Substituted arylsulfonamides as antiviral agents

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I) in which A means a group of formula or in which * specifies a carbon atom binding site of a pyridinyl ring, and # specifies the a carbon atom binding site of a phenyl ring, R1 means an amino group or a methyl-carbonylamino group, R2 means hydrogen, R3 means hydrogen, R4 means hydrogen, R5 means hydrogen or halogen, R6 means hydrogen or halogen, R7 means hydrogen, R8 means hydrogen, or one of its salts, its solvate or solvate of its salts, to a method of preparing it, to an agent for treatment and/or prevention of viral infections, on the basis of this compound. Also, the invention refers to the application of the compound of formula I for preparing the agent and to the method of viral infection control.

EFFECT: new arylsulfonamides which can are effective as antiviral agents, preferentially for cytomegalovirus control are prepared and described.

9 cl, 5 ex, 2 tbl, 1 dwg

 

The present invention relates to substituted arylsulfonamides and to methods for their preparation and to their use for the preparation of drugs intended for the treatment and/or prophylaxis of diseases, especially for use as antiviral agents, preferably for combating cytomegaloviruses.

In WO 02/085869 described substituted arylsulfonamides as relapsing and antiviral means, particularly to combat cytomegaloviruses.

One object of the present invention are new compounds with the same or greater antiviral activity, improved pharmacokinetics, particularly long half-life and/or improved availability when administered orally, the way metabolic decomposition for people and common laboratory animals such as rats and dogs, not significantly different, intended for the treatment of viral infectious diseases in humans and animals.

According to the invention it has been unexpectedly found that substituted arylsulfonamides described in this invention possess antiviral activity, have improved pharmacokinetic characteristics and the ways of their metabolic decomposition in humans, rats and dogs was not significantly different.

The present invention apply the to compounds of the formula

in which

But denotes a group of the formula

in which

* indicates the site of bonding with the carbon atom pyridinoline rings, and

# specifies the location of the binding carbon atom of the phenyl ring,

R1denotes hydrogen, an amino group or medicalbilling,

R2denotes hydrogen or halogen,

R3denotes hydrogen, halogen or cyano,

R4denotes hydrogen, halogen or cyano,

R5denotes hydrogen or halogen,

R6denotes hydrogen or halogen,

R7denotes hydrogen, halogen or C1-C3-alkyl,

R8denotes hydrogen, halogen or C1-C3-alkyl,

and their salts, solvate and to solvate their salts.

Connections proposed in the present invention, are compounds of formula (I) and their salts, solvate and solvate salts; as well as compounds shown below as a typical variant (variants) and described by formula (I) and (Ia)and their salts of the solvate and the solvate salts, unless the connections shown below and described by formula (I)are not already salts, solvate and solvate salts.

Connections proposed in the present invention, depending on the patterns may exist in stereoisomeric forms (enantiomers, diastereoisomer). In accordance with this present invention relates to the enantiomers or diastereoisomers and their respective mixtures. From such mixtures of enantiomers and/or diastereoisomers by known methods can be distinguished stereoisomers pure components.

If the connections proposed in the present invention may exist in tautomeric forms, the present invention includes all such tautomeric forms.

Salts, preferable to the objectives of the present invention are physiologically acceptable salts of the compounds proposed in the present invention. However, the scope of the present invention is enabled and salt, which are not suitable for use in pharmaceuticals but which can be used, for example, for the isolation or purification of compounds proposed in the present invention.

Physiologically acceptable salts of the compounds proposed in the present invention include the salts of the accession of inorganic acids, carboxylic acids and sulphonic acids, e.g. salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, econsultancy acid, toluensulfonate acid, benzosulfimide acid, naphthalenedisulfonic acid, acetic acid, triperoxonane acid, propional the th acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds proposed in this invention also include salts of customary bases, such as, for example and preferably, alkali metal salts (e.g. sodium and potassium salts), salts of alkaline earth metals (e.g. calcium salts and magnesium), and ammonium salts, derived from ammonia or organic amines containing from 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiethanolamine, monoethanolamine, diethanolamine, triethanolamine, dichlorohexane, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, Ethylenediamine and N-methylpiperidin.

A solvate, for the objectives of the present invention, means such forms of the compounds proposed in the present invention, in which solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a special form of a solvate, in which coordination takes place with water.

In addition, the present invention also relates to prodrugs of the compounds proposed in the present invention. The term "prodrugs" includes compounds which may themselves be biologically active or not is active, but during the presence in the body into compounds proposed in the present invention (for example, due to metabolism or hydrolysis).

For the objectives of the present invention, unless otherwise specified, the substituents have the following values.

Alkyl means a linear or branched alkyl radical, typically containing from 1 to 3, particularly preferably from 1 to 2, carbon atoms, for example and preferably methyl, ethyl, n-propyl and isopropyl.

Halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

In the formula group, which can be And end points of adjacent segments that are icons * or #, do not denote a carbon atom and not a group of CH2and lots of links with the atoms to which is attached A.

Preference is given to compounds of the formula (I), in which

But denotes a group of the formula

in which

* indicates the site of bonding with the carbon atom pyridinoline rings,

and

# specifies the location of the binding carbon atom of the phenyl ring,

R1denotes hydrogen, an amino group or medicalbilling,

R2, R3and R4denote hydrogen,

R5denotes hydrogen or halogen,

R6denotes hydrogen or halogen,

R7and R8 denote hydrogen,

and their salts, solvate and solvate their salts.

Preference is also given to compounds of the formula (I)where And denotes a group of the formula

in which

* indicates the site of bonding with the carbon atom pyridinoline rings,

and

# specifies the location of the binding carbon atom of the phenyl ring,

R1denotes the amino group or medicalbilling,

R2, R3and R4denote hydrogen,

R5denotes hydrogen,

R6denotes hydrogen or halogen,

R7and R8denote hydrogen,

and their salts, solvate and solvate their salts.

Preference is also given to compounds of the formula (I), in which

But denotes a group of the formula

in which

* indicates the site of bonding with the carbon atom pyridinoline rings,

and

# specifies the location of the binding carbon atom of the phenyl ring.

Preference is also given to compounds of the formula (I)in which R1denotes the amino group.

Preference is also given to compounds of the formula (I)in which R2denotes hydrogen.

Preference is also given to compounds of the formula (I)in which R3denotes hydrogen.

Preference is also given to compounds of the formula (I), in R 4denotes hydrogen.

Preference is also given to compounds of the formula (I)in which R5denotes hydrogen.

Preference is also given to compounds of the formula (I)in which R6denotes fluorine.

Preference is also given to compounds of the formula (I)in which R5denotes hydrogen and R6denotes fluorine.

Preference is also given to compounds of the formula (I)in which R7denotes hydrogen.

Preference is also given to compounds of the formula (I)in which R8denotes hydrogen.

Definitions of the radicals specified for the respective combinations and preferred combinations of radicals, optionally substituted on the definitions of radicals other combination, regardless of the specific combination of the radicals specified.

Special preference is also given to combinations of two or more of the above preferred ranges.

The present invention also relates to a method for producing compounds of formula (I), in which the compounds of formula

in which

A, R1, R2, R3, R4, R5and R6have the above values,

enter into reaction with compounds of the formula

in which

R7and R8have the above knowledge is enemy and

X1denotes halogen, preferably chlorine or bromine, or hydroxy-group.

If X1denotes halogen, the reaction is usually carried out in inert solvents, in the presence of a base, preferably in a temperature range from 0 to 40°C at atmospheric pressure.

Examples of inert solvents include halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents, such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, preferred are tetrahydrofuran or methylene chloride.

Examples of bases include carbonates of alkali metals such as cesium carbonate, sodium carbonate or potassium hydroxide, or organic bases, such as trialkylamine, for example, triethylamine or diisopropylethylamine or N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or pyridine is preferred diisopropylethylamine.

If X1denotes a hydroxy-group, the reaction is usually carried out in inert solvents, in the presence of a dehydrating reagent, if appropriate in the presence of a base, preferably in a temperature range from 0°C to room temperature at atmospheric pressure.

P is emery suitable for the present invention dehydrating reagents include carbodiimide (CBI), such as N,N'-diethyl-, N,N'-dipropyl-, N,N'-aminobutiramida, N,N'-dicyclohexylcarbodiimide, N-(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide (ejh) (if appropriate, in the presence of pentafluorophenol (NAH)), N-cyclohexylcarbodiimide-N'-propelaccelerator (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2 oxazole-3-sulfate or 2-tert-butyl-5-methyl-isoxazolidinone, or acylamino compounds such as 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline, or anhydride propriospinal acid, or isobutylparaben, or bis(2-oxo-3-oxazolidinyl)phosphorylchloride, or benzothiazolinone three(dimethylamino)fosfodiesterasa, or O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylpropylenediamine (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethylethylenediamine (TPTU) or O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine (HATU), or 1-hydroxybenzotriazole (HOBt) or benzotriazol-1-yloxytris-(dimethylamino)phosphodiesterase (THIEF), or mixtures thereof with bases. The condensation is preferably conducted using HATU.

Examples of bases include carbonates of alkali metals, such as, for example, carbonates or bicarbonates of sodium or potassium, and organic bases, such as trialkylamine, for example, ritilin or diisopropylethylamine, or N-methylmorpholine, N-methylpiperidine or 4-dimethylaminopyridine is preferred diisopropylethylamine.

Examples of inert solvents include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons, such as benzene, or nitromethane, dioxane, dimethylsulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran, or triamide hexamethylphosphoric acid, or a mixture of solvents, particularly preferred are dichloromethane, tetrahydrofuran or dimethylformamide.

The compounds of formula (III) are known or can be synthesized by known methods from the corresponding starting materials.

The compounds of formula (II) are known or can be obtained by reaction of compounds of the formula

in which

A, R1, R2, R3, R4, R5and R6have the above values,

with acid.

The reaction is usually carried out in polar solvents, preferably in a temperature range from room temperature to the boiling point of the solvent at atmospheric pressure.

Examples of acids include hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonate acid, econsultancy acid, toluensulfonate acid,benzosulfimide acid, naphtalenesulfonic acid and triperoxonane acid is particularly preferred is hydrochloric acid.

Examples of polar solvents include alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol or tetrahydrofuran, dioxane and acetic acid, or a mixture of solvents or solvent with water, especially preferred is ethanol.

The compounds of formula (IV) are known or can be obtained by the method

[A] reaction of compounds of the formula

in which

R3, R4, R5and R6have the above values,

with compounds of the formula

in which

R1and R2have the above values,

to obtain compounds of the formula

in which

R1, R2, R3, R4, R5and R6have the above values,

or

[In] the reaction of compounds of the formula

in which

R3, R4, R5and R6have the above values,

with compounds of the formula

in which

R1and R2have the above values,

to obtain compounds of the formula

in which

R1, R2, R3, R4, R5and R6have the above values,

or

[With] in the first stage reaction of compounds of formula (Vb) with compounds of the formula

in which

R1and R2have the above values,

and in the second stage with phosphorus oxychloride, to obtain compounds of the formula

in which

R1, R2, R3, R4, R5and R6have the above values,

or

[D] the reaction of compounds of the formula

in which

R3, R4, R5and R6have the above values, and

X2denotes halogen, preferably iodine or bromine,

with compounds of the formula

in which

R1and R2have the above values,

to obtain compounds of the formula

in which

R1, R2, R3, R4, R5and R6have the above values.

During the synthesis of the amino group, R1if appropriate, protect the amino group known to a person skilled in the art such as, for example, acyl, which after synthesis are removed under conditions known is the shaft skilled in the technical field.

Compounds of formula (IVa), (IVb), (IVc) and (IVd) together form the compounds of formula (IV).

The reaction in method [A], [B] and on the first stage of the method [S] is usually carried out in inert solvents, in the presence of a dehydrating reagent, preferably in a temperature range from room temperature to 100°C at atmospheric pressure.

Examples of inert solvents include hydrocarbons, such as benzene or toluene, or other solvents such as dioxane, dimethylformamide, dimethylsulfoxide or acetonitrile, or a mixture of solvents, especially preferred is dimethylformamide.

Examples of dehydrating reagents include carbodiimides, such as N,N'-diethyl-, N,N'-dipropyl-, N,N'-aminobutiramida, N,N'-dicyclohexylcarbodiimide, N-(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide (ejh) (if appropriate, in the presence of pentafluorophenol (NAH)), N-cyclohexylcarbodiimide-N'-propelaccelerator (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazole-3-sulfate or 2-tert-butyl-5-methyl-isoxazolidinone, or acylamino compounds such as 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline, or anhydride propriospinal acid, or isobutylparaben, or bis(2-oxo-3-oxazolidinyl)phosphorylchloride, Il is benzothiazolinone three(dimethylamino)fosfodiesterasa, or O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylpropylenediamine (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethylethylenediamine (TPTU) or O-(7-asobancaria-1-yl)-N,N,N, N'-tetramethylpropylenediamine (HATU), or 1-hydroxybenzotriazole (HOBt) or benzotriazol-1-yloxytris-(dimethylamino)phosphodiesterase (THIEF), or mixtures thereof with bases. Especially preferred is carbonyldiimidazole.

The reaction in the second stage of the method [S] is usually carried out in inert solvents, preferably in a temperature range from 50 to 100°C at atmospheric pressure. You can also use a mixture of solvents, the mixture of the solvent with POCl3or clean POCl3.

Examples of inert solvents include hydrocarbons, such as benzene or toluene, or other solvents such as dioxane, dimethylsulfoxide, dimethylformamide or acetonitrile, or a mixture of solvents, particularly preferred are dioxane and/or dimethylformamide.

The reaction in the method of [D] is usually carried out under reaction conditions Sonogashira in an argon atmosphere in an inert and degassed solvents, in the presence of a catalyst, if appropriate in the presence of an additional reagent, in the presence of a base and, if appropriate, triphenylphosphine, preferably in a temperature range from room temperature to the temperature of the boiling point of the solvent at atmospheric pressure (R.R. Tykwinski, Angew. Chem. Int. Ed. 2003, 42, 1566-1568, K. Sonogashira in Handbook of organopalladium chemistry for organic synthesis (Ed. E. - I. Negishi), 1133-1178 Wiley-Interscience, New York (2002)).

Examples of catalysts include palladium catalysts, the usual reaction Sonogashira, preferred are those catalysts, as, for example, three(dibenzylideneacetone)dipalladium, dichlorobis(triphenylphosphine)palladium, tetranitropentaerithrite(0), palladium(II)acetate complex of 1,1'-bis[(biphenylphosphine)ferrocene]palladium-II-chloride with dichloromethane composition (1:1).

Examples of additional reagents include copper iodide(I) and triphenylphosphine.

Examples of bases include amine bases such as triethylamine.

Examples of inert solvents include ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons, such as benzene, xylene or toluene, or other solvents, such as nitrobenzene, dimethylformamide, dimethylacetamide, dimethylsulfoxide or N-organic, preferred are solvents such as, for example, dimethylformamide, dimethylacetamide, dimethylsulfoxide or 1,2-dimethoxyethane.

Compounds of formula (VIa), (VIb), (VIc) and (VId) are known or can be synthesized by known methods from the corresponding starting materials.

Compounds of formula (Va), (Vb) and (Vc) are known or can be obtained by the reaction of the Affairs of the formula

in which

R3and R4have the above values, and

X3denotes halogen, preferably iodine or bromine, hydroxycarbonyl or cyano,

with compounds of the formula

in which

R5and R6have the above values.

The reaction is usually carried out in inert solvents in the presence of a base, preferably in a temperature range from 0 to 40°C at atmospheric pressure.

Examples of inert solvents include alcohols, such as methanol, ethanol, n-propanol, ISO-propanol, n-butanol or tert-butanol or tetrahydrofuran, acetone, dioxane or pyridine, or a mixture of solvents or a mixture of the solvent with water, especially preferred are tetrahydrofuran or isopropanol with a small amount of water.

Examples of bases include sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, or an amine base such as triethylamine or diisopropylethylamine, especially preferred is sodium acetate.

Compounds of formulas (VII) and (VIII) are known or can be synthesized by known methods from the corresponding starting materials.

In an alternative method, compounds of formula (IV) can be obtained using a different order of reactions C is the point.

Obtaining the compounds proposed in the present invention, can be illustrated by the following synthesis schemes.

The scheme of synthesis 1:

Scheme of synthesis of 2:

The scheme of synthesis 3:

The scheme of synthesis 4:

Connections proposed in the present invention, are characterized by a surprising range of effects that cannot be predicted. They possess antiviral activity against members of the group of herpes viridae (herpes viruses), in particular, in relation to cytomegalovirus (CMV) and in particular against human cytomegalovirus (CPSC).

Areas of evidence which can be mentioned as examples are:

1) Treatment and prevention of infection through CMVC in patients with AIDS (acquired immunodeficiency syndrome) (retinitis, pneumonitis, gastrointestinal infectious diseases).

2) Treatment and prevention of cytomegalovirus infection in patients who transplanted bone marrow or organ and which is often life threatening caused CMVC pneumonitis or encephalitis, or gastrointestinal system and caused CMVC infectious diseases.

3) Treatment and prevention caused CMVC info the traditional diseases in newborns and infants.

4) Treatment of acute infection by CPSC in pregnant women.

5) Treatment of infection by CMUC patients with weakened immune systems caused by cancer and cancer therapy.

6) Treatment of infected by CMVC with cancer patients in order to alleviate mediated CMVC progression of the tumor (see J. Cinati, et al., FEMC Microbiology Reviews 2004, 28, 59-77).

The present invention also relates to the use of compounds proposed in this invention for treatment and/or prophylaxis of diseases, in particular of infection by viruses, preferably above viruses, and the resulting infectious diseases. Virus below in the present invention means the virus, and the disease caused by infection with a virus.

The present invention also relates to the use of compounds proposed in this invention for treatment and/or prophylaxis of diseases, preferably for these diseases.

The present invention also relates to the use of compounds proposed in the present invention, for preparing a medicinal product intended for the treatment and/or prophylaxis of diseases, preferably for these diseases.

Connections proposed in the present invention, FAV is preferably used for preparation of medicines, which are suitable for the prophylaxis and/or treatment of infection by members of the group of herpes viridae (herpes viruses), preferably cytomegalovirus, preferably by human cytomegalovirus.

The present invention also relates to a method of treatment and/or prophylaxis of diseases, preferably of the aforementioned diseases, using an antiviral effective amount of the compounds proposed in the present invention.

The present invention also relates to medicines, including at least one connection proposed in the present invention, and at least one or more additional active ingredients, in particular intended for the treatment and/or prophylaxis of the aforementioned diseases. Active ingredients suitable for combination, which, for example and preferably, it can be noted are: antiviral active ingredients, such as valganciclovir, ganciclovir or acyclovir.

Connections proposed in the present invention, can act systemically and/or topically. To do this, you can enter them suitable way, such as, for example, oral, parenteral, pulmonary, nasal, sublingual, lingual, transbukkalno, rectal, dermal, transdermal, conjunctival, ush is Oh or local, or as implant or stent.

When these routes of administration of the compounds proposed in the present invention, can be entered in the appropriate formulation.

For oral administration are suitable preparative forms that operate in accordance with the prior art and produce connections proposed in the present invention rapidly and/or modified image and which include the compounds proposed in the present invention in crystalline and/or amortiziruemoe and/or dissolved form, such as, for example, tablets, tablets (uncoated or coated, for example, containing coating, which is resistant to gastric juice or dissolve with a delay or insoluble and regulate the release of compounds proposed in the present invention), tablets or films/wafers that rapidly disintegrate in the oral cavity, films/lyophilizate, capsules (for example, capsules of soft or hard gelatin), tablets, coated in sugar, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be carried out without the stage suction (for example, intravenously, intraarterially, vnutriarterialno, vnutrispinalnaya or natriumsalz) or with the inclusion of stage suction (for example, intramuscularly, podkoren is, intracutaneous, percutaneous or intraperitoneal). Preparative forms suitable for parenteral administration are, in particular, preparations for injection and infusion in the form of solutions, suspensions, emulsions, liofilizatow or sterile powders.

Examples of forms suitable for other routes of administration are preparative forms for inhalation (in particular intended for powder inhalers and spray devices), drops, solutions, sprays for the nose; tablets, films/wafers or capsules, which is administered lingually, sublingually or transbukkalno, suppositories, preparations for the ears and eyes, vaginal capsules, aqueous sospesi (lotions, medicine, want to shake), lipophilic suspensions, ointments, creams, transdermal therapeutic systems, milk, pastes, foams, spray powders, implants or stents.

Connections proposed in the present invention, can be prepared in a standard preparative forms. This is performed by known technologies, including mixing with inert, non-toxic, pharmaceutically acceptable inert fillers. These inert fillers, in particular, include carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing agents or spaceways the e agents (for example, sodium dodecyl sulphate, polychiorinated), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants such as ascorbic acid), colorants (e.g. inorganic pigments such as iron oxides) or agents that change the taste and/or smell.

The present invention also relates to medicines, which include at least one connection proposed in the present invention, usually together with one or more inert, non-toxic, pharmaceutically acceptable inert fillers, and their use for the above purposes.

To ensure effective results when administered intravenously, it is generally preferable to introduce a quantity, comprising from about 0.001 to 10 mg/kg, preferably about 0.01 to 5 mg/(kg body mass), and by oral administration the dosage is about 0.01 to 25 mg/kg, preferably from 0.1 to 10 mg/(kg body mass).

However, in appropriate cases it may be appropriate deviation from the specified quantities, in particular depending on the body weight, route of administration, the individual response to the active ingredient, type of drug and the time of the introduction or intervals between injections. Thus, in some cases, it may be shortcuts is accurate introduction number, smaller than the specified minimum, and in other cases it will be necessary to exceed the specified upper limit. In the case of the introduction of large amounts can be reasonably divided into several individual doses, to be implemented within days.

Unless otherwise stated, expressed in percent of the content in the descriptions of the studies and examples are mass; expressed in parts of the content are also mass. The ratio of the solvents, the ratio when diluted and the concentrations of solutions of liquids in liquids in all cases are three-dimensional.

A. Examples

Abbreviations:

Boctert-butoxycarbonyl
CDCl3deuterochloroform
PHIdirect chemical ionization (in MS)
DHMdichloromethane
DIAN,N'-diisopropylethylamine
DMSOthe sulfoxide
DMFN,N'-dimethylformamide
Ejh N-(3-dimethylaminoisopropyl)-N'-
ethylcarbodiimide
EAethyl acetate (ethyl ester of acetic acid)
EUionization by electron impact (in MS)
IERelectrospray ionization (in MS)
Fmoc9-fluorenylmethoxycarbonyl
hwatch
HPLChigh performance liquid chromatography
BBhigh vacuum
LC-MScombined liquid chromatography - mass
Spectroscopy
GAVEdiisopropylamide lithium
minminutes
MSmass spectroscopy
MTBEmethyl tert-butyl ether
NMR spectroscopy nuclear magnetic resonance
Pd-Cpalladium on coal
Rumor1-
benzotriazolilproizvodnykh
RP-HPLCHPLC with reversed-phase
Rtretention time (in HPLC)
THFtetrahydrofuran

General methods LC-MS and HPLC:

Method 1 (LC-MS): instrument Type MS: Micromass ZQ, device Type for HPLC: HP 1100 series; UV DAD; column: Phenomenex Synergi 2µ. Hydro OF Mercury 20 mm×4 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient mode: 0,0 min 90%A→a 2.5 min 30%A→a 3.0 min 5%A→4.5 min 5%A; flow rate: 0,0 min 1 ml/min, 2.5 minutes/a 3.0 min/4.5 min 2 ml/min; oven: 50°C.; UV detection: 210 nm.

Method 2 (LC-MS): Instrument: Micromass Quattro LCZ with HPLC Agilent series 1100; column: Phenomenex Synergi 2µ. Hydro OF Mercury 20 mm×4 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient mode: 0,0 min 90%A→a 2.5 min 30%A→a 3.0 min 5%A→4.5 min 5%A; flow rate: 0,0 min 1 ml/min, 2.5 minutes/a 3.0 min/4.5 min 2 ml/min; oven: 50°C.;UV detection: 208-400 nm.

Method 3 (LC-MS): instrument Type MS: Micromass ZQ; instrument Type for HPLC: Waters Alliance 2795; column: Phenomenex Synergi 2µ Hydro OF Mercury 20 mm×4 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient mode: 0,0 min 90%A→a 2.5 min 30%A→a 3.0 min 5%A→4.5 min 5%A; flow rate: 0,0 min 1 ml/min, 2.5 minutes/a 3.0 min/4.5 min 2 ml/min; oven: 50°C.; UV detection: 210 nm.

Method 4 (LC-MS): Instrument: Micromass Platform LCZ with HPLC Agilent series 1100; column: Thermo Hypersil GOLD 3µ 20×4 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient mode: 0,0 min 100%A→0.2 to min 100%A→a 2.9 min 30%A→a 3.1 min 10%A→a 5.5 min 10%A; oven: 50°C; flow rate: 0.8 ml/min; UV detection: 210 nm.

Method 5 (HPLC): Instrument: HP 1100 with DAD detection; column: Kromasil RP-18, 60×2 mm, and 3.5 μm; eluent A: 5 ml of perchloric acid/l of water, eluent b: acetonitrile; gradient mode: 0 min 2%B, 0.5 min 2%B, 4.5 min 90%B, 9 min 90%, and 9.2 min 2%B, 10 min 2%B; flow rate: 0.75 ml/min; oven 30°C.; UV detection: 210 nm.

Method 6 (HPLC): Instrument: HP 1100 with DAD detection; column: Kromasil RP-18, 60×2 mm, and 3.5 μm; eluent A: 5 ml of perchloric acid/l of water, eluent b: acetonitrile; gradient mode: 0 min 2%B, 0.5 min 2%B, 4.5 min 90%B, 6.5 minutes 90%, of 6.7 min 2%, and 7.5 min 2%B; flow rate: 0.75 ml/min; oven 30°C.; UV detection: 210 nm.

Method 7 (LC/MS): instrument Type MS: Micromass ZQ; instrument Type for the LC: HP 1100 series; UV DAD; column: Phenomenex Gemini 3µ 30×3.00 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient mode: 0,0 min 90%A→a 2.5 min 30%A→a 3.0 min 5%A→4.5 min 5%A; flow rate: 0,0 min 1 ml/min, 2.5 minutes/a 3.0 min/4.5 min 2 ml/min; oven: 50°C.; UV detection: 210 nm.

The source connections

Example 1A

4-(Benzylthio)benzonitrile

Sodium hydride (5 g, 60% dispersion in oil) was washed with hexane and dried in vacuum. The residue was dispersed in dry DMF (100 ml) at 0°C and for 30 min added dropwise benzylmercaptan (14,82 g). Then the reaction mixture was stirred for 30 min at room temperature. Carefully add 4-perbenzoate (accounted for 14.45 g) and the reaction mixture is stirred prior to entry into the reaction of the whole of the original substance (monitoring using HPLC, about 3 hours). The reaction mixture was poured into ice water (400 ml) and stirred for 5 minutes, the Product is collected by filtration, washed with water (three times) and dried on the filter. The crude product is recrystallized from cyclohexane, collected by filtration and washed with petroleum ether and dried. Get 23,04 g (86% of theoretical yield) of product.

LC-MS (method I): Rt=2,85 min

MS (IER): m/z=226 [M+H]+

Example 2A

4-(Benzylthio)-N'-hydroxybenzomorpholine

4-(Benzylthio)benzonitrile (23,00 g) and gidroxinimesoulid (10,66 g) prepared in dry ethanol (10 ml) and add triethylamine (17 ml). The reaction mixture is first stirred for 30 min at 50°C and then refluxed for 2 hours Then add water until the solution becomes turbid. The reaction mixture is cooled to room temperature and the resulting solid collected by filtration. The solid is washed with water and then dried at 85°C in a drying Cabinet.

The crude product is recrystallized from n-butanol, crystalline product is collected by filtration, washed with diethyl ether and dried at 65°C in a drying Cabinet. Get 23,40 g (88% of theoretical yield) of product as a solid.

LC-MS (method I): Rt=1,79 min

MS (IER): m/z=229 [M+H]+

Example 3A

N-(6-{3-[4-(Benzylthio)phenyl]-1,2,4-oxadiazol-5-yl}pyridine-2-yl)ndimethylacetamide

1,1-Carbonyldiimidazole (15,16 g) in small portions slowly added to 6-acetaminophen-2-carboxylic acid (of 16.84 g) in dry DMF (75 ml) (gas evolution). The resulting solution was stirred at room temperature for 1.5 h and Then added 4-(benzylthio)-N'-hydroxybenzomorpholine (23,00 g) and the reaction mixture was stirred at room temperature prior to entry into the reaction of the whole and the target substance (about 3 hours). The reaction mixture is heated to 100°C and stirred for 2 hours Then add water until the solution becomes slightly turbid, and the reaction mixture is cooled to room temperature. The crude product is collected by filtration, washed three times with water and dried in an oven at 65°C. Receive 24,42 g (67% of theoretical yield) of product as a solid.

LC-MS (method 1): Rt=2,98 min

MS (IER): m/z=403 [M+H]+

1H-NMR (400 MHz, DMSO-d6): δ=10,96 (s, 1H), scored 8.38 (d, 1H), 8,08 (t, 1H), 8,02-to 7.95 (m, 3H), 7,53 (d, 2H), 7,43 (d, 2H), 7,35-7,21 (m, 3H), 4,36 (s, 2H), of 2.15 (s, 3H).

Example 4A

6-{3-[4-(Benzylthio)phenyl]-1,2,4-oxadiazol-5-yl}pyridine-2-aminogidrohlorid

Water (50 ml) and concentrated hydrochloric acid (50 ml) was added to N-(6-{3-[4-(benzylthio)phenyl]-1,2,4-oxadiazol-5-yl}pyridine-2-yl)ndimethylacetamide (40,55 g) in ethanol (150 ml). The reaction mixture is refluxed until the entry into the reaction of the whole of the original substance (about 3 hours) and then cooled to room temperature. The solid is collected by filtration, washed three times with ethanol and dried in a vacuum drying Cabinet at 80°C. Receive 36,60 g (92% of theoretical yield) of product as a solid.

LC-MS (method 2): Rt=was 2.76 min

MS (IER): m/z=361 [M+H]+

1H-NMR (400 MHz, DMSO-d6): δ=of 7.95 (d, 2H), 7,73 (t, 1H), and 7.5 (d, 2H), 7,51 (m, 1H), 7,42 (d, 2H), 7,30 (t, 2H), 7,25 (m, 1H), 6,85 (d, 1H), to 4.38 (s, 2H).

Example 5A

4-[5-(6-Aminopyridine-2-yl)-1,2,4-oxadiazol-3-yl]benzoylformate

6-{3-[4-(Benzylthio)phenyl]-1,2,4-oxadiazol-5-yl}pyridine-2-amine (35,95 g) is cooled to 5°C in a mixture of acetic acid (200 ml) and water (100 ml) in a bath of ice. Chlorine is gradually added to the entry in the reaction of the whole of the original substance (monitoring by HPLC) and the temperature should not exceed 10°C. the Reaction mixture was stirred at 5°C for 15 min and then diluted with water with ice (200 ml). The crude product is collected by filtration, washed with water ice (three times) and diethyl ether (three times) and then dried in vacuum. Get 26,00 g (85% of theoretical yield) of product as a solid.

LC-MS (method 3): Rt=2,22 min

MS (IER): m/z=337 [M+H]+

Example 6A

2-Chloro-5-fluoro-1,3-dinitrobenzene

DMF (10 ml) and thionyl chloride (14 ml) are sequentially added to 4-fluoro-2,6-dinitrophenol (26,00 g) in benzene (50 ml). The resulting solution was stirred at room temperature for 5 min (precipitated intermediate product) and then refluxed for 1.5 hours (or before entry into the reaction of the whole of the original substance). The reaction mixture is cooled to room temperature, concentrated and the STATCOM poured into ice water. The precipitate is collected by filtration, washed three times with water and dried. After recrystallization from ethanol 23,50 g (83% of theoretical yield) of the product in crystalline form.

1H-NMR (400 MHz, DMSO-d6): δ=8,56 (d, 2H).

Example 7A

5-fluoro-1,3-aminobenzoyl

The triethylamine (12,6 ml) and palladium (10% on coal) (6.0 g) was added to 2-chloro-5-fluoro-1,3-dinitrobenzene (10,00 g) in methanol (450 ml). The reaction mixture hydronaut at room temperature under the hydrogen pressure is 3 bar, before entry into the reaction of the whole of the original substance (2 h). The reaction mixture was filtered through celite and concentrated. The residue is dissolved in DHM (150 ml) and treated with 10% citric acid solution. Then the aqueous phase is alkalinized 2 N. a solution of sodium hydroxide and extracted with DHM (three times 100 ml). The organic phase is dried over sodium sulfate and concentrated. Receive 5.0 g (88% of theoretical yield) of product in the form of oil.

LC-MS (method 4): Rt=0,58 min

MS (IER): m/z=127 [M+H]+

Example 8A

N-(3-Amino-5-forfinal)-1-cyanocyclohexane

1,1-Carbonyldiimidazole (3,29 g) was added to 1-cyanocyclohexane acid (2,05 g) in THF and the resulting solution was stirred at room temperature for 45 minutes Add 5-fluoro-1,3-aminobenzoyl (3,00 who) and the mixture is stirred for another 2.5 hours Then the solution is concentrated and the residue is dissolved in DHM (150 ml) and washed with water. The aqueous phase is twice extracted with DHM. The organic extracts are combined, dried over sodium sulfate and concentrated. The remainder chromatographic on silica gel (eluent: from DHM to DHM-methanol 50:1). After concentration of the appropriate fractions allot of 2.35 g (58% of theoretical yield) of product.

LC-MS (method 1): Rt=1,31 min

MS (IER): m/z=220 [M+H]+

Example 9A

N-(3-{[(4-Cyanophenyl)sulfonyl] amino} phenyl)ndimethylacetamide

3'-Aminoacetanilide (13,54 g) dissolved in 2-propanol (200 ml) and at room temperature was added a solution of sodium acetate (8,51 g) in water (100 ml). Add 4-cyanobenzenesulfonyl (20,0 g), the reaction mixture is heated to 30°C and stirred at room temperature for 3 hours the Reaction mixture was poured onto ice (250 ml), the obtained solid is collected by filtration, washed with water (three times) and then dried in a drying Cabinet. Obtain 27.8 g (98% of theoretical yield) of product as a solid.

LC-MS (method 1): Rt=1,79 min

MS (IER): m/z=316 [M+H]+

1H-NMR (400 MHz, DMSO-d6): δ=10,52 (s, 1H), 9,94 (s, 1H), with 8.05 (d, 2H), of 7.90 (d, 2H), 7,46 (s, 1H), 7,27 (d, 1H), 7,13 (t, 1H), 6,72 (d, 1H), from 2.00 (s, 3H).

Example 10A

N-{3-[({4-[(Z)-Amino(hydroxyimino)methyl]phenyl}sulfonyl)amino]FeNi is}ndimethylacetamide

N-(3-{[(4-Cyanophenyl)sulfonyl]amino}phenyl)ndimethylacetamide (27,00 g) prepared in ethanol (190 ml) and sequentially adds gidroxinimesoulid (7,14 g) and triethylamine (14,0 ml). The reaction mixture was stirred at 50°C for 2 h and then poured on ice, the substance is collected by filtration and dried in a vacuum chamber. Get 25,78 g (86% of theoretical yield) of product as a solid.

LC-MS (method 1): Rt=1,14 min

MS (IER): m/z=349 [M+H]+

Example 11A

N-(6-{3-[4-({[3-(Acetylamino)phenyl]amino}sulfonyl)phenyl]-1,2,4-oxadiazol-5-yl}pyridine-2-yl)ndimethylacetamide

1,1-Carbonyldiimidazole (9,78 g)dissolved in dioxane (100 ml), added dropwise to 6-acetylpiperidine-2-carboxylic acid (10,86 g) in a mixture of dioxane (100 ml) and DMF (60 ml) and the mixture is stirred at room temperature for 3 hours Then added N-{3-[({4-[(Z)-amino(hydroxyimino)methyl]phenyl}sulfonyl)amino]phenyl}ndimethylacetamide in the form of solids and the reaction mixture was stirred at room temperature for 16 hours Then the reaction mixture was stirred at 100°C for 4 h and then poured into ice water. The product was incubated for 10 min, collected by filtration, washed with water (three times) and dried in a vacuum drying Cabinet. Get 25,55 g (90% of theoretical yield) of the product VI is e solids.

HPLC (method 5): Rt=4,03 min

MS (IER): m/z=493 [M+H]+

Example 12A

N-(3-AMINOPHENYL)-4-[5-(6-aminopyridine-2-yl)-1,2,4-oxadiazol-3-yl]benzosulfimide

15% Hydrochloric acid (150 ml) was added to N-(6-{3-[4-({[3-(acetylamino)phenyl]amino}sulfonyl)phenyl]-1,2,4-oxadiazol-5-yl}pyridine-2-yl)ndimethylacetamide (20,00 g) in ethanol (200 ml). The reaction mixture is stirred at the boil under reflux for 6 h and then by heating the pH adjusted to 4 with 10% sodium hydroxide solution. The reaction mixture is cooled to 5°C. and stirred for 16 hours, the Crude product is collected by filtration with suction, washed with water (twice) and then dried. Get of 12.73 g (77% of theoretical yield) of product as a solid.

HPLC (method 5): Rt=3,53 min

MS (IER): m/z=409 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=10,16 (br s, 1H), 8,23 (d, 2H), of 7.97 (d, 2H), 7,63 (t, 1H), 7,45 (d, 1H), 6,85 (t, 1H), 6,74 (d, 1H), return of 6.58 (br s, 2H), 6.42 per (s, 1H), 6,28 (t, 1H), 5,44 (br s, 2H).

Example 13A

N-(6-Bromopyridin-2-yl)ndimethylacetamide

2-Amino-6-bromopyridine (of 5.40 g) and acetylchloride (2.66 ml) was prepared in methylene chloride (80 ml) and cooled to 0°C. Then dropwise added triethylamine (6,53 ml) and the mixture is then warmed to room temperature with stirring. To the reaction mixture was added 10% solution of hydroc is rbonate sodium and the reaction mixture is extracted with methylene chloride. The organic phase is washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. After flash chromatography (eluent: methylene chloride/methanol 1:0, 500:1) get of 5.84 g (86% of theoretical yield) of product.

HPLC (method 6): Rt=3,66 min

MS (PHI/NH3): m/z=215 and 217 [M+H]+, 232 and 234 [M+NH4]+, 249 and 251 [M+NH4+NH3]+

1H-NMR (400 MHz, DMSO-d6): δ=10,79 (s, 1H, NH), 8,08 (d, 1H), 7,71 (t, 1H), 7,3 l (d, 1H), 2,09 (s, 3H).

Example 14A

N-[6-(3-Hydroxy-3-methylbut-1-Jn-1-yl)pyridin-2-yl]ndimethylacetamide

N-(6-Bromopyridin-2-yl)ndimethylacetamide (of 5.84 g) prepared in diethylamine (50 ml).

After addition of 2-methyl-3-butyn-2-ol (of 2.51 g), bis(triphenylphosphine)palladium(II)chloride (381 mg) and copper iodide(1) (52 mg) the mixture was stirred at room temperature for 2 h Then the reaction mixture was concentrated and purified using flash chromatography (eluent: methylene chloride/methanol 200:1, 100:1, 50:1). Get 5.20 g (88% of theoretical yield) of product.

HPLC (method 6): Rt=3,30 min

MS (method M-40, PHI/NH3): m/z=219 [M+H]+

1H-NMR (400 MHz, DMSO-d6): δ=is 10.68 (s, 1H, NH), with 8.05 (d, 1H), of 7.75 (t, 1H), 7,14 (d, 1H), of 5.55 (s, 1H, OH), 2,07 (s, 3H), of 1.46 (s, 6H).

Example 15A

N-(6-Ethynylpyridine-2-yl)ndimethylacetamide

N-[6-(3-Hydroxy-3-methylbut-1-Jn-1-yl)pyridin-2-yl]ndimethylacetamide (5,20 is) prepared in toluene (50 ml), add sodium hydride (95 mg) and the mixture was stirred at 120°C for 1.5 h, the Reaction mixture was concentrated, the residue diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, concentrated and purified using flash chromatography (eluent: methylene chloride/methanol 1:0, 500:1, 200:1, 100:1). Get 1,75 g (43% of theoretical yield) of product.

HPLC (method 6): Rt=3,18 min

MS (method M-40, PHI/NH3): m/z=161 [M+H]+, 178 [M+NH4]+,

1H-NMR (400 MHz, DMSO-d6): δ=is 10.68 (s, 1H, NH), 8,10 (d, 1H), 7,78 (t, 1H), 7,26 (d, 1H), or 4.31 (s, 1H), 2,08 (s, 3H).

Example 16A

N-(3-{[(4-Itfinal)sulfonyl]amino}phenyl)ndimethylacetamide

4-Identicality chloride (10.0 g) prepared in isopropanol (100 ml)was added sodium acetate (3.12 g), dissolved in a little water, and the mixture is stirred at room temperature for 30 minutes Then added N-(3-AMINOPHENYL)ndimethylacetamide (4,96 g) and the mixture is additionally stirred over night. The reaction mixture was diluted with water and saturated aqueous sodium chloride and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, concentrated and purified using flash chromatography (eluent: methylene chloride/methanol 1:0, 100:1, 80:1). Get 9,62 g (70% of theoretical yield) of product.

HPLC (method 6): Rt=4,14 min

MS (IER+, IER-): m/z=417 [M+H]+, 415 [M-H]-,

1H-NMR (400 MHz, DMSO-d6): δ=10,31 (s, 1H, NH), to 9.91 (s, 1H, NH), to 7.93 (d, 2H), 7,51 (d, 2H), 7,45 (s, 1H), 7,26 (d, 1H), 7,12 (t, 1H), 6.73 x (d, 1H), from 2.00 (s, 3H).

Example 17A

N-(6-{[4-({[3-(Acetylamino)phenyl[amino}sulfonyl)phenyl]ethinyl}pyridine-2-yl)ndimethylacetamide

N-(3-{[(4-Itfinal)sulfonyl] amino }phenyl)ndimethylacetamide (4,60 g), tetrakis(triphenylphosphine)palladium(0) (1.28 g) and copper iodide(I) (421 mg) was prepared in DMF) in an argon atmosphere, was added N-(6-ethynylpyridine-2-yl)ndimethylacetamide (2.66 g) and triethylamine (15,4 ml) and the mixture is stirred at room temperature for 2 hours the Mixture is then diluted with water, extracted with methylene chloride and the organic phase is dried and purified by using flash chromatography (eluent: methylene chloride/methanol 1:0, 200:1, 100:1, 50:1, 30:1).

Get of 3.56 g (48% of theoretical yield) of product.

HPLC (method 6): Rt=3,86 min

MS (IER+, IER-): m/z=449 [M+H]+, 447 [M-H]-,

1H-NMR (400 MHz, DMSO-d6): δ=of 10.76 (s, 1H, NH), 10,38 (s, 1H, NH), to 9.93 (s, 1H, NH), 8,13 (d, 1H), 7,88 for 7.78 (m, 3H), 7,73 (d, 2H), of 7.48 (s, 1H), 7,37 (d, 1H), 7,26 (d, 1H), 7,12 (t, 1H), 6,76 (d, 1H), 2,09 (s, 3H), from 2.00 (s, 3H).

Example 18A

N-(3-AMINOPHENYL)-4-[(6-aminopyridine-2-yl)ethinyl]benzosulfimide

N-(6-{[4-({[3-(Acetylamino)phenyl]amino}sulfonyl)phenyl]ethinyl}pyridine-2-yl)ndimethylacetamide (3.12 g) was prepared in ethanol (45 ml), priba the amount of 20% hydrochloric acid (45 ml) and the mixture was stirred at 60°C for 3 hours The reaction mixture was concentrated and the residue is stirred with acetonitrile. After collecting substances by filtration with suction, additional washing with acetonitrile and drying in high vacuum gain of 3.45 g (quantitative yield) of product.

HPLC (method 6): Rt=3,65 min

MS (IER+, IER-): m/z=365 [M+H]+, 363 [M-N]-,

1H-NMR (400 MHz, DMSO-d6): δ=10,70 (s, 1H, NH), to $ 7.91 for 7.78 (m, 5H), from 7.24 (t, 1H), to 7.09 (d, 1H), 7,02 (s, 1H), of 6.96-6,83 (m, 3H).

Example 19A

4-[5-(6-Acetylpiperidine-2-yl)-1,2,4-oxadiazol-3-yl]benzoylformate

N-(6-{3-[4-(Benzylthio)phenyl]-1,2,4-oxadiazol-5-yl}pyridine-2-yl)ndimethylacetamide (11,55 g) is stirred in a mixture of acetic acid (80 ml) and water (50 ml) in a bath of ice and cooled to 5°C. Chlorine is gradually added to the entry in the reaction of the whole of the original substance (monitoring by HPLC) and the temperature should not exceed 10°C. the Reaction mixture was stirred at 5°C for 15 min and then diluted with water with ice (100 ml). The crude product is collected by filtration, washed with water ice (three times) and diethyl ether (three times) and then dried in vacuum. Get 9.60 g (88% of theoretical yield) of product as a solid.

LC-MS (method 3): Rt=2,31 min

MS (IER): m/z=379 [M+H]+

Typical embodiments of the

Example 1

N-{3-[({4-[5-(b-Amino is iridin-2-yl)-1,2,4-oxadiazol-3-yl]phenyl}sulfonyl)amino]-5-forfinal}-1-cyanocyclohexane

N-(3-Amino-5-forfinal)-1-cyanocyclohexane (2,46 g) was added to 4-[5-(6-aminopyridine-2-yl)-1,2,4-oxadiazol-3-yl]benzoylperoxide (of 3.78 g) in dry pyridine (120 ml). The resulting solution was stirred at room temperature for 18 h and then poured into ice water. The crude product is collected by filtration, washed with water and dried. After chromatography on silica gel (methylene chloride to methylene chloride/methanol 50:1) and concentration of appropriate fractions allocate 2.28 g (40% of theoretical yield) of product.

LC-MS (method 3): Rt=2,07 min

MS (IER): m/z=520 [M+H]+

1H-NMR (400 MHz, DMSO-d6): δ=of 8.37 (d, 2H), 8,01 (d, 2H), to 7.64 (t, 1H), 7,45 (d, 1H), 7,35 (s, 1H), 7,21 (br d, 1H), 6.73 x (d, 1H), 6,68 (br d, 1H), 6,56 (br s, 2H), 1,65 (s, 4H).

Example 2

N-{3-[({4-[5-(b-Aminopyridine-2-yl)-1,2,4-oxadiazol-3-yl] phenyl} sulfonyl)amino]phenyl}-1-cyanocyclohexane

N-(3-AMINOPHENYL)-4-[5-(6-aminopyridine-2-yl)-1,2,4-oxadiazol-3-yl]benzosulfimide (4,50 g) prepared in dry DMF (110 ml), was added HATU (6,28 g), 1-cyanocyclohexane acid (2,45 g) and N,N-diisopropylethylamine (2,90 ml) and the reaction mixture is stirred in an argon atmosphere at room temperature for 1 h and then concentrated. The remainder chromatographic on silica gel (eluent: methylene chloride/methanol (from 100:1 to 20:1). After to the center of the corresponding fractions can be distinguished 4,99 g (90% of theoretical yield) of product.

LC-MS (method 2): Rt=2,13 min

MS (IER): m/z=502 [M+H]+

1H-NMR (400 MHz, DMSO-d6): δ=10,47 (s, 1H), 10,06 (s, 1H), 8,23 (d, 2H), of 7.97 (d, 2H), to 7.64 (t, 1H), 7,53 (s, 1H), 7,45 (d, 1H), 7,28 (d, 1H), 7,17 (t, 1H), at 6.84 (d, 1H),6.73 x(d, 1H), 1,65 (s, 4H).

Example 3

N-{3-[({4-[5-(6-Aminopyridine-2-yl)-1,2,4-oxadiazol-3-yl]phenyl}sulfonyl)amino]-2-were}-1-cyanocyclohexane

Receive by analogy with example 2, using 3'-amino-2'-methylphenylacetic as the original substance.

LC-MS (method 3): Rt=1,91 min

MS (IER): m/z=516 [M+H]+

1H-NMR (400 MHz, DMSO-d6): δ=to 9.91 (s, 1H), 9,67 (s, 1H), compared to 8.26 (d, 2H), 7,87 (d, 2H), 7,65 (t, 1H), 7,47 (d, 1H), 7,10 (m, 2H), at 6.84 (dd, 1H), 6,76 (d, 1H), 1.91 a (s, 3H), and 1.63 (m, 4H).

Example 4

N-{3-[({4-[(6-Aminopyridine-2-yl)ethinyl]phenyl}sulfonyl)amino]phenyl}-1-cyanocobalaminitamin

N-(3-AMINOPHENYL)-4-[(6-aminopyridine-2-yl)ethinyl]benzosulfimide the dihydrochloride (750 mg), 1-cyanocyclohexane acid (229 mg), HATU (783 mg) and N,N-diisopropylethylamine (1,04 ml) is stirred overnight at room temperature in dry DMF (7 ml). The reaction mixture was purified using preparative HPLC (eluent: water (with the addition of a mixture of 1% hydrochloric acid)/acetonitrile, flow rate 50 ml/min) and receive 400 mg (47% of theoretical yield) of product.

HPLC (method 6): Rt=a 3.87 min

<> MS (IER+, IER-): m/z=458 [M-HCl+H]+, 456 [M-HCl-H]-,

1H-NMR (400 MHz, DMSO-d6): δ=10,45 (s, 1H, NH), 10,07 (s, 1H, NH), 7,83 (d, 2H), 7,79-7,66 (m, 3H), 7,51 (s, 1H), 7,27 (d, 1H), 7,17 (t, 1H), 7,01 (d, 1H), PC 6.82 (d, 2H), 1,65 (s, 4H).

Example 5

N-{3-[({4-[5-(6-Acetylpiperidine-2-yl)-1,2,4-oxadiazol-3-yl]phenyl}sulfonyl)amino]-5-forfinal}-1-cyanocyclohexane

N-(3-Amino-5-forfinal)-1-cyanocyclohexane (100 mg) was added to 4-[5-(6-acetylpiperidine-2-yl)-1,2,4-oxadiazol-3-yl]benzoylperoxide (148 mg) in dry pyridine (2 ml). The resulting solution was stirred at room temperature for 18 h and then poured into ice water. The crude product is collected by filtration, washed with water and dried. After purification using preparative RP-HPLC (eluent acetonitrile:water gradient mode) and concentration of appropriate fractions allocate 53 mg (24% of theoretical yield) of product.

LC-MS (method 7): Rt=2,46 min

MS (IER): m/z=562 [M+H]+

1H-NMR (400 MHz, DMSO-d6): δ=10,99 (s, 1H), 10,78 (s, 1H), 10,26 (s, 1H), 8,40 (d, 1H), 8,17 (d, 2H), of 8.06 (m, 4H), 7,37 (s, 1H), 7,21 (d, 1H), of 6.68 (d, 1H), 2,15 (s, 3H), l,66 (s, 4H).

Century, the Study of physiological activity

Activity in vitro of the compounds proposed in this invention can be demonstrated using the following studies:

Investigation of the anti-CPSC (against qi is megalovirus person) cytopathogenicity

The compounds used in the form of a 50 mm solution in dimethyl sulfoxide (DMSO). As a compound for comparison use ganciclovir®. After addition of 2 μl of the original solution in DMSO concentrations of 50, 5, 0.5 and 0.05 mm, respectively, in portions 98 ál of culture medium to the cells, placed in rows 2 And-H 96-well plate to conduct two studies in the series to 11 tablet spend dilution 1:2 portions environment 50 ál. The wells in rows 1 and 12 contain 50 ál of the environment. Then all wells (row 1 = control cells) pipette placed in 150 μl of a suspension of 1×104cells (embryonic fibroblasts of preputium [NHDF]) and in rows 2-12 put the mixture infected by CPSC and uninfected cells NHDF (MH3 (multiplicity of infection) = 0,001-0,003), i.e. 1-3 infected cells at 1000 uninfected cells. The number 12 (without the addition of substances) acts as a virus control. Final concentration in the study are 250-0,0005 μm. Tablets incubated at 37°C/5% CO2for 6 days, until all cells in viral control will not be infected (100% cytopathogenic effect [of the centre e]). The cells are then fixed and stained by adding a mixture of formalin with dye Institute (30 min), washed with bidistilled water and dried in a drying Cabinet at 50°C. Then spend the visual is e learning tablets with an overhead microscope (device for the study of breeding colonies, produced by the firm Technomara).

By using research of tablets you can get the following information:

SS50(NHDF) = substance concentration in μm, at which the detected visible cytotoxic effects on the cells compared to uninfected control cells;

EU50(CPSC) = substance concentration in μm, which leads to suppression of the centre e (cytopathogenic effect) by 50% compared to not exposed to viral control;

SI (selectivity factor) = SS50(NHDF)/EC50(CPSC).

In vitro typical values of compounds proposed in the present invention, shown in the table:

Table a
Example No.NHDF CC50[µm]CMVC EU50[µm]SI CMVC
1710,0116450
21410,00720140
31020,00251000
4470,0212240
5710,0262730

The applicability of the compounds proposed in the present invention, for infection control CMVC can be demonstrated using the following animal models:

Model CMVC xenograft Gelfoam®

Animals:

Use immunodeficient mice Fox Chase SCID.NOD or NOD.CB17-Prkdc/J at 5-6 weeks of age (16-20 g), purchased from firms breeding Taconic M&B, Denmark; Jackson, USA. Animals kept in sterile conditions (including litter and food) in insulators.

Growing virus:

The human cytomegalovirus (CPSC), strain Davis or AD169, grown in vitro in embryonic fibroblasts of preputium person (NHDF cells). After infection of NHDF cells at multiplicity of infection (INL), is equal to 0,01-0,03, virus-infected cells are harvested after 5 to 10 days and stored in the presence of a minimum maintenance environment (MEAs), 20% fetal calf serum (FCS) (about./vol.), 1% glutamine (about./vol.), 1% of a mixture of penicillin/streptomycin (about./about.) with the addition of 10% DMSO at -80°C. After 10-fold serial dilution of virus-infected cells to determine the titer in 24-hole tablets containing merging is to be NHDF cells, after fixation and staining with the dye solution from the Institute in formaldehyde.

Preparation of sponges, transplantation, treatment and research:

Sponge of collagen 1×1×1 cm (Gelfoam®; Peasel & Lorey, order no. 407534; K.T. Chong et al., Abstracts of the 39thInterscience Conference on Antimicrobial Agents and Chemotherapy, 1999, p.439) first moistened with phosphate buffered saline (SFF)contained air bubbles are removed by degassing, and then they are stored in MPs, 10% FCS (vol./vol.), 1% glutamine (about./vol.), 1% of a mixture of penicillin/streptomycin (about./vol.). 1×10 virus-Infected NHDF cells (infection through CMVC Davis or CPSC AD169 INL=0,03) taken after 3 h after infection and 20 ál map, 10% FCS (vol./vol.), 1% glutamine (about./vol.), 1% of a mixture of penicillin/streptomycin (about./about.) dropwise applied onto a wet sponge. Sponges incubated for 3-4 h to ensure the adhesion of cells. Then, after the addition of the environment (map, 10% FCS) (about./vol.), 1% glutamine (about./vol.), 1% of a mixture of penicillin/streptomycin (about./vol.), sponges incubated over night. For transplantation in immunodeficient mice anaesthetize aventinum or a mixture of ketamine/xylazine/acepromazine, wool from the back removed with a razor, cut 1-2 epidermis, relieve tension and wet sponges transplanted under the skin of the back. The wound closed with glue for fabrics or clamps. After 4-6 h after transplantation is ISA can for the first time to treat (one dose administered on the day of surgery). In the following days, conduct oral treatment three times per day (7.00 and 14,00 and 19,00 h), twice a day (at 8 and 18 h) or once a day (9 h) for 8 days. The daily dose is, for example, 1 or 3 or 10 or 30 or 100 mg/(kg body weight), injected volume is 10 ml/(kg body mass). Compounds prepared in the form of a suspension of 0.5% tylose/SFP with 2% DMSO or other suitable mixture, promoting the dissolution of compounds, for example, 2% ethanol, and 2.5% Solutol, 95.5% of SFF. 10 days after transplantation and after about 16 h after the last injection of compound animal painlessly kill and remove the sponge. Virus-infected cells isolated from sponges through cleavage by collagenase (330 IU/1.5 ml) and stored in the presence of MPs, 10% FCS (vol./vol.), 1% glutamine (about./vol.), 1% of a mixture of penicillin/streptomycin (about./vol.), 10% DMSO at -140°C. the Study was conducted after a 10-fold serial dilution of virus-infected cells by determining the titer in 24-hole tablets containing confluent NHDF cells after fixation and staining with the dye solution from the Institute in formaldehyde. The number of infected cells or virus infected particles (the study of infectious cents) after administration of the compounds is correlated with the number obtained for the control group, which was treated by placebo. Statistical processing is performed using appropriate computer programs, such as GraphPad Prism.

Pharmacokinetic studies

The pharmacokinetics of active substances examined after intravenous or oral administration of doses ranging from 1 mg/kg intravenously and 3 mg/kg orally three male Wistar rats in the treatment cycle. For periodic sampling of blood the day before the experiment in the jugular vein of the animals implanted catheter. Substances injected intravenously and orally in the form of a solution. In most cases, the composition of the plasma (plasma of rats with the addition of 1-2% ethanol or DMSO, 2 ml/kg) is used for intravenous and composition based on PEG (polyethylene glycol (10% ethanol, 40% PEG 400, 50% water, 5 ml/kg) is used for oral administration.

After the introduction of the active substance in the blood samples taken through the catheter within 24 hours containing heparin tubes for samples. After sampling blood samples are centrifuged and the supernatant (plasma) pipette transferred into Eppendorf tubes. Before analysis, the plasma samples stored at a temperature not higher than -15°C.

For processing the samples thawed. Then plasma proteins are precipitated by adding acetonitrile, which is an internal standard. As an internal standard chosen by the substance of the same structural class, which is structurally more similar to the active connection. the La preparation of the calibration samples active substance in different concentrations was added to the aliquot of pure plasma and process them together with samples of unknown composition. In addition, prepare additional samples for quality control three different concentrations, which serve to validate methods of analysis.

The determination of concentrations of active substance in the sample is performed using high-performance liquid chromatography with mass spectrometric detection (LC/MS-MS). The concentration of the active substance in samples of unknown composition is determined by the relative heights or peak areas when comparing with a calibration graph using Concalc for Windows (CCW, Integrierte Labordatensysteme, version 2.5 or later, Bayer AG). Then, for each animal on changes in plasma concentrations over time pharmacokinetic parameters are calculated using a block analysis using the program KINCALC, version 2,50,02 (Bayer AG, 2001).

Then for compounds that have found improved pharmacokinetic parameters in rats, conduct pharmacokinetic studies after administration to mice and dogs. Based on these data, carried out the first evaluation of pharmacokinetic parameters for a person using interspecific transfer pharmacokinetic data according to the method Boxenbaum.

Through these studies it is possible to obtain the following data:

Vss= volume of distribution;

CL = rate of elimination;

t1/2= half-life;

AUC= total area under the curve medicine - concentration from time to time;

Cmax= maximum concentration;

F = bioavailability.

Pharmacokinetic data for the compounds of example 1 after single intravenous and oral administration to male Wistar rats (n=3 for each study or n=3, respectively) are shown in table C. the Compounds proposed in the present invention, exhibit improved pharmacokinetic characteristics.

/tr>
Table
Table 15
Intravenous dose1.3 mg/kg intravenous1
Vss[l/kg]0,321
CLplasma[l/(h·kg)]0,064
CLblood[l/(h·kg)]0,128
t1/2[h]4.26 deaths
Oral dose3 mg/kg r.o.,2
AUCnormal oral[kg·h/l]8,58
Cmax, normal, oral[kg/l]1,08
F [%]55,3
1the solution in the plasma of rats with the addition of 1% DMSO, 2 ml/kg
2: solution in 10% ethanol, 40% PEG 400, 50% water, 5 ml/kg

Identification of metabolites

Interspecies differences in the metabolism of the active compounds can have a big impact on its development. The task is to find substances that path metabolic decomposition which in humans and experimental animals, such as rats and dogs, do not vary greatly. For new active substances are first incubated in vitro with liver microsomes of rats, dogs and humans to map the phase I metabolism. Then interest compounds additionally incubated with hepatocytes of rats and humans to explore the full phase I and phase II metabolism in the liver and their mappings.

All new active compounds are incubated at a concentration equal to 20 μm. To do this, prepare the initial solution concentration of 2 mm in acetonitrile and then the pipette is introduced into inkubiruemykh portion at a dilution of 1:100, so that the portions contained not more than 1% acetonitrile. Liver microsomes incubated at 37°C in 50 mm califorina buffer with pH 7.4 with addition and without addition system, producing NADPH, with the holding of 1 mm NADP +, 10 mm glucose-6-phosphate and 1 UNIT of glucose-6-phosphate dehydrogenase. Primary hepatocytes also incubated at 37°C in suspension medium E. Williams After incubation for 0-4 h reaction in inkubiruemykh the stop portions acetonitrile (final concentration of approximately 30%) and proteins separated by centrifugation at about 15000×g. Samples, which thus stopped the reaction, analyze immediately or until analyzed, stored at -20°C.

Tests conducted using high-performance liquid chromatography with ultraviolet mass-spectrometric detection (HPLC-UV-MS). This supernatant is incubated them samples chromatographic on a suitable column with reversed phase C18 using different mixtures of acetonitrile and 10 mm ammonium formate. For the identification of metabolites using a UV-chromatogram together with mass-spectrometric data. Characteristics of the metabolites formed from the respective investigated species, map and used for the detection of differences between species.

C. Typical embodiments of the pharmaceutical compositions

Connections proposed in the present invention, the following way can be included in pharmaceutical drugs:

Tablet:

Composition:

100 mg of the Compound of example 1, 50 mg of lactose (monohydrate), 0 mg of corn starch (natural), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate. Weight pills 212 mg. a Diameter of 8 mm, the radius of curvature of 12 mm

Preparation:

The mixture of the active ingredient, lactose and starch granularit with 5% (wt./wt.) aqueous solution of PVP. Then the granules are dried and mixed with magnesium stearate for 5 minutes the mixture is pressed using a conventional tabletiruemogo press (geometrical parameters tablets see above). In accordance with the recommendations of the pressing is carried out with a force of 15 kN.

The suspension, which can be administered orally:

Composition:

1000 mg of the Compound of example 1, 1000 mg of ethanol (96%), 400 mg Rhodigel (xanthan gum, FMC, Pennsylvania, USA) and 99 g of water.

10 ml Suspension for oral administration is equivalent to 100 mg single dose of the compounds proposed in the present invention.

Preparation:

Rhodigel is suspended in ethanol and the suspension is added the active ingredient. While mixing, add water. The mixture is stirred for about 6 h until complete swelling Rhodigel.

The solution, which can be administered intravenously:

Composition:

10-500 mg of the Compound of example 1, 15 g of polyethylene glycol 400 and 250 g of water for injection.

Preparation:

The compound of example 1 under stirring together with polyethylene glycol 400 is dissolved in water. The solution is sterilized by filtration (pore diameter ,22 μm) and aseptically Packed in heat-sterilized vials for injection. Last stoppered for infusion and Cavalcanti caps.

1. The compound of the formula

where And denotes a group of the formula
or
in which * indicates the site of bonding with the carbon atom pyridinoline rings, and
# specifies the location of the binding carbon atom of the phenyl ring,
R1denotes the amino group or medicalbilling,
R2denotes hydrogen,
R3denotes hydrogen,
R4denotes hydrogen,
R5denotes hydrogen or halogen,
R6denotes hydrogen or halogen,
R7denotes hydrogen,
R8denotes hydrogen, or
one of its salts, its MES or MES salts thereof.

2. The compound according to claim 1, characterized in that
But denotes a group of the formula

in which * indicates the site of bonding with the carbon atom pyridinoline rings, and
# specifies the location of the binding carbon atom of the phenyl ring,
R1denotes the amino group or medicalbilling,
R2, R3and R4denote hydrogen,
R5denotes hydrogen or halogen,
R6denotes hydrogen or halogen,
R7and R8denote hydrogen,
or one of its salts, its MES or Olivet its salts.

3. The compound according to claim 2, characterized in that a denotes a group of the formula

in which * indicates the site of bonding with the carbon atom pyridinoline rings, and
# specifies the location of the binding carbon atom of the phenyl ring,
R1denotes the amino group or medicalbilling,
R2, R3and R4denote hydrogen,
R5denotes hydrogen,
R6denotes hydrogen or halogen,
R7and R8denote hydrogen,
or one of its salts, its MES or MES salts thereof.

4. The method of obtaining the compounds of formula (I) according to claim 1, characterized in that the compound of the formula

in which A, R1, R2, R3, R4, R5and R6have the meanings according to claim 1,
enter into reaction with the compound of the formula

in which R7and R8have the meanings indicated in claim 1, and
X1denotes halogen, preferably chlorine or bromine, or hydroxy-group.

5. The compound according to any one of claims 1 to 3, intended for the treatment and/or prophylaxis of viral infections.

6. A drug intended for the treatment and/or prevention of viral infections comprising the compound according to any one of claims 1 to 3 in combination with an inert, non-toxic, pharmaceutically acceptable in the bound filler.

7. The use of compounds according to any one of claims 1 to 3 for the preparation of medicines intended for the treatment and/or prophylaxis of viral infections.

8. The use according to claim 7, characterized in that the viral infection is a human cytomegalovirus (CPSC) or another representative of the group of herpes viridae (herpes viruses).

9. The way to combat viral infection by introducing an antiviral effective amount of at least one compound according to any one of claims 1 to 3, the medicinal product according to claim 6 or drugs specified in paragraph 7 or 8.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula , where R1 represents aryl, heteroaryl or (C5-C6)-cycloalkyl, each of which has an optional substitute halogen or (C1-C6)-alkyl; R2 represents hydrogen or (C1-C4)-alkyl; R3 represents -P(=O)-(alkoxy)2 or Y1Y2N-SO2-, cycloalkyl, aryl, heteroaryl, heterocyclyl, cycloalkenyl, each of which has an optional substitute: halogen, hydroxy, carboxy, Y1Y2N-, Y1Y2NC(=O)-, Y1Y2N-SO2, R7-SO2-NR6-, R7-C(=O)-NR6-, or alkyl, alkoxy, alkoxycarbonyl, each of which has an optional substitute halogen, -P(=O)-(alkoxy)2, Y1Y2NC(=O)-, Y1Y2N-SO2-, R7 -SO2-NR6 -, aryl or heteroaryl and when R3 is cycloalkyl, cycloalkenyl, heterocyclyl, it also optionally substituted by oxo; L1 represents a bond or (C1-C6)-alkylene, which is optionally substituted by -P(=O)-(alkoxy)2; R4, R5 and R6 are hydrogen, R7 represents alkyl; both Y1 and Y2 independently is hydrogen, alkyl which has an optional substitute: hydroxy, amino, alkylamino, dialkylamino, alkoxy, cycloalkyl, or Y1 and Y2 together with nitrogen atom whereto attached form heterocyclyl which optionally contains one more heteroatoms selected from oxygen, nitrogen or sulphur where heterocyclyl has an optional substitute alkyl or oxo; provided when L1 represents a bond, R3 is not optionally substituted by phenyl, optionally substituted by naphthyl, optionally substituted by benzoimidazolyl, optionally substituted by benzothiazolyl or optionally substituted by tetrazolyl; or to its pharmaceutically acceptable salt, and also to a pharmaceutical composition including a compound of formula I.

EFFECT: there are produced and described new compounds which can be effective in treating allergic or inflammatory disorders, particularly such disorders, as allergic rhinitis, asthma or chronic obstructive pulmonary disease.

25 cl, 118 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R1 is a 3-7-member carbocyclic ring and n is a number ranging from 1 to 8, and the rest of the radicals are described in the claim.

EFFECT: possibility of using such compounds and compositions in therapy as metabotropic glutamate receptor modulators.

33 cl, 367 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-quinolyloxazoles of formula (I) or pharmaceutically acceptable salts thereof, having PDE4 inhibiting properties, a pharmaceutical composition based on said compounds and use thereof to prepare a medicinal agent which inhibits inflammatory cell recruitment in respiratory tracts. , where is , X is O, R1 is alkyl, R3 and R4 are independently selected from H, R5 and R6 are independently selected from a group comprising H, alkyl, hydroxyalkyl, t equals 1 or 2. Values of substitutes R7-R11, R13 are given in the formula of invention.

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: chemistry.

SUBSTANCE: in formula (I) Cy1 is a 6-member heterocyclyl containing N as a heteroatom, a 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S and O, phenyl or phenyl condensed with a 5-member heterocycle containing O as a heteroatom, each optionally having 1-3 identical or different substituting Cy1 groups which are: (C1-C6)-acyl, cyano, carboxy, hydroxy, (C1-C6)alkylsulphonyl, (C3-C6)-cycloalkyl, a 6-member heterocyclyl containing 1-2 heteroatoms selected from O and N, phenyl, a 5-member heteroaryl containing 1-3 heteroatoms selected from N, S and O, Y1Y2N-, Y1Y2NC(=O)-, Y1Y2NSO2-, (C1-C6)-alkyl-SO2-N(R5)-C(=O)-, R6-C(=O)-N(R5)-, R7-NH-C(=O)-NH-; (C1-C6)-alkoxycarbonyl; (C1-C6)-alkyl, which optionally contains 1-3 identical or different substitutes which are halogen, carboxy, cyano, hydroxy, Y1Y2N-, Y1Y2N-C(=O)-, R6-C(=O)-N(R5)-, R8-SO2-N(R5)-C(=O)-, 5-member heterocyclyl, containing N as a heteroatom, 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; or (C1-C6)-alkoxycarbonyl; as well as (C1-C6)-alkoxy which optionally have 1-3 identical or different substitutes which are carboxy, (C1-C6)-alkoxycarbonyl, cyano, 3-member heterocyclyl containing O as a heteroatom, or 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; where phenyl or heteroaryl fragments in the substituting Cy1 groups optionally and independently have substitutes represented by hydroxy, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxy, (C1-C6)-alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-; and where cycloalkyl fragments in the substituting Cy1 groups which optionally and independently have substitutes represented by (C1-C6)-alkoxy, carboxy; Cy2 is a 9-member cycloalkenyl, phenyl, 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteratoms selected from N, S and O, or phenyl condensed with a 5,6-member heterocycle containing 1-2 heteroatoms selected from N and O, each independently and optionally having 1-3 identical or different substitutes represented by (C1-C6)-alkoxy, (C1-C3)-alkyl, hydroxy, halogen, halogen-(C1-C6)-alkoxy, nitro, Y1Y2N-; L1 is an alkylene with a straight or branched chain containing 1-6 carbon atoms, optionally substituted carboxy; or L1 is -CH2-(C1-C5)halogenalkylene; L2 is a bond, -O- or -CH2-O-. Other values of radicals are given in the formula of invention.

EFFECT: novel compounds have prostaglandin D2 receptor antagonist properties, can be used in treating primarily allergic disorders such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy and other diseases.

39 cl, 1 tbl, 99 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel AMPA receptor antagonists - 1H-quinazoline-2,4-dione derivatives, selected from the group: N-(6-imidazol-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-morpholin-4-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrrol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(7-nitro-2,4-dioxo-6-[1,2,4]triazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrrolidin-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-azetidin-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-[1,2,3]triazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-morpholin-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(2,4-dioxo-6-[1,2,4]triazol-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; (2,4-dioxo-6-[1,2,4]triazol-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)amide ethanesulphonic acid; N-(6-imidazol-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(2,4-dioxo-6-thiomorpholin-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(6-[1,4]oxazepan-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide and N-(6-azetidin-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide and physiologically acceptable salts thereof.

EFFECT: compounds can be used in treating such diseases as epilepsy and schizophrenia.

9 cl, 106 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I: where Y1 and Y2 are independently selected from N and CR10, where R10 is selected from group, including hydrogen, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, R1 is selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino, C1-C6alkylsulfanyl, dimethylaminoethoxy and pyperasinyl, substituted up to 2 radicals C1-C6alkyl, R2 and R5 are independently selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy and dimethylamino, R3 and R4 are independently selected from group, including hydrogen, halogen, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, or R1 and R5 with phenyl, to which they are bound, form C5-C10heteroaryl, R6 and R7 are independently selected from group, including hydrogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkyl, on condition that R6 and R7 both do not represent hydrogen, R8 is selected from group, including hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkoxy, R9 is selected from -S(O)2R11, -C(O)R11, -NR12aR12b and -R11, where R11 is selected from group, including aryl, cycloalkyl and heterocycloalkyl, R12a and R12b are independently selected from (C1-C6)alkyl and hydroxy(C1-C6)alkyl, and said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in composition of R9 optionally contain as substituents from 1 to 3 radicals, independently selected from group, including (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, C6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl and C3-C8heterocycloalkyl, where said arylalkyl substituent in composition of R9 optionally contains as substituents from 1 to 3 radicals, independently selected from group, including halogen, cyano, (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino and methyl-pyperasinyl, as well as to its pharmaceutically acceptable salts, hydrates, solvates and isomers. In addition, invention relates to method of inhibiting hedgehog pathway in cell and to method of inhibiting undesirable cell proliferation, when cell contacts with compound described above.

EFFECT: obtained and described are novel compounds, which can be applied in medicine.

13 cl, 153 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of general formula (I-B), where values of radicals are described in formula of invention, or to its pharmaceutically acceptable salts, which possess activity of inhibiting cholesterol ester transfer protein, due to which said compounds or salts can be used for prevention and/or treatment of arteriosclerotic diseases, hyperlipemia or dislipidemia or similar diseases.

EFFECT: obtaining pharmaceutical compositions for prevention and treatment of arteriosclerosis, as well as application of formula I-B compounds for manufacturing of medication.

15 cl, 36 tbl, 252 ex

FIELD: chemistry.

SUBSTANCE: invention relates to thiophene derivatives of formula (I):

where A denotes -CONH-CH2-, -CO-CH=CH-, -CO-CH2CH2-, -CO-CH2-O-, -CO-CH2-NH-, or ; R1 denotes hydrogen, C1-5-alkyl or C1-5-alkoxy; R2 denotes hydrogen, C1-2-alkyl, C1-5-alkoxy, trifluoromethyl or halogen, R3, R31, R32, R33, R34, R4, R5, R6, R7, k, m, n are described in claim 1. The invention also relates to a pharmaceutical composition for preventing or treating diseases and disorders associated with an activated immune system, based on said compounds and to use thereof as therapeutically active compounds for preventing or treating diseases or disorders such as graft rejection, graft versus host reaction and autoimmune syndromes.

EFFECT: improved properties of the compound.

27 cl, 2 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent which modulates PPARδ (peroxisome proliferator-activated receptor δ). In formula I

, p is equal to 1; L2 is selected from a group which includes -XOX- and -XSX-, where X is independently selected from a group which includes a bond and C1-C4alkylene; R13 is selected from a group which includes halogen, C1-C6alkyl; R14 is selected from a group which includes -XOXC(O)OR17 and -XC(O)OR17, where X denotes a bond or C1-C4alkylene and R17 denotes hydrogen; R15 and R16 are independently selected from a group which includes -R18 and -YR18, where Y is selected from a group which includes C2-C6alkenylene, and R18 is selected from a group which includes C6-C10aryl, pyridinyl, pyrimidinyl, quinolinyl, benzo[b]furanyl, benzoxazolyl, 1,5-benzodioxanyl, 1,4-benzodioxanyl and 3,4-dihydro-2H-benzo[b][1,4]dioxepin; where any of phenyl, pyridinyl, pyrimidinyl, benzoxazolyl in R18 is independently substituted with 1-2 radicals, independently selected from a group which includes halogen, C1-C6alkyl, C2-C7alkenyl, C1-C6alkoxy group, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy group, C3-C12cycloalkyl, phenyl, morpholinyl, pyrrolidinyl, piperidinyl, -XNR17R17, -XC(O)NR17R17, -XC(O)R19 and -XOXR19, where X denotes a bond or C1-C4alkylene; R17 is selected from a group which includes C1-C6alkyl, and R19 is selected from a group which includes C3-C12cycloalkyl, piperidinyl and phenyl. The invention also relates to use of the disclosed compounds to prepare a medicinal agent which modulates PPARδ activity, a pharmaceutical composition having PPARδ activity modulating properties, which contains a therapeutically effective amount of the disclosed compound and to use of the pharmaceutical composition in preparing a medicinal agent which modulates PPARδ activity.

EFFECT: improved properties of compounds.

10 cl, 1 tbl, 69 ex

Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention describes novel derivatives of 2,6-diaminopyridine of formula (I), where R1 is piperidine which is optionally substituted with up to four substitutes independently selected from a group comprising: (a) hydrogen, (b) lower alkyl, (c) lower alkyl substituted with an oxo group or aryl, (d) CO2R7, (e) COR12, (f) C(O)NR13R14, and (g) S(O)nR15; R2 is phenyl which can be substituted with up to four substitutes independently selected from a group comprising: (a) lower alkyl, (b) lower alkyl substituted with a halide or OR10, (c) halide, or (d) OR12; R5 and R6 are independently selected from a group comprising (a) hydrogen and (b) lower alkyl; R7 is selected from a group comprising (a) hydrogen and (b) lower alkyl; R10 is selected from a group comprising (a) lower alkyl, (b) aryl and (c) aryl substituted with a halide or NR5R6; R12 is selected from a group comprising (a) hydrogen and (b) lower alkyl; R13 and R14 are independently selected from a group comprising (a) hydrogen and (b) lower alkyl, R15 is selected from a group comprising (a) aryl, (b) aryl substituted with a halide, CO2R12, SO2R10, COR12, lower alkyl or lower alkyl substituted with a halide, OR12, oxo group, CO2R12, C(O)NR5R6 or NR5R6, (c) heteroaryl, (d) heteroaryl substituted with a halide, CO2R12, SO2R10, COR12, lower alkyl and lower alkyl substituted with a halide, OR12, oxo group, CO2R12, C(O)NR5R6 or NR5R6, (e) NR5R6, (f) lower alkyl, (g) lower alkyl substituted with a halogen, OR12, oxo group, CO2R12, C(O)NR5R6 or NR5R6, (h) a heterocycle and (i) a heterocycle substituted with CO2R12, COR12, SO2R10, lower alkyl, C(O)NR5R6 or NR5R6; n equals 0, 1 or 2; as well as a pharmaceutical composition having inhibitory effect on cyclin-dependant kinase and a method of producing the compound of formula I.

EFFECT: novel compounds which have antiproliferative activity and can be used for treating or curbing cancer are obtained and described.

28 cl, 58 ex, 4 tbl

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of formula (I) , where A is optionally substituted monocyclic aryl and heteroaryl group, B is optionally substituted monocyclic nitrogen-containing heterocyclic group, and either a) R1 is hydrogen atom and R2 is group selected out of -NH2 and optionally substituted alkinyl group, or b) R2, R1 and -NH- group with linked R1 form fragment selected out of fragments of formulae , , and , where Ra is selected out of hydrogen atom and group selected out of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, -OR3, where R3 is independently selected out of group including hydrogen atom and lower alkyl or cycloalkyl groups, Rb is selected out of hydrogen atom and group selected out of optionally substituted alkyl or optionally substituted cycloalkyl group; application of claimed compounds in medicine obtainment for treatment of pathological states or diseases, the course of which is alleviated by antagonistic effect on adenosine receptor A2B, and pharmaceutical composition with antagonistic effect on adenosine receptor A2B.

EFFECT: compounds applicable in treatment of such diseases as asthma, bronchostenosis, allergic diseases, hypertension, atherosclerosis, reperfusion injury, myocardial ischemia, retinopathy, inflammation, gastrointestinal disorders related to cell proliferation, diabetes and/or autoimmune diseases.

26 cl, 49 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: described is compound representing 2,5-disubstituted 3-mercaptopentanic acid of formula (I) or its pharmaceutically acceptable salt, where R' represents phenyl, possibly substituted, naphtyl, pyridinyl, 1,2,3,4-tetrahydropyrimidine-2,4-dion-yl, substituted with C1-4alkyl, or tetrahydrothienyl; R2 represents aminopyridinyl, aminothiazolyl or 3-azabicyclo[3.2.1]octyl; R3 represents C1-4alkoxy, possibly substituted with phenyl (substituted with halogen) or pyridinyl; NR5R6 or N-bonded 5- or 6-member heterocyclic ring representing pyrrolidinyl, piperidinyl or piperazinyl ring, non-substituted or monosubstituted, or condensed with benzene ring, which is possibly substituted with C1-4alkoxy; R4 represents N-bonded pyrrolidinyl ring, monosubstituted with C1-4alkyl, which is substituted with NHphenyl; R5 and R6 independently represent hydrogen, C1-4alkyl, possibly substituted, or C2-4alkenyl; and method of obtaining it.

EFFECT: obtaining compounds inhibiting carboxypeptidase and which can be used in prevention and treatment of diseases in which inhibiting carboxypeptidase is useful.

7 cl, 1 tbl, 53 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the production method for 2,3-dichloropyridine, in which interaction is provided between 3-amino-2-chloropyridine with nitrite of alkaline metal in presence of aqueous hydrochloric acid with production of diazonium salt; and then diazonium salt is decomposed in presence of copper catalyst, in which at least approximately 50% of copper is represented by copper with oxidation extent (II).

EFFECT: increased yield of finished product in production scale.

27 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: there is disclosed compounds of formula II , where each R2 independently stands for H, halogen, cyano, NO2, OR5, NR6R7, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo, arylalkyl, substituted arylalkyl, heterocycloalkyl or substituted heterocycloalkyl; B represents O, S, SO or SO2; each W and X independently represents C or N; n is within 0 to 4 if both W and X represent C, 0 to 3, if either X or W represent N, and 0 to 2 if both X and W represent N; R3, R5, R6, R7 are independently chosen from H, alkyl, substituted alkyl, alkenyl, alkinyl, substituted alkinyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo; R4 represents optionally substituted 5-6-merous heteroaryl containing nitrogen atom provided (a) if R4 stands for pyridyl, R4 is not substituted with both hydroxy and methoxy groups; and (b) R4 stands for pyrimidinyl, it is n-substituted =O; A is chosen from following compounds of formula: , where D stands for S or O; m is within 0 to 6; R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 are independently chosen from H, halogen, NR30R31, OR32, CO2R33, SO2R36, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkinyl, substituted alkinyl, -CN, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; R28 and R29 are independently chosen from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl or together they form carbocyclic or heterocyclic ring consisting of 3 to 8 atoms; and R30, R31, R32, R33 and R36 are independently chosen from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkinyl, substituted alkinyl, cycloalkyl, substituted cycloalkyl, alkoxycarbonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo, heterocycloalkyl or substituted heterocycloalkyl as pharmaceutical composition for cancer treatment containing compound of formula II.

EFFECT: production of new compounds and based pharmaceutical composition applied for cancer treatment.

18 cl, 147 ex

FIELD: chemistry.

SUBSTANCE: invention concerns 2,4-bis(trifluorethoxy)pyridine compound represented by the formula (1), where X1 is fluorine or hydrogen atom or its salt as inhibitor of acyl-coenzyme A of cholesterol acyltransferase (ACAT), and medicine and pharmaceutical composition based on them, its application, method of obtainment, and new intermediary compounds.

EFFECT: obtaining compounds which can be applied in prevention or treatment of diseases mediated by ACAT activity, such as hyperglycemia and arterial sclerosis.

10 cl, 4 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new aminopyridine derivative of the formula (I-A) , where R2 and R3 are independently selected from hydrogen, C1-C6-alkyl; R5 represents the group of formula or, or where R9, R10, R11, R12 and R13 independently represent hydrogen, halogen, cyanogen, C1-C6-alkoxy; R14 and R15 independently have values, determined above for R9-R13, to the pharmaceutical composition on the basis of the said connections, possessing antagonistic activity with respect to mGluR5 receptors. The invention also relates to the method of treating the disorders of the central nervous system as well as other disorders modulated by receptors mGluR5 and to the application of connections of the formula I, for preparing medicine.

EFFECT: obtaining new connections and a pharmaceutical composition on their basis, for the purposes of treating disorders of the central nervous system.

13 cl, 13 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of aniline of the general formula (I): and their pharmaceutically acceptable salts and isomeric forms possessing properties of phosphodiesterase-4 inhibitors. Compounds can be used, fore example, for enhancing cognitive ability. In compounds of the general formula (I) R1 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more halogen atoms; R2 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkoxy or their combinations, (C3-C10)-cycloalkyl, (C4-C16)-cycloalkylalkyl wherein alkyl fragment comprises from 1 to 4 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and alkyl fragment that can be linear or branched and comprises from 1 to 5 carbon atoms and wherein radical arylalkyl can be unsubstituted or substituted in aryl fragment with one or more substitutes of the following order: halogen atom, alkoxy group comprising from 1 to 4 carbon atoms or their combinations, and in alkyl fragment one group -CH2CH2- is optionally replaced for group -CH=CH-, and one group -CH2- is optionally replaced for -O- for -NH-, partially unsaturated carbocyclic group comprising from 5 to 9 carbon atoms that can comprise condensed benzene ring, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including one atom chosen from oxygen (O), or heterocyclylalkyl group wherein heterocyclic fragment can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including 1-2 atoms chosen from nitrogen (N) or sulfur (S) atoms, and alkyl fragment that can be linear or branched comprises from 1 to 5 carbon atoms; R3 means partially unsaturated carbocyclylalkyl group wherein carbocyclic fragment comprises from 5 to 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein arylalkyl radical can be linear or substituted in aryl fragment with one or more substitutes of the following group: trifluoromethyl, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations, heterocyclylalkyl group wherein heterocyclic fragment can be aromatic, partially or completely saturated and comprises from 5 to 10 atoms in cycle including 1-2 atoms chosen from N, O or S, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein heterocyclylalkyl group can be linear or substituted in heterocyclic fragment with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations; R4 means (C6-C12)-aryl that can be linear or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C2-C4)-alkenyl, hydroxy, (C1-C4)-alkoxy, (C2-C4)-alkoxyalkoxy, nitro, trifluoromethyl, -OCF3, amino group, aminoalkyl, aminoalkoxy, hydroxy-(C1-C4)-alkyl, hydroxamic acid, tetrazol-5-yl, 2-(heterocyclyl)-tetrazol-5-yl, carboxy, alkoxycarbonyl, cyano, acyl, alkylsulfonyl, phenoxy, trialkyloxy, R5-L or their combinations, or heteroaryl comprising from 5 to 10 atoms in cycle including 1-2 atoms chosen from N wherein heteroaryl can be linear or substituted with one or more substitutes of the following order: (C1-C4)-alkyl, (C1-C4)-alkoxy, carboxy, alkoxycarbonyl or their combinations; R5 means hydrogen atom, (C1-C8)-alkyl, (C3-C10)-cycloalkyl, C6-aryl, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 10 atoms in cycle from which at least atom means N or O, and wherein heterocyclic group can be linear or substituted with one or more (C1-C4)-alkyls, or group heterocyclylalkyl, and others. Also, invention relates to intermediates compounds and to a method for enhancing the cognitive ability.

EFFECT: valuable biological and biochemical property of compounds.

49 cl, 8 sch, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel polycyclic compounds of the formula (I): wherein radicals and symbols have values given in the invention claim. Compounds of the formula (I) possess properties of H3 receptors antagonist. Also, invention relates to a pharmaceutical composition containing compounds of the formula (I). Also, invention relates to a method for treatment of disease of group comprising difficulty in nasal breath, obesity, somnolence, narcolepsy, attention deficiency with hyperactivity, Alzheimer's disease and schizophrenia that involves using compounds of the formula (I) and, optionally, in combination of H receptor antagonist.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

39 cl, 3 tbl, 31 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing inhibitory effect on activity of dipeptidyl peptidase IV (DPP IV) that can be used, for example, in treatment of diabetes mellitus type 2. In compounds of the formula (I) X means nitrogen atom (N) or -C-R5; R1 and R2 mean independently hydrogen atom, (C1-C6)-alkyl; R3 means saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, or perfluoro-(C1-C6)-alkyl; R4 means (lower)-alkyl, (lower)-alkoxy-, (lower)-alkylthio-group, saturated or aromatic 7-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-, amino-group or perfluoro-(C1-C6)-alkyl, 4-fluorophenyloxy-(C1-C6)-alkyl or (C3-C6)-cycloalkyl; R5 means hydrogen atom or (C1-C6)-alkyl. Also, invention relates to methods for synthesis of compounds of the formula (I), pharmaceutical compositions and their using for preparing medicaments used in treatment and/or prophylaxis of DPP IV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

21 cl, 93 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula (I) or to their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity, and to a based pharmaceutical composition. (I) where P represents phenyl optionally substituted by 1 or 2 substitutes independently selected from halogen, C1-4alkyl, cyano, trifluoromethyl, C1-4alkoxy and trifluormethylthio, and R2 has the values specified in the patent claim.

EFFECT: preparation of new compounds of general formula (I) or their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity.

16 cl, 340 ex

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