ring, oxiranyl, methylpiperidine
or a group having the formula
;
R2represents alkyl containing 1-6 carbon atoms, cycloalkyl containing 3-8 carbon atoms, phenyl or [alkyl containing 1-6 carbon atoms, which is substituted by phenyl, alkoxygroup containing 1-6 carbon atoms, morpholino, piperidino, a group having the formula

where R21represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
or a group having the formula

where R22and R23each represents an atom of odor is Yes or alkyl, containing 1-6 carbon atoms],
R3represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
R4represents a hydrogen atom, alkyl containing 1-6 carbon atoms, benzyl, benzyl substituted by 1-2 groups selected from phenyl, halogen atom, methyl, methoxy, trifloromethyl or hydroxy-group, phenethyl, alkyl containing 1-6 carbon atoms, which is substituted by alkoxygroup containing 1-6 carbon atoms, a halogen atom or a hydroxyl or phenyl, or
R3and R4together form a 3-6-membered saturated hydrocarbon ring,
R5represents a hydrogen atom or alkyl containing 1-6 carbon atoms, and
Y represents a group having the formula

where R6represents alkyl containing 1-10 carbon atoms, alkyl containing 1-10 carbon atoms, which is substituted by 1-5 groups selected from phenyl; phenyl substituted with 1-2 substituents selected from nitro, halogen atom and triptorelin group; cycloalkyl containing 3-8 carbon atoms, halogen atom, naphthyl and pyridyl", "alkenyl containing 2-8 carbon atoms, which is substituted by 1-5 phenyl groups, phenyl, phenyl substituted by 1-5 groups selected from phenyl, phenyl substituted by methoxy group or acetyl group, oxazolyl, pyrazolyl, methylpyrimidine, cyano, the volume of halogen, of alkyl containing 1-6 carbon atoms, trifloromethyl, cryptometer, dipterocarp, hydroxy-group, alkoxygroup containing 1-6 carbon atoms, cyanoethoxy, fenoxaprop, fenoxaprop substituted by a methoxy group, pyridyloxy, acetyl group, pyridylcarbonyl group, methoxycarbonyl group, methoxycarbonylethyl, nitro, acetamidoxime, sulfamoyl group, methanesulfonyl group, pyrrolidinylcarbonyl group, morpholinomethyl group, methyluridine, butylurea, methoxyethylmercury, trimethylurea, morpholinylcarbonyl and pyridinedicarboxylate", naphthyl, naphthyl substituted by dimethylaminopropoxy, heterocyclic group selected from imidazolyl, pyrazolyl, thiazolyl, isoxazolyl, furil, teinila, pyridyl, chinoline, izochinolina, benzofuranyl, benzothiazyl, dihydrobenzofuranyl, coumarinyl, 2,3-dihydrobenzo[1,4]dioxine, 3,4-dihydro-2H-benzo[b][1,4]dioxane, benzo[1,3]dioxolane, 2-oxo-2,3-dihydroisoxazole, benzo[1,2,5]thiadiazolyl, 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazinyl and phthalimidopropyl, or heterocyclic group selected from imidazolyl, pyrazolyl, thiazolyl, isoxazolyl, furil, teinila, pyridyl, chinoline, izochinolina, benzofuranyl, benzothiazyl, dihydrobenzofuran the sludge, coumarinyl, 2,3-dihydrobenzo[1,4]dioxine, 3,4-dihydro-2H-benzo[b][1,4]dioxane, benzo[1,3]dioxolane, 2-oxo-2,3-dihydroisoxazole, benzo[1,2,5]thiadiazolyl, 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazinyl and phthalimidopropyl, substituted by 1-5 substituents selected from a halogen atom, alkyl containing 1-6 carbon atoms, methoxycarbonyl group, ethoxycarbonyl group, benzolsulfonate group and oxazoline group,
except for [connection, where a represents an oxygen atom, and R1is a hydrogen atom], [join, where a represents a sulfur atom, and R1is a hydrogen atom], [join, where a represents a sulfur atom, and R3and R4each is simultaneously a hydrogen atom], [join, where a represents a sulfur atom, and R2is a phenyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal, and R1is 3-methoxybenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal, and R1is 3-terbisil], [join, where a represents a sulfur atom, R2is ethyl,
R3The R 5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal, and R1is 2-propenyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal, and R1is 4-tert-butylbenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal, and R1represents methyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6represents 4-chlorophenyl, and R1represents methyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6represents 4-chlorophenyl, and R1is 2-propenyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6represents 4-chlorophenyl, and R1is 4-methoxybenzyl], [join, where a represents a sulfur atom, R2is ethyl, R and R5each represents a hydrogen atom, R4is stands, R6represents 4-chlorophenyl, and R1is 4-tert-butylbenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6represents 4-chlorophenyl, and R1is 3,4-dichlorobenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6represents 4-chlorophenyl, and R1is 2-Chlorobenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6represents 4-chlorophenyl, and R1is 3-terbisil], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6represents 4-chlorophenyl, and R1is 2-methyl-2-propenyl], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6represents 4-chlorophenyl, and R1is 2-propenyl], [join, where a represents a sulfur atom, R 2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6represents 4-chlorophenyl, and R1is methoxycarbonylmethyl], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6represents 4-chlorophenyl, and R1is 4-trifloromethyl], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6represents 4-chlorophenyl, and R1is 3,4-dichlorobenzyl], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6represents 4-chlorophenyl, and R1is 4-bromobenzyl] and [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal, and R1is 4-methylbenzyl].

2. Pharmaceutical composition for treatment or prevention of diseases mediated by the binding of S1P and Edg-1, containing a compound having the following formula (I)or its pharmaceutically acceptable salt as the e active ingredient:

where a represents a sulfur atom, an oxygen atom, a group having the formula-SO-, or a group having the formula-SO2-,
R1represents a hydrogen atom, alkyl containing 1 to 16 carbon atoms, alkenyl containing 2-8 carbon atoms, quinil containing 2-8 carbon atoms, [alkyl containing 1-6 carbon atoms, which is substituted phenyl groups, phenyl, substituted by 1-5 groups selected from phenyl, cyano, halogen atom, alkyl containing 1-6 carbon atoms, trifloromethyl, methoxycarbonyl, alkylthio containing 1-6 carbon atoms, dimethylamino, nitro, acetamido, cycloalkyl containing 3-8 carbon atoms, hydroxyl, alkylthio containing 1-6 carbon atoms, alkoxy containing 1-6 atoms carbon, benzyloxy, phenoxy, trifluoromethyl, deformation, benzosulfimide, naphthyl, tricyclohexyl containing 7-10 carbon atoms, 1-venilation, imidazolium, indolium, pyridium, oxetanyl, akaranam, methylpiperidino, benzylpiperidine, morpholino, 2-oxopyrrolidin-1-yl, 2-Oxymetazoline-1-yl group having the formula
-CO2R11,
where R11represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
group having the formula

where R12and R13each represents a hydrogen atom or alkyl, with the holding of 1-6 carbon atoms, group having the formula

where R14and R15each represents a hydrogen atom, alkyl containing 1-6 carbon atoms, phenyl or 4-pyridylcarbonyl, or a group having the formula
-COR16,
where R16represents alkyl containing 1-6 carbon atoms, or phenyl], alkenyl containing 2-8 carbon atoms, which is substituted by phenyl or benzyloxycarbonyl, quinil containing 2-8 carbon atoms, which is substituted by phenyl, cycloalkyl containing 3-8 carbon atoms, cycloalkyl containing 3-8 carbon atoms, condensed with a benzene ring, oxiranyl, methylpiperidine or a group having the formula
;
R2represents alkyl containing 1-6 carbon atoms, cycloalkyl containing 3-8 carbon atoms, phenyl or [alkyl containing 1-6 carbon atoms, which is substituted by phenyl, alkoxygroup containing 1 to 6 carbon atoms, morpholino, piperidino, a group having the formula

where R21represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
or a group having the formula

where R22and R23each represents a hydrogen atom or alkyl containing 1-6 carbon atoms],
R3represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
R4 represents a hydrogen atom, alkyl containing 1-6 carbon atoms, benzyl; benzyl substituted by 1-2 groups selected from phenyl, halogen atom, methyl, methoxy, trifloromethyl or hydroxy-group; phenethyl, alkyl containing 1-6 carbon atoms, which is substituted by alkoxygroup containing 1-6 carbon atoms, a halogen atom or a hydroxyl or phenyl, or
R3and R4together form a 3-6-membered saturated hydrocarbon ring, R5represents a hydrogen atom or alkyl containing 1-6 carbon atoms, and
Y represents a group having the formula

where R6represents alkyl containing 1-10 carbon atoms, alkyl containing 1-10 carbon atoms, which is substituted by 1-5 groups selected from phenyl; phenyl substituted with 1-2 substituents selected from nitro, halogen atom and triptorelin group; cycloalkyl containing 3-8 carbon atoms, halogen atom, naphthyl and pyridyl", "alkenyl containing 2-8 carbon atoms, which is substituted by 1-5 phenyl groups, phenyl, phenyl substituted by 1-5 groups selected from phenyl, phenyl substituted by methoxy group or acetyl group, oxazolyl, pyrazolyl, methylpyrimidine, cyano, the halogen atom, alkyl containing 1-6 carbon atoms, trifloromethyl, cryptometer, dipterocarp, hydroxycu the dust, alkoxygroup containing 1-6 carbon atoms, cyanoethoxy, fenoxaprop, fenoxaprop substituted by a methoxy group, pyridyloxy, acetyl group, pyridylcarbonyl group, methoxycarbonyl group, methoxycarbonylethyl, nitro, acetamidoxime, sulfamoyl group, methanesulfonyl group, pyrrolidinylcarbonyl group, morpholinomethyl group, methyluridine, butylurea, methoxyethylmercury, trimethylurea, morpholinylcarbonyl and pyridinedicarboxylate", naphthyl, naphthyl substituted by dimethylaminopropoxy, heterocyclic group selected from imidazolyl, pyrazolyl, thiazolyl, isoxazolyl, furil, teinila, pyridyl, chinoline, izochinolina, benzofuranyl, benzothiazyl, dihydrobenzofuranyl, coumarinyl, 2,3-dihydrobenzo[1,4]dioxine, 3,4-dihydro-2H-benzo[b][1,4]dioxane, benzo[1,3]dioxolane, 2-oxo-2,3-dihydroisoxazole, benzo[1,2,5]thiadiazolyl, 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazinyl and phthalimidopropyl, or heterocyclic group selected from imidazolyl, pyrazolyl, thiazolyl, isoxazolyl, furil, teinila, pyridyl, chinoline, izochinolina, benzofuranyl, benzothiazyl, dihydrobenzofuranyl, coumarinyl, 2,3-dihydrobenzo[1,4]dioxine, 3,4-dihydro-2H-benzo[b][1,4]dioxane, benzo[1,3]dioxolane, 2-oxo-2,3-Digue is robinsonstyle, benzo[1,2,5]thiadiazolyl, 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazinyl and phthalimidopropyl, substituted by 1-5 substituents selected from a halogen atom, alkyl containing 1-6 carbon atoms, methoxycarbonyl group, ethoxycarbonyl group, benzolsulfonate group and oxazoline group.

3. The pharmaceutical composition according to claim 2, where the disease is an autoimmune disease, such as Crohn's disease, irritable bowel syndrome, Sjogren syndrome, multiple sclerosis or systemic lupus erythematosus, or rheumatoid arthritis, asthma, atopic dermatitis, rejection reaction after organ transplantation, malignant disease, retinopathy, psoriasis, osteoarthritis and age-related macular degeneration of the retina.

4. The compound having the following formula (I)or its pharmaceutically acceptable salt

where a represents a sulfur atom, an oxygen atom, a group having the formula-SO-, or a group having the formula-SO2-,
R1represents a hydrogen atom, alkyl containing 1 to 16 carbon atoms, alkenyl containing 2-8 carbon atoms, quinil containing 2-8 carbon atoms, [alkyl containing 1-6 carbon atoms, which is substituted phenyl groups, phenyl, substituted by 1-2 groups selected from phenyl, cyano, halogen atom, alkyl containing 1-6 atoms is of Pereda, trifloromethyl, methoxycarbonyl, alkylthio containing 1-6 carbon atoms, dimethylamino, nitro, acetamido, cycloalkyl containing 3-8 carbon atoms, hydroxyl, alkylthiol containing 1-6 carbon atoms, alkoxygroup containing 1-6 carbon atoms, benzyloxy, phenoxy, trifluoromethyl, deformation, benzosulfimide, naphthyl, tricyclohexyl containing 7-10 carbon atoms, 1-venilation, 1-imidazolyl, 3-indolium, 2-pyridium, 4-pyridium, 2-oxetanyl, 3-akaranam, 3-methylpiperidino, 4-methylpiperidino, 4-benzylpiperidine, morpholino, 2-oxopyrrolidin-1-yl, 2-Oxymetazoline-1-yl group having the formula-CO2R11,
where R11represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
group having the formula

where R12and R13each represents a hydrogen atom or alkyl containing 1-6 carbon atoms, a group having the formula

where R14and R15each represents a hydrogen atom, alkyl containing 1-6 carbon atoms, phenyl or 4-pyridylcarbonyl, or a group having the formula
-COR16,
where R16represents alkyl containing 1-6 carbon atoms, or phenyl], alkenyl containing 2-8 carbon atoms, which is substituted by phenyl or benzyloxycarbonyl, quinil, content is the seer of 2-8 carbon atoms, which is substituted by phenyl, cycloalkyl containing 3-8 carbon atoms, cycloalkyl containing 3-8 carbon atoms, condensed with a benzene ring, oxiranyl, 4-methylpiperidine or a group of the formula
;
R2represents alkyl containing 1-6 carbon atoms, cycloalkyl containing 3-8 carbon atoms, phenyl or [alkyl containing 1-6 carbon atoms, which is substituted by phenyl, alkoxygroup containing 1-6 carbon atoms, morpholino, piperidino, a group having the formula

where R21represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
or a group having the formula

where R22and R23each represents a hydrogen atom or alkyl containing 1-6 carbon atoms],
R3represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
R4represents a hydrogen atom, alkyl containing 1-6 carbon atoms, benzyl; benzyl substituted by 1-2 groups selected from phenyl, halogen atom, methyl, methoxy, trifloromethyl or hydroxy-group; phenethyl, alkyl containing 1-6 carbon atoms, which is substituted by alkoxygroup containing 1-6 carbon atoms, a halogen atom or a hydroxyl or phenyl, or
R3and R4together form a 3-6-membered saturated hydrocarbon ring, R 5represents a hydrogen atom or alkyl containing 1-6 carbon atoms, and
Y represents a group having the formula

where R6represents alkyl containing 1-10 carbon atoms, alkyl containing 1-10 carbon atoms, which is substituted by 1-5 groups selected from phenyl; phenyl substituted with 1-2 substituents selected from nitro, halogen atom and triptorelin group; cycloalkyl containing 3-8 carbon atoms, halogen atom, naphthyl and pyridyl", "alkenyl containing 2-8 carbon atoms, which is substituted by 1-5 phenyl groups, phenyl, phenyl substituted by 1-5 groups selected from phenyl, phenyl substituted by methoxy group or acetyl group, oxazolyl, pyrazolyl, methylpyrimidine, cyano, the halogen atom, alkyl containing 1-6 carbon atoms, trifloromethyl, cryptometer, dipterocarp, hydroxy-group, alkoxygroup containing 1-6 carbon atoms, cyanoethoxy, fenoxaprop, fenoxaprop substituted by a methoxy group, pyridyloxy, acetyl group, pyridylcarbonyl group, methoxycarbonyl group, methoxycarbonylethyl, nitro, acetamidoxime, sulfamoyl group, methanesulfonyl group, pyrrolidinylcarbonyl group, morpholinomethyl group, methyluridine, butylurea, the method is similaritylookup, trimethylpropyl, morpholinylcarbonyl and pyridinedicarboxylate", naphthyl, naphthyl substituted by dimethylaminopropoxy, heterocyclic group selected from imidazolyl, pyrazolyl, thiazolyl, isoxazolyl, furil, teinila, pyridyl, chinoline, izochinolina, benzofuranyl, benzothiazyl, dihydrobenzofuranyl, coumarinyl, 2,3-dihydrobenzo[1,4]dioxine, 3,4-dihydro-2H-benzo[b][1,4]dioxane, benzo[1,3]dioxolane, 2-oxo-2,3-dihydroisoxazole, benzo[1,2,5]thiadiazolyl, 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazinyl and phthalimidopropyl, or heterocyclic group selected from imidazolyl, pyrazolyl, thiazolyl, isoxazolyl, furil, teinila, pyridyl, chinoline, izochinolina, benzofuranyl, benzothiazyl, dihydrobenzofuranyl, coumarinyl, 2,3-dihydrobenzo[1,4]dioxine, 3,4-dihydro-2H-benzo[b][1,4]dioxane, benzo[1,3]dioxolane, 2-oxo-2,3-dihydroisoxazole, benzo[1,2,5]thiadiazolyl, 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazinyl and phthalimidopropyl, substituted 1-5 substituents selected from a halogen atom, alkyl containing 1-6 carbon atoms, methoxycarbonyl group, ethoxycarbonyl group, benzolsulfonate group and oxazoline group,
except for [connection, where a represents an oxygen atom, and R1is a hydrogen atom], [join, where a represents a sulfur atom, and R 1is a hydrogen atom], [join, where a represents a sulfur atom, and R3and R4each is simultaneously a hydrogen atom], [join, where a represents a sulfur atom, and R2is a phenyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal, and R1is 3-methoxybenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal, and R1is 3-terbisil], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal, and R1is 2-propenyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal, and R1is 4-tert-butylbenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal, and R1the stand is made by methyl], [join, where a represents a sulfur atom, R2is ethyl,
R3and R5each represents a hydrogen atom, R4is stands, R6represents 4-chlorophenyl, and R1represents methyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6represents 4-chlorophenyl, and R1is 2-propenyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6represents 4-chlorophenyl, and R1is 4-methoxybenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6represents 4-chlorophenyl, and R1is 4-tert-butylbenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6represents 4-chlorophenyl, and R1is 3,4-dichlorobenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6represents 4-chlorophenyl, and R1before the hat 2-Chlorobenzyl], [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is stands, R6represents 4-chlorophenyl, and R1is 3-terbisil], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6represents 4-chlorophenyl, and R1is 2-methyl-2-propenyl], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6represents 4-chlorophenyl, and R1is 2-propenyl], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6represents 4-chlorophenyl, and R1is methoxycarbonylmethyl], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6represents 4-chlorophenyl, and R1is 4-trifloromethyl], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6represents 4-lorgeril, and R1is 3,4-dichlorobenzyl], [join, where a represents a sulfur atom, R2is stands, R3and R5each represents a hydrogen atom, R4is benzyl, R6represents 4-chlorophenyl, and R1is 4-bromobenzyl] and [join, where a represents a sulfur atom, R2is ethyl, R3and R5each represents a hydrogen atom, R4is benzyl, R6is 4-forfinal, and R1is 4-methylbenzyl].

5. The compound or its pharmaceutically acceptable salt according to claim 4, where in the formula (I) R5represents a hydrogen atom.

6. The compound or its pharmaceutically acceptable salt according to claim 5, where in the formula (I), a represents an oxygen atom.

7. The compound or its pharmaceutically acceptable salt according to claim 6, where in the formula (I) R2is alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-6 carbon atoms, or alkyl containing 1-4 carbon atoms, which is substituted by a methoxy group or morpholinopropan".

8. The compound or its pharmaceutically acceptable salt according to claim 6, where in the formula (I) R2represents methyl, ethyl, isopropyl or cyclopropyl.

9. The compound or its pharmaceutically acceptable salt according to claim 6, where in the formula (I) R3represents a hydrogen atom.

10. The compound or the pharmaceutically priemysel according to claim 9, where in the formula (I)
R4represents methyl, ethyl, benzyl or benzyl substituted by 1-2 groups selected from phenyl, halogen atom, methyl, methoxy, trifloromethyl or hydroxy-group.

11. The compound or its pharmaceutically acceptable salt according to claim 9, where in the formula (I)
R4represents methyl, benzyl or benzyl, mono - and disubstituted Deputy selected from a halogen atom and methyl".

12. The compound or its pharmaceutically acceptable salt according to claim 11, where in the formula (I) R2represents methyl, ethyl, isopropyl or cyclopropyl.

13. The compound or its pharmaceutically acceptable salt according to claim 9, where in the formula (I)
R1represents alkyl containing 1-6 carbon atoms, alkenyl containing 3-5 carbon atoms,
2-PROPYNYL, cycloalkyl containing 3-6 carbon atoms, or alkyl containing 1-6 carbon atoms, which is substituted by cycloalkyl containing 3-6 carbon atoms, trifluoromethyl, phenyl, hydroxyl, methoxy, dimethylamino or morpholinopropan".

14. The compound or its pharmaceutically acceptable salt according to claim 9, where in the formula (I)
R1represents methyl, ethyl, propyl, isopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl or
3-methoxypropyl.

15. The compound or its pharmaceutically acceptable salt 14, where in the formula (I) R4represents methyl, benzyl or benzyl, mono - and disubstituted by the Deputy selected from a halogen atom and methyl".

16. The compound or its pharmaceutically acceptable salt according to clause 15, where in the formula (I) R2represents methyl, ethyl, isopropyl or cyclopropyl.

17. The compound or its pharmaceutically acceptable salt according to claim 9, where in the formula (I)
R6represents phenyl, phenyl substituted by 1-3 groups selected from a halogen atom, alkyl containing 1-4 carbon atoms, trifloromethyl, alkoxygroup containing 1-6 carbon atoms, triptoreline, deformedarse, acetyl, nitro and cyano", 2-naphthyl, 2-benzothiazyl, 2-benzofuranyl, 2-thienyl, substituted by 1 or 2 halogen atoms, or benzo[1,2,5]thiadiazolyl.

18. The compound or its pharmaceutically acceptable salt according to claim 9, where in the formula (I)
R6represents phenyl, phenyl, substituted
1-2 groups selected from a halogen atom, methyl, trifloromethyl, methoxy, triptoreline", 2-naphthyl, 2-benzothiazyl or 2-benzofuranyl.

19. The compound or its pharmaceutically acceptable salt p, where in the formula (I) R1represents methyl, ethyl, propyl, isopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl or 3-methoxypropyl.

20. The compound or its pharmaceutically acceptable salt according to claim 19, where in the formula (I) R4represents methyl, benzyl or benzyl, mono - and disubstituted Deputy selected from a halogen atom and methyl".

21. The compound Il is its pharmaceutically acceptable salt according to claim 20, where in the formula (I) R2represents methyl, ethyl, isopropyl or cyclopropyl.

22. The compound or its pharmaceutically acceptable salt according to claim 5, where in the formula (I) And represents a sulfur atom, and R3represents a hydrogen atom.

23. The compound or its pharmaceutically acceptable salt according to item 22, where in the formula (I) R2represents methyl, ethyl, isopropyl or cyclopropyl.

24. The compound or its pharmaceutically acceptable salt according to item 22, where in the formula (I) R4represents methyl, benzyl or benzyl, mono - and disubstituted Deputy selected from a halogen atom and methyl".

25. The compound or its pharmaceutically acceptable salt according to paragraph 24, where in the formula (I) R2represents methyl, ethyl, isopropyl or cyclopropyl.

26. The compound or its pharmaceutically acceptable salt according to item 22, where in the formula (I) R1represents alkyl containing 1-6 carbon atoms, alkenyl containing 3-5 carbon atoms, 2-PROPYNYL, cycloalkyl containing 3-6 carbon atoms or alkyl containing 1-6 carbon atoms, which is substituted by cycloalkyl containing 3-6 carbon atoms, trifluoromethyl, phenyl, hydroxyl, methoxy, dimethylamino or morpholinopropan".

27. The compound or its pharmaceutically acceptable salt according to item 22, where in the formula (I) R1represents methyl, ethyl, propyl, isopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl 3-methoxypropyl.

28. The compound or its pharmaceutically acceptable salt according to item 27, where in the formula (I) R4represents methyl, benzyl or benzyl, mono - and disubstituted Deputy selected from a halogen atom and methyl".

29. The compound or its pharmaceutically acceptable salt p, where in the formula (I) R2represents methyl, ethyl, isopropyl or cyclopropyl.

30. The compound or its pharmaceutically acceptable salt according to item 22, where in the formula (I) R6represents phenyl, phenyl substituted with 1-2 groups selected from a halogen atom, methyl, trifloromethyl, methoxy, triptoreline", 2-naphthyl, 2-benzothiazyl or 2-benzofuranyl.

31. The compound or its pharmaceutically acceptable salt according to item 22, where in the formula (I) R1represents methyl, ethyl, propyl, isopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl or
3-methoxypropyl.

32. The compound or its pharmaceutically acceptable salt p, where in the formula (I) R4represents methyl, benzyl or benzyl, mono - and disubstituted Deputy selected from a halogen atom and methyl".

33. The compound or its pharmaceutically acceptable salt p, where in the formula (I) R2represents methyl, ethyl, isopropyl or cyclopropyl.

34. The compound having the following formula (I)or its pharmaceutically acceptable salt

where a represents an oxygen atom is,
R1represents alkyl containing 1 to 16 carbon atoms, alkenyl containing 2-8 carbon atoms, quinil containing 2-8 carbon atoms, [alkyl containing 1-6 carbon atoms, which is substituted phenyl groups, phenyl, substituted by 1-2 groups selected from phenyl, cyano, halogen atom, alkyl containing 1-6 carbon atoms, trifloromethyl, methoxycarbonyl, alkylthio containing 1-6 carbon atoms, dimethylamino, nitro, acetamido, cycloalkyl containing 3-8 carbon atoms, hydroxyl, alkylthiol containing 1-6 carbon atoms, alkoxygroup containing 1-6 carbon atoms, benzyloxy phenoxy, trifluoromethyl, deformation, benzosulfimide, naphthyl, tricyclohexyl containing 7-10 carbon atoms, 1-venilation, 1-imidazolyl, 3-indolium, 2-pyridium, 4-pyridium, 2-oxetanyl, 3-akaranam, 3-methylpiperidino, 4-methylpiperidino, 4-benzylpiperidine, morpholino, 2-oxopyrrolidin-1-yl, 2-Oxymetazoline-1-yl group having the formula
-CO2R11
where R11represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
group having the formula

where R12and R13each represents a hydrogen atom or alkyl containing 1-6 carbon atoms, a group having the formula

where R14and Rsup> 15each represents a hydrogen atom, alkyl containing 1-6 carbon atoms, phenyl or 4-pyridylcarbonyl, or a group having the formula
-COR16,
where R16represents alkyl containing 1-6 carbon atoms, or phenyl], alkenyl containing 2-8 carbon atoms, which is substituted by phenyl or benzyloxycarbonyl, quinil containing 2-8 carbon atoms, which is substituted by phenyl, cycloalkyl containing 3-8 carbon atoms, cycloalkyl containing 3-8 carbon atoms, condensed with a benzene ring, oxiranyl, 4-methylpiperidine or a group of the formula
;
R2represents alkyl containing 1-6 carbon atoms, cycloalkyl containing 3-8 carbon atoms, phenyl or [alkyl containing 1-6 carbon atoms, which is substituted by phenyl, alkoxygroup containing 1-6 carbon atoms, morpholino, piperidino, a group having the formula

where R21represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
or a group having the formula

where R22and R23each represents a hydrogen atom or
alkyl containing 1-6 carbon atoms],
R3represents a hydrogen atom,
R4represents a hydrogen atom, alkyl containing 1-6 carbon atoms, benzyl, benzyl substituted by 1-2 groups selected from Enola, atom of halogen, methyl, methoxy, trifloromethyl or hydroxy-group, phenethyl, alkyl containing 1-6 carbon atoms, which is substituted by alkoxygroup containing 1-6 carbon atoms, a halogen atom or hydroxyl, or phenyl, or
R3and R4together form a 3-6-membered saturated hydrocarbon ring,
R5represents a hydrogen atom, and
Y represents a hydrogen atom.

35. The compound having the following formula (I)or its pharmaceutically acceptable salt

where a represents an oxygen atom,
R1represents alkyl containing 1 to 16 carbon atoms, alkenyl containing 2-8 carbon atoms, quinil containing 2-8 carbon atoms, [alkyl containing 1-6 carbon atoms, which is substituted phenyl groups, phenyl, substituted by 1-2 groups selected from phenyl, cyano, halogen atom, alkyl containing 1-6 carbon atoms, trifloromethyl, methoxycarbonyl, alkylthio containing 1-6 carbon atoms, dimethylamino, nitro, acetamido, cycloalkyl containing 3-8 carbon atoms, hydroxyl, alkylthiol containing 1-6 carbon atoms, alkoxygroup containing 1-6 carbon atoms, benzyloxy, phenoxy, trifluoromethyl, deformation, benzosulfimide, naphthyl, tricyclohexyl containing 7-10 carbon atoms, 1-venilation, 1-imidazolyl, 3-indolium, 2-pyrid the scrap, 4-pyridium, 2-oxetanyl, 3-akaranam, 3-methylpiperidino, 4-methylpiperidino, 4-benzylpiperidine, morpholino, 2-oxopyrrolidin-1-yl, 2-Oxymetazoline-1-yl group having the formula
-CO2R11,
where R11represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
group having the formula

where R12and R13each represents a hydrogen atom or alkyl containing 1-6 carbon atoms, a group having the formula

where R14and R15each represents a hydrogen atom, alkyl containing 1-6 carbon atoms, phenyl or 4-pyridylcarbonyl, or a group having the formula
-COR16,
where R16represents alkyl containing 1-6 carbon atoms, or phenyl], alkenyl containing 2-8 carbon atoms, which is substituted by phenyl or benzyloxycarbonyl, quinil containing 2-8 carbon atoms, which is substituted by phenyl, cycloalkyl containing 3-8 carbon atoms, cycloalkyl containing 3-8 carbon atoms, condensed with a benzene ring, oxiranyl, 4-methylpiperidine or a group of the formula
;
R2is alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-6 carbon atoms or alkyl containing 1-4 carbon atoms, which is substituted by a methoxy group or morphol the but",
R3represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
R4represents a hydrogen atom, alkyl containing 1-6 carbon atoms, benzyl, benzyl substituted by 1-2 groups selected from phenyl, halogen atom, methyl, methoxy, trifloromethyl or hydroxy-group, phenethyl, alkyl containing 1-6 carbon atoms, which is substituted by alkoxygroup containing 1-6 carbon atoms, a halogen atom or hydroxyl, or phenyl, or
R3and R4together form a 3-6-membered saturated hydrocarbon ring,
R5represents a hydrogen atom, and
Y represents a hydrogen atom.

36. The compound or its pharmaceutically acceptable salt p, where in the formula (I) R2represents methyl, ethyl, isopropyl or cyclopropyl.

37. The compound or its pharmaceutically acceptable salt according to clause 34, where in the formula (I) R4represents methyl, benzyl or benzyl, mono - and disubstituted Deputy selected from a halogen atom and methyl, and R2represents methyl, ethyl, isopropyl or cyclopropyl.

38. The compound or its pharmaceutically acceptable salt according to clause 34, where in the formula (I) R1represents alkyl containing 1-6 carbon atoms, alkenyl containing 3-5 carbon atoms, 2-PROPYNYL, cycloalkyl containing 3-6 carbon atoms, or alkyl containing 1-6 carbon atoms, which is substituted cyclol the sludge, containing 3-6 carbon atoms, trifluoromethyl, phenyl, hydroxyl, methoxy, dimethylamino or morpholinopropan".

39. The compound or its pharmaceutically acceptable salt according to clause 34, where in the formula (I) R1represents methyl, ethyl, propyl, isopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl or 3-methoxypropyl.

40. The compound or its pharmaceutically acceptable salt according to § 39, where in the formula (I) R4represents methyl, benzyl or benzyl, mono - and disubstituted Deputy selected from a halogen atom and methyl".

41. The compound or its pharmaceutically acceptable salt p, where in the formula (I) R2represents methyl, ethyl, isopropyl or cyclopropyl.

42. A method of treating autoimmune diseases, such as Crohn's disease, irritable bowel syndrome, Sjogren syndrome, multiple sclerosis or systemic lupus erythematosus, or rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, malignant disease, retinopathy, psoriasis, osteoarthritis and age-related macular degeneration of the retina, the compound of formula (I) or its pharmaceutically acceptable salt

where a represents a sulfur atom, an oxygen atom, a group having the formula-SO-, or a group having the formula-SO2-,
R1represents a hydrogen atom alkyl, containing 1-16 carbon atoms, alkenyl containing 2-8 carbon atoms, quinil containing 2-8 carbon atoms, [alkyl containing 1-6 carbon atoms, which is substituted phenyl groups, phenyl, substituted by 1-5 groups selected from phenyl, cyano, halogen atom, alkyl containing 1-6 carbon atoms, trifloromethyl, methoxycarbonyl, alkylthio containing 1-6 carbon atoms, dimethylamino, nitro, acetamido, cycloalkyl containing 3-8 carbon atoms, hydroxyl, alkylthio containing 1-6 carbon atoms, alkoxy containing 1-6 carbon atoms, benzyloxy, phenoxy, trifluoromethyl, deformation, benzosulfimide, naphthyl, tricyclohexyl containing 7-10 carbon atoms, 1-venilation, imidazolium, indolium, pyridium, oxetanyl, akaranam, methylpiperidino, benzylpiperidine, morpholino, 2-oxopyrrolidin-1-yl, 2-Oxymetazoline-1-yl group having the formula
-CO2R11,
where R11represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
group having the formula

where R12and R13each represents a hydrogen atom or alkyl containing 1-6 carbon atoms, a group having the formula

where R14and R15each represents a hydrogen atom, alkyl containing 1-6 carbon atoms, phenyl is whether 4-pyridylcarbonyl, or a group having the formula
-COR16,
where R16represents alkyl containing 1-6 carbon atoms, or phenyl], alkenyl containing 2-8 carbon atoms, which is substituted by phenyl or benzyloxycarbonyl, quinil containing 2-8 carbon atoms, which is substituted by phenyl, cycloalkyl containing 3-8 carbon atoms, cycloalkyl containing 3-8 carbon atoms, condensed with a benzene ring, oxiranyl, methylpiperidine or a group having the formula
;
R2represents alkyl containing 1-6 carbon atoms, cycloalkyl containing 3-8 carbon atoms, phenyl or [alkyl containing 1-6 carbon atoms, which is substituted by phenyl, alkoxygroup containing 1-6 carbon atoms, morpholino, piperidino, a group having the formula

where R21represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
or a group having the formula

where R22and R23each represents a hydrogen atom or alkyl containing 1-6 carbon atoms],
R3represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
R4represents a hydrogen atom, alkyl containing 1-6 carbon atoms, benzyl, benzyl substituted by 1-2 groups selected from phenyl, halogen atom, methyl, methoxy, trifloromethyl or GI is roxyrama", phenethyl, alkyl containing 1-6 carbon atoms, which is substituted by alkoxygroup containing 1-6 carbon atoms, a halogen atom or hydroxyl, or phenyl, or
R3and R4together form a 3-6-membered saturated hydrocarbon ring, R5represents a hydrogen atom or alkyl containing 1-6 carbon atoms, and
Y represents a group having the formula

where R6represents alkyl containing 1-10 carbon atoms, alkyl containing 1-10 carbon atoms, which is substituted by 1-5 groups selected from phenyl; phenyl substituted with 1-2 substituents selected from nitro, halogen atom and triptorelin group; cycloalkyl containing 3-8 carbon atoms, halogen atom, naphthyl and pyridyl", "alkenyl containing 2-8 carbon atoms, which is substituted by 1-5 phenyl groups, phenyl, phenyl substituted by 1-5 groups selected from phenyl, phenyl substituted by methoxy group or acetyl group, oxazolyl, pyrazolyl, methylpyrimidine, cyano, the halogen atom, alkyl containing 1-6 carbon atoms, trifloromethyl, cryptometer, dipterocarp, hydroxy-group, alkoxygroup containing 1-6 carbon atoms, cyanoethoxy, fenoxaprop, fenoxaprop substituted by a methoxy group, pyridyloxy, acetyl group, pyridylcarbonyl GRU is dust, methoxycarbonyl group, methoxycarbonylethyl, nitro, acetamidoxime, sulfamoyl group, methanesulfonyl group, pyrrolidinylcarbonyl group, morpholinomethyl group, methyluridine, butylurea, methoxyethylmercury, trimethylurea, morpholinylcarbonyl and pyridinedicarboxylate", naphthyl, naphthyl substituted by dimethylaminopropoxy, heterocyclic group selected from imidazolyl, pyrazolyl, thiazolyl, isoxazolyl, furil, teinila, pyridyl, chinoline, izochinolina, benzofuranyl, benzothiazyl, dihydrobenzofuranyl, coumarinyl, 2,3-dihydrobenzo[1,4]dioxine, 3,4-dihydro-2H-benzo[b][1,4]dioxane, benzo[1,3]dioxole, 2-oxo-2,3-dihydroisoxazole, benzo[1,2,5]thiadiazolyl, 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazinyl and phthalimidopropyl, or heterocyclic group selected from imidazolyl, pyrazolyl, thiazolyl, isoxazolyl, furil, teinila, pyridyl, chinoline, izochinolina, benzofuranyl, benzothiazyl, dihydrobenzofuranyl, coumarinyl, 2,3-dihydrobenzo[1,4]dioxine, 3,4-dihydro-2H-benzo[b][1,4]dioxane, benzo[1,3]dioxolane, 2-oxo-2,3-dihydroisoxazole, benzo[1,2,5]thiadiazolyl, 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazinyl and phthalimidopropyl, substituted by 1-5 substituents selected from a halogen atom, alkyl containing 1-6 atoms ug is erode, methoxycarbonyl group, ethoxycarbonyl group, benzolsulfonate group and oxazoline group.

43. The use of the following compounds of formula (I) or its pharmaceutically acceptable salt to obtain funds for the treatment of autoimmune diseases, such as Crohn's disease, irritable bowel syndrome, Sjogren syndrome, multiple sclerosis or systemic lupus erythematosus, or rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, malignant disease, retinopathy, psoriasis, osteoarthritis and age-related macular degeneration of the retina,

where a represents a sulfur atom, an oxygen atom, a group having the formula-SO-, or a group having the formula-SO2-,
R1represents a hydrogen atom, alkyl containing 1 to 16 carbon atoms, alkenyl containing 2-8 carbon atoms, quinil containing 2-8 carbon atoms, [alkyl containing 1-6 carbon atoms, which is substituted phenyl groups, phenyl, substituted by 1-5 groups selected from phenyl, cyano, halogen atom, alkyl containing 1-6 carbon atoms, trifloromethyl, methoxycarbonyl, alkylthio containing 1-6 carbon atoms, dimethylamino, nitro, acetamido, cycloalkyl containing 3-8 carbon atoms, hydroxyl, alkylthio containing 1-6 atoms in which laroda, alkoxy containing 1-6 carbon atoms, benzyloxy, phenoxy, trifluoromethyl, deformation, benzosulfimide, naphthyl, tricyclohexyl containing 7-10 carbon atoms, 1-venilation, imidazolium, indolium, pyridium, oxetanyl, akaranam, methylpiperidino, benzylpiperidine, morpholino, 2-oxopyrrolidin-1-yl, 2-Oxymetazoline-1-yl group having the formula
-CO2R11,
where R11represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
group having the formula

where R12and R13each represents a hydrogen atom or alkyl containing 1-6 carbon atoms, a group having the formula

where R14and R15each represents a hydrogen atom, alkyl containing 1-6 carbon atoms, phenyl or 4-pyridylcarbonyl, or a group having the formula
-COR16,
where R16represents alkyl containing 1-6 carbon atoms, or phenyl], alkenyl containing 2-8 carbon atoms, which is substituted by phenyl or benzyloxycarbonyl, quinil containing 2-8 carbon atoms, which is substituted by phenyl, cycloalkyl containing 3-8 carbon atoms, cycloalkyl containing 3-8 carbon atoms, condensed with a benzene ring, oxiranyl, methylpiperidine or a group having the formula
; R2represents alkyl containing 1-6 carbon atoms, cycloalkyl containing 3-8 carbon atoms, phenyl or [alkyl containing 1-6 carbon atoms, which is substituted by phenyl, alkoxygroup containing 1-6 carbon atoms, morpholino, piperidino, a group having the formula

where R21represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
or a group having the formula

where R22and R23each represents a hydrogen atom or alkyl containing 1-6 carbon atoms],
R3represents a hydrogen atom or alkyl containing 1-6 carbon atoms,
R4represents a hydrogen atom, alkyl containing 1-6 carbon atoms, benzyl, benzyl substituted by 1-2 groups selected from phenyl, halogen atom, methyl, methoxy, trifloromethyl or hydroxy-group, phenethyl, alkyl containing 1-6 carbon atoms, which is substituted by alkoxygroup containing 1-6 carbon atoms, a halogen atom or hydroxyl, or phenyl, or
R3and R4together form a 3-6-membered saturated hydrocarbon ring,
R5represents a hydrogen atom or alkyl containing 1-6 carbon atoms, and
Y represents a group having the formula

where R6represents alkyl containing 1-10 carbon atoms, alkyl with is containing a series of 1-10 carbon atoms, which is substituted by 1-5 groups selected from phenyl; phenyl substituted with 1-2 substituents selected from nitro, halogen atom and triptorelin group; cycloalkyl containing 3-8 carbon atoms, halogen atom, naphthyl and pyridyl", "alkenyl containing 2-8 carbon atoms, which is substituted by 1-5 phenyl groups, phenyl, phenyl substituted by 1-5 groups selected from phenyl, phenyl substituted by methoxy group or acetyl group, oxazolyl, pyrazolyl, methylpyrimidine, cyano, halogen atom, alkyl containing 1-6 carbon atoms, trifloromethyl, cryptometer, dipterocarp, hydroxy-group, alkoxygroup containing 1-6 carbon atoms, cyanoethoxy, fenoxaprop, fenoxaprop substituted by a methoxy group, pyridyloxy, acetyl group, pyridylcarbonyl group, methoxycarbonyl group, methoxycarbonylethyl, nitro, acetamidoxime, sulfamoyl group, methanesulfonyl group, pyrrolidinylcarbonyl group, morpholinomethyl group, methyluridine, butylurea, methoxyethylmercury, trimethylurea, morpholinylcarbonyl and pyridinedicarboxylate", naphthyl, naphthyl substituted by dimethylaminopropoxy, heterocyclic group selected from imidazolyl, pyrazolyl, thiazolyl, isoxazolyl is, Furie, teinila, pyridyl, chinoline, izochinolina, benzofuranyl, benzothiazyl, dihydrobenzofuranyl, coumarinyl, 2,3-dihydrobenzo[1,4]dioxine, 3,4-dihydro-2H-benzo[b][1,4]dioxane, benzo[1,3]dioxolane, 2-oxo-2,3-dihydroisoxazole, benzo[1,2,5]thiadiazolyl, 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazinyl and phthalimidopropyl, or heterocyclic group selected from imidazolyl, pyrazolyl, thiazolyl, isoxazolyl, furil, teinila, pyridyl, chinoline, izochinolina, benzofuranyl, benzothiazyl, dihydrobenzofuranyl, coumarinyl, 2,3-dihydrobenzo[1,4]dioxine, 3,4-dihydro-2H-benzo[b][1,4]dioxane, benzo[1,3]dioxolane, 2-oxo-2,3-dihydroisoxazole, benzo[1,2,5]thiadiazolyl, 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazinyl and phthalimidopropyl, substituted by 1-5 substituents selected from a halogen atom, alkyl containing 1-6 carbon atoms, methoxycarbonyl group, ethoxycarbonyl group, benzolsulfonate group and oxazoline group.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I: where A,Y,R and R2 assume values given in the description. The invention also relates to methods of producing compounds of formula I and their intermediate compounds, pharmaceutical compositions and methods of using the compounds and their pharmaceutical compositions for inhibiting caspase.

EFFECT: novel compounds have useful biological properties.

44 cl, 5 tbl, 66 ex

FIELD: chemistry.

SUBSTANCE: novel compound is N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or its pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with CFTR activity modulation properties.

2 cl, 485 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) which are protein tyrosine kinase 1B(PTP-1B) inhibitors and can be used in medicinal preparations for treating and preventing diseases related to high concentration of glucose in blood, for example diabetes and obesity. In formula (I) X is a X-1 group or X-2: , where R1 and R2 are each independently selected from a group consisting of hydrogen, lower alkyl, alkoxy-lower alkyl and hydroxyl-lower alkyl, under the condition that, R1 and R2 both represent hydrogen; R3, R4, R6 and R7 are each independently selected from a group consisting of hydrogen, lower alkyl; lower alkyl substituted with halogen or hydroxy; lower alkoxy; lower alkoxy substituted with halogen, hydroxy or lower alkoxy; hydroxyl, halogen, lower alkylthio, lower alkylsufanyl, lower alkylsufanyl, aminosufonyl, cyano, nitro, carbamoyl, lower mono- or dialkylcarbamoyl, lower alkanoyl, benzoyl, phenyl, phenyl substituted with halogen, phenyloxy, lower mono- or dialkylamino, hydroxy-substituted lower alkylamino, lower alkanoylamino, lower alkylsulfonylamino, heterocycloalkyl, hydroxy-substituted heterocycloalkyl, heterocyclyloxy, heterocyclylcarbonyl; where each heterocycloalkyl in the said values represents a 5-6-membr ring containing 1-2 heteroatoms selected from nitrogen and oxygen, and which can be substituted with lower alkyl or phenyl-lower alkyl; carboxyl, lower alkoxycarbonyl and a substitute of formula: ; R8 is selected from a group consisting of hydrogen, lower alkylthio, halogen, alkoxy-lower alkoxy, lower alkoxy, halogen-lower alkyl, hydroxy-lower alkyl; represents a 5-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of hydrogen, sulphur and nitrogen; R8 and R9 each independently represents hydrogen or lower alkyl.

EFFECT: novel compounds have useful biological properties.

31 cl, 7 dwg, 152 ex

FIELD: chemistry.

SUBSTANCE: invention proposes 5-member heterocyclic inhibitors of kinase p38, including kinase p38α and kinase p38β, based on pyrazoles and imidazoles, with the general formula given below , in which ring B is phenyl, and C is a pyrazole or imidazole ring, and the rest of the symbols assume values given in paragraph 1 of the formula of invention.

EFFECT: there are described pharmaceutical compositions containing said compounds, as well as methods of using the compounds and compositions, including a method of treating, preventing or suppressing one or more symptoms of diseases and conditions mediated by kinase p38 which include, but not limited to, inflammatory diseases and conditions.

31 cl, 6 tbl, 175 ex

FIELD: chemistry.

SUBSTANCE: proposed phosphodiesterase 4 inhibitors are characterised by formulae II, III, V, VI, where X is CH or N; L is a single bond, -(CH2)nCONH-, -(CH2)nCON(CH2CH3)-, (CH2)nSO2, (CH2)nCO2 or alkylene, optionally substituted oxo or hydroxy; n assumes values from 0 to 3; R1 is optionally substituted alkyl; R3 - H, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted phenyl, phenylalkyl, heterocyclyl, heterocyclylalkyl or cycloalkylalkyl; R4 and R5 represent alkyl; R6 - cycloalkyl, R7 is H; R8 is H, carboxy, alkoxycarbonyl, -CO-alkyl, optionally substituted alkyl.

EFFECT: new phosphodiesterase 4 inhibitors have improved properties.

55 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel sulphonamide derivatives of general formula (I) , where R1 is phenyl, thiophenyl or furanyl, unsubstituted or substituted with one or two substitutes selected from a group consisting of halogen, lower alkyl, lower alkyl substituted with halogen, -O-lower alkyl substituted with halogen, NO2 or CN; R2-R4 and R2'-R4' is hydrogen, lower alkyl, phenyl or lower alkyl substituted with halogen; R5 is phenyl, pyridinyl, benzo[1,3]dioxolyl or benzofuranyl, unsubstituted or substituted with 1-3 substitutes selected from a group consisting of halogen, lower alkyl, lower alkyloxy, CN, nitro, amino, hydroxy, lower alkyl substituted with hydroxy, lower alkyl substituted with halogen, or substituted with -C(O)-NR"2, -(CR2)m-C(O)-R', -(CH2)m-heteroaryl, unsubstituted or monosubstituted -(CH2)m-lower alkoxy, lower alkyl, -(CH2)m-O-benzene or CH2OH, -O-C(O)-lower alkyl, -O-C(O)-NR2, -O-(CH2)m-C(O)OH, -O-lower alkynyl, -O-lower alkyl, substituted with halogen, -O-(CH2)m-heterocyclyl, -O-(CH2)m-phenyl, unsubstituted or monosubstituted hydroxy, -O-(CH2)m-heteroaryl, unsubstituted or monosubstituted with lower alkyl, -(CH2)m-NH-C(O)R', -(CH2)m-NH-S(O)2-R', -S(O)2-lower alkyl, -S(O)2-heterocyclyl, -S(O)2NH-cycloalkyl, or is C3-6cycloalkyl; R' is hydrogen, lower alkyl, lower alkynyloxy, hydroxy, C3-6cycloalkyl, heterocyclyl, which is unsubstituted or substituted with one or two substitutes selected from COOH, -C(O)O-lower alkyl, halogen or lower alkyl, or is phenyl, benzyl, heteroaryl, -(CH2)m-lower alkoxy or -(CHR)m-C(O)O-lower alkyl; R" is hydrogen, C3-6cycloalkyl, which is unsubstituted or substituted with one or two substitutes selected from halogen, or is lower alkyl, lower alkyl substituted with halogen, lower alkyl substituted with hydroxy, -(CH2)m-heterocyclyl, -NR2, heteroaryl, benzyl or -(CHR)m-C(O)O-lower alkyl; R is hydrogen or lower alkyl; X is -CHR-; m equals 0, 1, 2 or 3; and its pharmaceutically acceptable salts of an acid compound, optically pure enantiomers, racemates or diastereomeric mixtures. The invention also relates to medicine containing a formula I compound.

EFFECT: obtaining novel compounds which inhibit γ-secretase.

16 cl, 230 ex

FIELD: medicine.

SUBSTANCE: invention relates to 2,4-pyrimidindiamins, such as N4-(4-Chlorine-3-methoxyphenyl)-5-fluorine-N2-[3-(N-ethylamino)carbonylmethylenoxyphenyl]-2,4-pyrimidindiamin, N4-(3-Chlorine-4-methjopxycarbonylmethylenoxyphenyl)-5-fluorine- N2-[3-(N-methylamino)carbonylmethylenoxyphenyl]-2,4-pyrimidindiamin, N4-[3-Chlorine-4-(N-methylamino)carbonylmethylenoxyphenyl]-5-fluorine-N2-[3-(]N methylamino)carbonylmethylenoxyphenyl]- 2,4-pyrimidindiamin, N4-[3-Chlorine-4-(2-hydroxyethylenoxy)phenyl]-5-fluorine-N2-[3-(N- methylamino)carbonylmethylenoxyphenyl]- 2,4-pyrimidindiamin and other compounds given in item 1 of claimed invention as Syk-kinase inhibitors, as well as to based on them pharmaceutical composition and their application.

EFFECT: claimed compounds can be applied for treatment of autoimmune diseases, systemic http://lingvo.yandex.ru/?text=lupus%20erythematosus, rheumatoid arthritis, etc.

12 cl, 27 dwg, 11 tbl, 1797 ex

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of formula (I): , in which: Ra and Ra', identical or different, mean atom of hydrogen or alkyl, R1 means atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl or aryl, R2 means group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which, x = 0, 1, 2, 3 or 4, y = 0 or 1, Y means atom of hydrogen or the following group: hydroxyl, alkyl, cycloalkyl, alkyloxyl, aryl, heteroaryl or -NR11R12, besides, Y is not an atom of hydrogen, when x=y=0, R11 and R12, identical or different, mean atom of hydrogen or the following group: alkyl, cycloalkyl, alkyloxyl or -NR13R14, or R11 and R12 together with atom of nitrogen, to which they are connected, create mono- or bicyclic structure, which contains 4-10 links and unnecessarily contain additionally 1-3 heteroatoms and/or 1-3 ethylene unsaturated links, besides this cycle is not necessarily substituted in any of positions with 1-3 groups, selected from atoms of halogen and hydroxyl, alkyl, cycloalkyl and alkyloxygroups; R13 and R14, identical or different, mean atom of hydrogen or alkyl, R3 means 1-3 groups, identical or different, available in any position of cyclic structure, to which they are connected, and selected from atoms of halogen; R5 means atom of hydrogen, R4 is selected from groups of formulae (a), (b), (c), which are not necessarily substituted with aryl group, described below: (a), (b), (c), in which p=0,1,2 or 3; m=0,1 or 2, and either a) X means link -N(R10)-, in which R10 is selected from: -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, - or R10 with atom of nitrogen, with which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not with neighboring to mentioned atom of nitrogen, creates bridge, containing 3-5 links, or, b) X means link -C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0,1,2,3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocycloalkyl, condensed with aryl, besides, alkyl, cycloalkyl or aryl groups are not necessarily substituted with 1 or several groups, selected from groups: R, R', -OR, -NRR', -COR; R7 is selected from atoms of hydrogen and halogen and the following groups: alkyls, -OR, -NRR', -NR-CO-R', -NR-COOR', -R8 and R9 are selected, independently from each other, from atom of hydrogen and the following groups: alkyls, cycloalkyls, aryls, -CO-alkyls, besides, alkyls and aryls are unnecessarily substituted with one or several groups, selected from groups: R, R', -OR, or R8 and R9 together create heterocycloalkyl,- R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, besides, mentioned hetero aryl groups represent aromatic groups, including from 5 to 10 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen and/or sulfur; besides mentioned heterocycloalkyl groups represent cycloalkyl groups, including from 5 to 6 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (VI), (XVIII), (XIX).

EFFECT: new biologically active compounds have activity of agonists of melanocortin receptors.

27 cl, 16 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of common formula IC1: , where A represents cyano; B represents hydrogen; R1, R2, R3 and R4 independently represent hydrogen; alkyl; halogen or nitro; R5 and R6 independently represent hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; heteroaryl; heteroarylalkyl; alkenyl; carboxyalkyl; cyanoalkyl; diphenylalkyl; aryl, arylalkoxyaryl, arylalkyl, arylalkylaryl, arylcarbonylaryl or aryloxyaryl, or R5 and R6, together with atom of nitrogen, to which they are connected, create heterocyclic ring system; or to salts of such compound; at the same time "heteroaryl" used separately or in combination, is related to mono-, bi- or tricyclic aromatic ring system, which contains up to 14 atoms included in ring, in which at least one ring contains at least one heteroatom, independently chosen from nitrogen, oxygen or sulfur, besides specified heteroaryl group may be unsubstituted or substituted with one to three substituents, independently selected from alkyl and alkoxy; "diphenylalkyl" is related to alkyl group, where each of two atoms of hydrogen is substituted with unsubstituted phenyl group; "aryl" is related to carbocyclic group, selected from group, which consists of phenyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, antryl, phenantryl, fluorenyl, indanyl, 2,3-dihydrobenzo[1,4]dioxynyl and benzo[1,3]dioxolyl group, besides specified aryl group may be unnecessarily substituted with functional groups in number from one to three, which are separately and independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, cyano, halogen, halogenlkoxy, halogenalkyl and nitro groups, where in certain specific cases, if aryl group represents condensed system from several rings, in which not all the rings are aromatic, one of carbon atoms of which is not included into aromatic ring may be in oxidised condition, and according fragment of ring -CH2- will be substituted by fragment-C(O); "arylalkoxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkoxygroup, where aryl group is unsubstituted; "arylalkyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkyl group, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "aryloxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via oxygen bridge, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "arylcarbonyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via carbonyl group, where aryl group is unsubstituted; "heterocyclic ring system", used separately or in combination, is related to monocyclic, bicyclic or polycyclic ring system, which contains up to 15 atoms included into ring, at least one of which represents heteroatom, independently selected from nitrogen, oxygen or sulfur, besides specified ring system may be saturated, partially unsaturated, unsaturated or aromatic, where specified heterocyclic fragment may be unnecessarily substituted with one or more substituents, every of which separately and independently is selected from group made of halogen and halogenalkyl, excluding the following compounds: {3-[(E)-2-cyano-2-(4-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-m-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(3-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-phenylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-benzylcarbamoyl-2-cyanovinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-o-tolylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-t-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(4-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-ethylphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2~cyano-2-(4- ethoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-isopropylcarbamoylvinyl)indole-1-yl]acetic acid; {3-[(E)-2-cyano-2-(3-etoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-[[2-(1H-indole-3-yl)ethyl]amino]-3-oxo-1-propenyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-chlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-(4-methyl-piperidine-1-yl)-3-oxopropenyl]indole-1-yl}acetic acid; {3-[(E)-2-(3-chloro-4-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(3-phenylpropylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2,3-dichlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-(5-chloro-2-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxybenzylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; and {3-[(E)-2-cyano-3-oxo-3-(4-phenyl-piperazine-1-yl)propenyl]indole-1-yl}acetic acid. Invention is also related to pharmaceutical composition, and also to application of compounds of clause 1.

EFFECT: production of biologically active compounds, which have activity of antagonist coupled with G-protein of chemoattractant receptor of molecules homologue released by Th2-cells.

11 cl, 156 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I: where A,Y,R and R2 assume values given in the description. The invention also relates to methods of producing compounds of formula I and their intermediate compounds, pharmaceutical compositions and methods of using the compounds and their pharmaceutical compositions for inhibiting caspase.

EFFECT: novel compounds have useful biological properties.

44 cl, 5 tbl, 66 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula , where X, R1, R2, R3, R4 and R5 assume values given in the description and paragraphs of the formula of invention, and their pharmaceutically acceptable salts.

EFFECT: compounds have antagonistic activity on histamine receptor 3 (H3).

25 cl, 3 tbl, 215 ex

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: chemistry.

SUBSTANCE: described are piperazine indoles of general formula , in which R1 represents 2-indanyl, R2 represents 1-methylpropyl, R3 and R4 together with nitrogen atoms to which they are bonded represent a morpholino group, and pharmaceutically acceptable salts thereof. Also described is a pharmaceutical composition based on formula (I) compound.

EFFECT: compounds have antagonistic effect on oxytocin receptor.

6 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts which have inhibitory properties towards mGluR5. In formula I , P represents phenyl; R1 is bonded to P through a carbon atom on ring P and is selected from a group consisting of halogen, C1-6alkylhalogen, OC1-6alkylhalogen, C1-6alkyl, OC1-6alkyl and C0-6alkylcyano; X1 is selected from a group consisting of N, NR4 and CR4; X2 is selected from a group consisting of C and N; X3 is selected from a group consisting of N and O; X4 is selected from a group consisting of N and O; X5 is selected from a group consisting of a bond, CR4R4', NR4, O, S, SO, SO2; X6 represents N; X7 is selected from a group consisting of C and N; Q represents triazolyl.

EFFECT: invention also relates to a pharmaceutical composition containing a therapeutically effective amount of the disclosed compound as an active ingredient, use of the compound in making a medicinal agent for treating disorders mediated by mGluR5 and to a method of inhibiting activation of mGluR5 receptors.

25 cl, 82 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to piperidine-amino-benzidazoles having formula (I) and to addition salts or stereochemically isomeric forms, where Q is C1-6alkyl optionally substituted with one or two substitutes, each independently selected from a group consisting of trifluoromethyl, C3-7cycloalkyl, Ar2, hydroxyl, Ar2 - oxy-, hydroxycarbonyl, aminocarbonyl, C1-4alkylcarbonyl, aminocarbonyloxy, C1-4alkoxycarbonyl, Ar2(CH2)ncarbonyloxy, C1-4alkoxycarbonyl-(CH2)noxy, mono- or di(C1-4alkyl)aminocarbonyl, aminosulfonyl, mono(C1-4alkyl)aminosulfonyl, or heterocycle selected from a group consisting of pyrrolidinyl, dihydropyrrolyl, imidazolyl, triazolyl, homopiperidinyl, pyridyl and tetrahydropyridyl; or where Q is C1-6alkyl substituted with two substitutes, where substitute is an amino group and the other is C1-6alkyloxycarbonyl; G is -CH2-; R1 is pyridyl optionally substituted with two substitutes selected from a group consisting of hydroxyl, C1-6alkyl; each n equals 1; one of R2a and R3a is C1-6alkyl and the other is hydrogen; when R2a is not hydrogen, R2b is C1-6alkyl and R3b is alkyl; and R3a, R2a, R2b all represent hydrogen; or R5 is hydrogen; t equals 2; Ar2 is phenyl or phenyl substituted with one or more, for example 2 substitutes selected from halogen, C1-6alkyloxy, aminosulfonyl and C1-4alkoxycarbonyl. The invention also relates to a pharmaceutical composition based on compound of formula I and use of the said compounds in making medicinal agents.

EFFECT: novel piperadine-amino-benzimidazoles are obtained, having inhibitory effect on respiratory syncytial virus replication.

10 cl, 3 tbl, 5 ex

Pyrazoles // 2381217

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where one of R1 and R2 is hydrogen or alkyl, and the other is (CH2)PY, where p=0 or 1, Y is a saturated mono-, bi- or tricyclic 5-10-member cycloalkyl ring optionally substituted with alkyl, or R1 and R2 together with N form a 7-10-member saturated bicyclic ring Z, optionally substituted with halogen, or a 5-7-member monocyclic ring Z, optionally substituted with alkyl, phenyl, phenylalkyl or pyridinyl; R3 is [2,2']bithiophenyl, 1-methylindole, 2,3-dihydrobenzo[1,4]dioxin, benzo[1,3]dioxole, benzothiophene, dibenzofuran, furan, naphthalene, quinoline, thianthrene, thiophene or pyrrole, or biphenyl substituted with halogen, or phenyl optionally substituted with one or more amino, cyano, formyls, halogens, hydroxyl, hydroxymethyls, acyls, acylamino, alkoxy, nitro, trifluoromethoxy, trifluoromethyls, phenoxy or benzyloxy, or R3 is a group, where Ar is phenyl substituted with halogen; and R4 is alkyl; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition with inhibitory activity towards the 11β-hydroxysteroid dehydrogenase1 (11(β-HSD1) enzyme.

EFFECT: pyrazole composition is disclosed.

22 cl, 1 tbl, 116 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to derivatives of substituted pyridazinylamine of formula or to their pharmaceutically acceptable salts or hydrates, where X is C or N; Y is O or S; W is C or N; R1, R2, R3 each independently represents hydrogen or halogen; R4, R5, R6 each independently represents hydrogen, halogen, C1-C8-straight or branched alkyl, C1-C8-straight or branched alkoxy, nitro, cyano, -COOR7, -CH2COOR7, -COR7; R7 independently represents hydrogen or C1-C8-straight or branched alkyl. The invention also relates to a method of producing said compounds, to pharmaceutical compositions containing said compounds and to use of the said compounds as picornavirus inhibitors for preventing and/or treating diseases caused by pircornaviruses.

EFFECT: novel compounds have useful biological properties.

10 cl, 1 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of formula (I) or to salts thereof: , where R1 is a hydrogen atom, amino group, R11-NH-, where R11 is a C1-6alkyl group, hydroxy-C1-6alkyl group, C1-6alkoxycarbonyl-C1-6alkyl group, R12-(CO)-NH-, where R12 is a C1-6alkyl group or C1-6alkoxy-C1-6alkyl group, C1-6alkyl group, hydroxy-C1-6-alkyl group, C1-6alkoxy group or C1-6alkoxy-C1-6alkyl group; R2 is a hydrogen atom, C1-6alkyl group, amino group or di-C1-6alkylamino group; one of X and Y represents a nitrogen atom, while the other represents a nitrogen or oxygen atom; ring A is a 5- or 6-member heteroaryl ring or benzene ring which can have 1 or 2 halogen atoms; Z is a single bond, methylene group, ethylene group, oxygen atom, sulphur atom, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S- or -SCH2-; R3 is hydrogen or a halogen atom, or C1-6alkyl group, C3-8cycloalkyl group, C6-10aryl group, 5- or 6-member heteroaryl group, where these groups can have 1 or 2 substitutes selected from a group of α substitutes: and [group of α substitutes] group of α substitutes is a group consisting of a halogen atom, cyano group, C1-6alkyl group, C1-6alkoxy group, C1-6alkoxycarbonyl group, C3-8cycloalkyl group, C1-6alkenyl group and C1-6alkynyl group; R4 is a hydrogen atom or halogen atom; except compounds in which all of R1, R2 and R4 represent a hydrogen atom while Z represents a single bond or R3 is a hydrogen atom; as well as a pharmaceutical composition and a medicinal agent with antifungal activity, based on these compounds, to an antifungal agent and use of formula I compounds for preparing an antifungal agent.

EFFECT: novel compounds with excellent antifungal effect are obtained and described.

36 cl, 228 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

where R1 is hydrogen, alkyl, cycloalkyl, hydroxy group, hydroxyalkyl, alkoxy group, alkoxyalkyl, aminoalkyl, aryl, heterocyclyl, alkylsulfonyl, alkylsulfanyl, alkylcarbonylalkyl, alkylcarbonyloxyalkyl, aminocarbonylalkyl, heterocyclylcarbonylalkyl, alkoxycarbonylalkyl, alkoxyalkylaminocarbonylalkyl, cycloalkylalkoxyalkyl, arylalkyloxyalkyl, aryloxyalkyl, haloidalkyl, haloidalkoxy group or haloidalkoxyalkyl, R2 is hydrogen, alkyl, cycloalkylalkoxyalkyl, alkoxyalkyl, arylalkoxyalkyl, haloidalkoxyalkyl, pyrrolidyl, morpholinyl, thiomorpholinyl, arylalkyl, arylalkoxy group, aryloxy group or heterocyclylalkyl, R3 is hydrogen or alkyl, R4 is hydrogen, alkyl or haloid, R5 is phenyl, naphthyl, piperidyl or 1,2,3,4-tetrahydroisoquinolinyl optionally substituted with one or more substitutes independently selected from alkyl, cycloalkyl, haloid, alkoxy group, nitro group, trifluoromethyl, trifluoromethoxy group, trifluoromethylcarbonyl group, aryl, aryloxy group, alkoxycarbonylalkoxy group and alkylsulfonyl, R6 is hydrogen or alkyl, and their pharmaceutically acceptable salts and esters, under the condition that N-(6-(1,1-dimethylethyl)-2-pyridinyl)-4-methylbenzenesulfamide is excluded, and in cases when R1 is hydrogen or methyl, R2 is not hydrogen or methyl, as well as a pharceutical composition based on these compounds.

EFFECT: novel chemical compounds which can be used in treating and preventing diabetes, obesity and eating disorders are obtained and described.

15 cl, 192 ex

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