New naphthyridine derivative monohydrate and method for preparing it

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound, namely 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluor-1,5-naphthyridin-2(1H)-one monohydrate which possess strong antibacterial activity. This compound is highly safe and applicable in the production of pharmaceutical preparations as a parent drug. What is furthermore described is a method for preparing 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluor-1,5-naphthyridin-2(1H)-one monohydrate of formula 19 and methods for preparing intermediate compounds.

EFFECT: preparing the compounds possessing strong antibacterial activity.

8 cl, 1 tbl, 17 ex

 

The AREA of TECHNICAL APPLICATIONS

The present invention relates to a new monohydrate derived naphthiridine and how to obtain it.

The LEVEL of TECHNOLOGY

In medical practice to use a large variety of antibiotics and synthetic antibacterial agents for the treatment of infectious diseases. However, recently been found resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and penicillin-resistant Streptococcus pneumoniae (PRSP). Treatment of patients infected with resistant microorganisms, was a serious problem. In addition, appeared multiresistant micro-organisms that have acquired resistance to many drugs. Infectious diseases caused by multidrug-resistant microorganisms, such as disease, difficult to treat, was a major global problem.

The emergence of antimicrobial agents that are effective against these resistant microorganisms, it was absolutely necessary, and, for example, the connection quinolone considered to be effective against MRSA, disclosed in WO 99/07682 (PATENT DOCUMENT 1). Moreover, the compounds disclosed in WO 2004/002490 (PATENT DOCUMENT 2) and in WO 2004/002992 (PATENT DOCUMENT 3)are known as compounds having mechanisms de the acts, different from the mechanisms of action of existing drugs.

PATENT DOCUMENT 1: Publication of international patent, brochure No. WO 99/07682

PATENT DOCUMENT 2: international publication of an international patent, brochure No. WO 2004/002490

PATENT DOCUMENT 3: international publication of an international patent, brochure No. WO 2004/002992

DISCLOSURE of INVENTIONS

PROBLEMS THAT SHOULD be SOLVED by the INVENTION

There is a need for the development of drugs having high security and strong antibacterial activity against gram-positive bacteria, gram-negative bacteria and resistant bacteria. In addition, the high expectations associated with the applicable method of obtaining this medication and generated in the production of applicable intermediate products.

The WAYS to SOLVE PROBLEMS

In such circumstances, the authors of the present invention conducted extensive research and found that the monohydrate of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she (1) has strong antibacterial activity and a high degree of safety; (2) does not detect the ability to grow, absorbing moisture from the atmosphere or a hygroscopic; (3) easy circulation; (4) is obtained using the solvent, topanga to the human body; (5) is obtained in conditions that do not bring significant harm to the environment; and (6) suitable for mass production.

In addition, the authors of the present invention found that the monohydrate of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-(1H)-it can easily be obtained through interaction

(1) derived naphthiridine represented by the formula [7]

[Formula 7]

and produced by the interaction of the pyridine derivative represented by formula [1]

[Formula 1]

,

with an ester of acrylic acid with the formation of a derivative of acrylic acid represented General formula [2]

[Formula 2]

,

where R1represents an alkyl group,

then, restoring/ciclitira derived acrylic acid with the formation of derived dihydronaphthalene represented by the formula [3]

[Formula 3]

,

then the interaction derived derived dihydronaphthalene with the compound represented the General formula [4]

[Formula 4]

,

where L1represents a leaving group; Y represents a protected carbonyl group,

get n otvagnoe of dihydronaphthalene, we present the General formula [5]

[Formula 5]

,

where the Deputy Y defined above,

then oxidizing the obtained derived dihydronaphthalene with the formation of a derivative naphthiridine, we present the General formula [6]

[Formula 6]

,

where the Deputy Y defined above,

and then removing the protection derived naphthiridine

(2) a derivative of piperidine, we present the General formula [17]

[Formula 17]

,

where R4represents aminosidine group,

and the resulting interaction derived koiwai acid, represented the General formula [8]

[Formula 8]

,

where R2is a protective group of hydroxyl,

with a compound represented the General formula [9]

[Formula 9]

,

where L2represents a leaving group; X represents a leaving group,

to derive koiwai acid, represented the General formula [10]

[Formula 10]

,

where R2and X is defined above,

then removing the protection derived koiwai acid, with the formation of the derived koiwai acid, represented the General formula [11]

[Fo the mule 11]

,

where X is defined above,

then the interaction derived koiwai acid with ammonia receive a pyridine derivative represented by the formula [12]

[Formula 12]

,

then oxidizing the obtained derivative of pyridine, to obtain the pyridine derivative represented by formula [13] [Formula 13]

,

then the interaction of the obtained derivative of pyridine to piperidine derivative represented General formula [14]

[Formula 14]

,

where R3represents aminosidine group,

get a piperidine derivative represented General formula [15]

[Formula 15]

,

where R3defined above,

then protect aminogroup to get a piperidine derivative represented General formula [16]

[Formula 16]

,

where R4defined above; R3defined above,

and then remove the protection from the obtained derivative of piperidine to obtain (3) derived naphthiridine, we present the General formula [18]

[Formula 18]

,

where R4defined above,

and then remove the protection derived naphthiridine.

The authors from whom retene hereafter discovered, that derived koiwai acid, represented the General formula [19]

[Formula 19]

,

where R2arepresents a hydrogen atom or a protective group of hydroxyl, X is a leaving group, is an important intermediate product.

Advantages of the INVENTION

The monohydrate of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she of the present invention (1) has strong antibacterial activity and a high degree of security, (2) does not detect the ability to grow, absorbing moisture from the atmosphere, or hygroscopicity, (3) is easy to handle, (4) is obtained by the use of safe for the human body solvent, (5) is obtained under conditions that do not bring much harm to the environment, and (6) is suitable for mass production and, therefore, is applicable as a bulk pharmaceutical product.

The method of receiving according to the present invention has such features as (1) high output, (2) no need to use column chromatography on silica gel, (3) therefore, a small amount of waste, and (4) non-use of toxic or unstable reagents, and therefore is applicable to obtain the mono is ikata 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it.

In addition, the derived koiwai acid, represented the General formula [19]

[Formula 19]

,

where R2aand X is defined above, is a useful intermediate product.

The BEST WAY of carrying out the INVENTION

Hereinafter the present invention will be described in detail. In the present description, unless otherwise specified, the term "halogen atom" means, for example, fluorine atom, chlorine atom, bromine atom and iodine atom. The term "alkyl group" denotes, for example, C1-6alkyl group branched or non-branched chain such as methyl, ethyl, sawn, ISO-propyl, bucilina, second-bucilina, isobutylene, tert-bucilina and pencilina group. The term "kalkilya group" denotes, for example, ar-C1-6alkyl group, such as benzyl, diphenylmethyl, trityl, phenethyl and naphthylmethyl. The term "alkoxyalkyl group" denotes, for example, C1-6alkyloxy C1-6alkyl group, such as methoxymethyl and 1-ethoxyethyl. The term "aracelikarsaalyna group" denotes, for example, ar-C1-6alkyloxy C1-6alkyl group, such as benzoyloxymethyl and penetrometer. The term "alkylsulfonyl group" denotes, for example, C1-6alkylsulfonyl group, such as methylsulphonyl, t is attorneysoffices and ethylsulfonyl. The term "arylsulfonyl group" denotes, for example, a group such as benzazolyl and toluensulfonyl. The term "alkylsulfonate" denotes, for example, C1-6alkylsulfonates, such as methylsulfonate, tripterocalyx, ethylsulfonyl. The term "arylsulfonamides" denotes, for example, such a group as benzosulfimide, toluensulfonate.

The term "acyl group" denotes, for example, formyl group, C2-6alkanoyloxy group c straight or branched chain, such as acetyl, propionyl, butyryl, isovaleryl and pivaloyl, and ar-C1-6alkylcarboxylic group, such as benzylcarbamoyl; cyclic carbonyl group such as benzoyl and naphtol, and a heterocyclic carbonyl group such as nicotinyl, tenor, pyrrolidinecarbonyl and furor. The term "alkoxycarbonyl group" denotes, for example, C1-6allyloxycarbonyl group c straight or branched chain, such as methoxycarbonyl, etoxycarbonyl, 1,1-dimethylpropanolamine, isopropoxycarbonyl, 2-ethylhexyloxymethyl, tert-butoxycarbonyl and tert-pentyloxybenzoyl. The term "aracelikarsaalyna group" denotes, for example, ar-C1-6allyloxycarbonyl group, such as benzyloxycarbonyl and ventilatsioonil.

The term "CIS is oradatabase heterocyclic group" means, for example, a group such as tetrahydropyranyl and tetrahydrofuranyl. The term "sulfur-containing heterocyclic group" denotes, for example, a group such as tetrahydropyranyl. The term "protected carbonyl group" denotes, for example, a group formed from a carbonyl group and / or alcohol, such as (hydroxy)(methoxy)methylene, (hydroxy)(ethoxy)methylene, (hydroxy)(propoxy)methylene, (hydroxy)(isopropoxy)methylene, (hydroxy)(butoxy)methylene, (hydroxy)(pentyloxy)methylene, (hydroxy)(hexyloxy)methylene, (hydroxy)(heptyloxy)methylene, (hydroxy)(octyloxy)methylene, (hydroxy)(1,1-DIMETHYLPROPANE)methylene dimethoxymethane, diethoxymethane, disproportionation, diisopropanolamine, diputaciones, bis(benzyloxy)methylene, 1,3-dioxolane-2-ilidene and 1,3-dioxane-2-ilidene, group, formed from the carbonyl group and thiol, such as bis(methylthio)methylene, bis(ethylthio)methylene, bis(benzylthio)methylene, 1,3-ditiolan-2-ilidene and 1,3-dition-2-ilidene, and the group, such as oxazoline-2-ilidene, imidazolidin-2-ilidene, thiazolidin-2-ilidene. The term "leaving group" denotes, for example, halogen atom, alkylsulfonate and arylsulfonate.

The term "hydroxylamine group" includes all groups that represent normal applicable protective hydroxyl groups. Examples include the groups described is in "Greene's Protective Groups in Organic Synthesis" by M. Wuts and W. Greene, 4thedition, John Wiley & Sons, INC., 2006, p.16-366. Specific examples include an acyl group, alkoxycarbonyl group, aracelikarsaalyna group, alkyl group, aracelio group, oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, alkoxyalkyl group, kalkylarksmall group, alkylsulfonyl group and arylsulfonyl group.

The term "aminosidine group" includes all groups that use as a normal aminosidine group. Examples include groups described in "Greene's Protective Groups in Organic Synthesis" by M. Wuts and W. Greene, 4thedition, John Wiley & Sons, INC., 2006, p.696-926. Specific examples include an acyl group, alkoxycarbonyl group, aracelikarsaalyna group, aracelio group, alkylsulfonyl group and arylsulfonyl group.

Preferred monohydrate 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it is used in the present invention are the following compounds.

The monohydrate crystals of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it is with the angles of diffraction 2θ, components of 6.8°; 8,2°; 14,2° and 15.7°, the powder x-ray diffraction pattern, are preferred.

In updat is out, characteristic peaks in the powder x-ray diffraction can vary depending on the measurement conditions. For this reason, the peak of powder x-ray diffraction of the compound of the present invention should not be strictly interpreted.

In the present invention, the preferred methods of obtaining include the following methods.

The method of obtaining, in which R1represents an ethyl group, through group or boutelou group is preferred; however, the method of obtaining, in which R1is butilkoi group is more preferred.

The method of obtaining, in which R2represents an acyl group, aracelio group or oxygen-containing heterocyclic group is preferred. This method of production, in which R2is an oxygen-containing heterocyclic group is preferable, and the method of obtaining, in which R2represents tetrahydropyranyloxy group is even more preferred.

The method of obtaining, in which R3is an acyl group, alkoxycarbonyl group or aranceles group, is preferred. This method of production, in which R3represents aracelio group is more predpochtite is determined as being, and the way to obtain in which R3represents a benzyl group is more preferable.

The method of obtaining, in which R4represents an acyl group, alkoxycarbonyl group or aracelio group, is preferred. This method of production, in which R4represents an acyl group or alkoxycarbonyl group is more preferable, and the method of obtaining, in which R4represents alkoxycarbonyl group is even more preferred.

The method of obtaining, in which X represents a chlorine atom is preferred.

The method of obtaining, in which Y represents dimethoxymethylsilyl group, dioxymethylene group, disproportinately group, 1,3-dioxolane-2-ridenow group or 1,3-dioxane-2-ridenow group, is preferred. This method of production, in which Y represents dimethoxymethylsilyl group, dioxymethylene group or 1,3-dioxolane-2-ridenow group is more preferable, and the method of obtaining, in which Y represents dimethoxymethylsilyl group is even more preferred.

For compound represented the General formula [19], preferred compounds include the following compounds.

The is a group of in which R2arepresents a hydrogen atom, acyl group, aracelio group or oxygen-containing heterocyclic group is preferred. In this connection, in which R2arepresents a hydrogen atom or oxygen-containing heterocyclic group is more preferable that the compound in which R2arepresents a hydrogen atom or tetrahydropyranyloxy group is still more preferable; and a compound in which R2arepresents a hydrogen atom is most preferable.

The method of receiving according to the present invention described below.

[Method of obtaining 1]

,

where R1defined above.

(1-1)

The compound of General formula [2] can be obtained by the interaction of the compounds of formula [1] with the acrylic ester in the presence of a catalyst, in the presence or absence of a base and in the presence or absence of ligand. The reaction can be performed, for example, by the method described in Chem. Rev." by I.P.Beletskaya and A.V.Cheprakov, 2000, Vol.100, p.3009-3066; or in any way, it is relevant.

(1-2)

The compound of the formula [3] can be obtained by reduction/cyclization of compounds of General formula [2] in the presence of a catalyst.

The reduction can be realized,for example, the method described in "Comprehensive Organic Transformations" by Richard C. Larock, VCH Publishers, INC., 1989, pp.6-17; or in any way, it is relevant.

The solvent used in the reaction, recovery, can be any solvent so far as it does not affect the course of the reaction. Examples include alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol, dimethyl ether of diethylene glycol, diethyl ether of diethylene glycol, disutility ether and onomatology ether of ethylene glycol; sulfoxidov, such as dimethyl sulfoxide; esters such as ethyl acetate and butyl acetate; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; ketones such as acetone and 2-butanone, and water. These solvents may be used in mixture. Preferred examples of solvents are methanol and ethanol.

The catalyst used in the reaction, recovery, includes, for example, palladium on carbon carrier, palladium acetate, platinum oxide, rhodium on carbon carrier and ruthenium chloride. The preferred catalyst is palladium on a carbon carrier.

The reducing agent used in the reaction, recovery, includes the in itself, for example, hydrogen, formic acid, formate, such as sodium formate, ammonium formate and formate of triethylamine; and cyclohexane. Preferred reducing agents include hydrogen and formic acid.

The amount of catalyst may be a lot of compounds of General formula [2], multiplied by the magnitude values from 0.001 to 5, preferably, the mass multiplied by the value, which takes values from 0.01 to 0.5.

The amount of reducing agent may represent the number of moles of the compounds of General formula [2], multiplied by the value, which takes values from 1 to 100, preferably from 1 to 5.

The reduction can be performed at a temperature of from -30 to 150°C, preferably from 0 to 100°C, during the time from 30 minutes to 120 hours.

The solvent used in the cyclization reaction may be any solvent so far as it does not influence the course of the reaction. Examples include alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol, dimethyl ether of diethylene glycol, diethyl ether of diethylene glycol, disutility ether and onomatology ether of ethylene glycol; sulfoxidov, such as dimethylsulfate is; esters, such as ethyl acetate and butyl acetate; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; ketones such as acetone and 2-butanone, and water. These solvents may be used in mixture. Preferred solvents include toluene and xylene.

The cyclization reaction can be performed at a temperature of from 0 to 200°C, preferably from 50 to 130°C, for a time from 30 minutes to 120 hours.

(1-3)

The compound of the formula [3] can be obtained by the interaction of the compounds of formula [1] with the acrylic ester, in the presence of a catalyst, in the presence or absence of a base, in the presence or absence of ligand and in the presence of a reducing agent. The reaction is a reaction taking place in a single vessel, to obtain the compounds of formula [3]. The reaction can be performed according to the method of obtaining a (1-1) and the method of obtaining (1-2).

[Method of obtaining 2]

,

where L1and Y is defined above.

(2-1)

Known compounds of General formula [4] represents, for example, 2-(2-methyl bromide)-1,3-dioxolane, 2-bromo-1,1-diethoxyethane and 2-bromo-1,1-dimethoxyethane.

The compound of General formula [5] can be obtained by the interaction of the compounds of General formula [4] with the compound of the formula [3] in the presence of a base.

The solvent used in this reaction may be any solvent so far because it has no effect on the course of the reaction. Examples include amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol, dimethyl ether of diethylene glycol, diethyl ether of diethylene glycol and onomatology ether of ethylene glycol; sulfoxidov, such as dimethyl sulfoxide; esters such as ethyl acetate, and water. These solvents may be used in mixture. Preferred solvents are N,N-dimethylacetamide and dimethylsulfoxide.

The base used in this reaction includes, for example, organic bases such as pyridine, dimethylaminopyridine, triethylamine, tert-butyl sodium and tert-butyl potassium, and inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium phosphate and cesium carbonate. Preferred bases are potassium carbonate and potassium phosphate.

The amount of base used compounds of General formula [4] can represent the number of moles of the compounds of General formula [3], multiplied by led the rite, component from 1 to 50, preferably from 1 to 5.

The reaction can be performed at a temperature of from -30 to 150°C, preferably from 0 to 100°C, during the time from 30 minutes to 48 hours.

(2-2)

The compound of General formula [6] can be obtained by oxidation of compounds of General formula [5] in the presence or absence of a radical initiator, in the presence or absence of a base. The reaction can be performed, for example, by the methods described in Chem. Rev., by C. Djerassi, p.271-317, Vol.43, 1948 and "Bioorg. Med. Chem. Lett.", by most of the songs Express A. Hunt, 2003, Vol.13, p.467-470, or by any means, they are relevant.

The solvent used in this reaction may be any solvent so far as it does not affect the course of the reaction. Examples include amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene and chlorobenzene; ethers, such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol, dimethyl ether of diethylene glycol, diethyl ether of diethylene glycol and onomatology ether of ethylene glycol; sulfoxidov, such as dimethyl sulfoxide; and esters such as ethyl acetate. These solvents can be used in mixture. The preferred solvent is chlorine shall INSOL.

The oxidizing agent used in this reaction includes, for example, bromide, chlorine, iodine, N-bromosuccinimide, N-chlorosuccinimide, N-jodatime and manganese dioxide. The preferred oxidizing agent is N-bromosuccinimide.

The radical initiator used in the reaction as needed, includes, for example, azobisisobutyronitrile, benzoyl peroxide and 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile). Preferred radical initiator is 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile).

The base used in this reaction as needed, includes, for example, organic bases such as pyridine, dimethylaminopyridine, triethylamine, tert-butyl sodium and tert-butyl potassium, and inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, barium carbonate and cesium carbonate. The preferred base is potassium carbonate.

The amount of oxidizer is the number of moles of the compounds of General formula [5], multiplied by the amount of from 1 to 30, preferably from 1 to 5.

The amount of radical initiator used, as appropriate, represents the number of moles of the compounds of General formula [5], multiplied by the amount of from 0.0001 to 0.5, predpochtite the flax from 0.001 to 0.1.

The reaction can be performed at a temperature of from -30 to 150°C, preferably from 0 to 100°C, for a time of 30 minutes to 48 hours.

The compound of General formula [6] is, for example, 1-(2,2-diatexite)-7-fluoro-1,5-naphthiridine-2(1H)-he. 1-(2,2-diatexite)-7-fluoro-1,5-naphthiridine-2(1H)-it can be obtained by the interaction of 7-fluoro-1,5-naphthiridine-2(1H)-one with 2-bromo-1,1-diethoxyethane.

The reaction may be carried out by the method described in WO 2007/138974, or in any way, it is relevant.

(2-3)

The compound of the formula [7] can be obtained by removing the protecting compounds of General formula [6]. The reaction can be performed, for example, by the method described in "Greene's Protective Groups in Organic Synthesis" by M. Wuts and W. Greene, 4thedition, John Wiley & Sons, INC., 2006, p.435-505, or in any way consistent with him.

[Method of obtaining 3]

where R2, R3, R4L2and X is defined above.

The compound of General formula [8] can be obtained from koiwai acid.

(3-1)

Known compounds of General formula [9] include, for example, 1-bromo-2-chlorate and 1,2-dibromethane.

The compound of General formula [10] can be obtained by the interaction of the compounds of General formula [9] with a compound of General formula [8] in the presence of a base.

The reaction may be carried out according to the method of obtaining 2-1.

(3-2)

The compound of General formula [11] can is about to receive, removing protection compounds of General formula [10]. The reaction can be performed, for example, by the method described in "Greene's Protective Groups in Organic Synthesis" by M. Wuts and W. Greene, 4thedition, John Wiley & Sons, INC., 2006, p.16-366, or in any way consistent with him.

In addition, the compound of General formula [11] can be obtained by the interaction of the compounds of General formula [9] with koiwai acid. The reaction may be carried out according to the method of obtaining 3-1.

(3-3)

The compound of formula [12] can be obtained by the interaction of the compounds of General formula [11] with ammonia.

The solvent used in this reaction may be any solvent so far as it does not affect the course of the reaction. Examples include alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol, dimethyl ether of diethylene glycol, diethyl ether of diethylene glycol and onomatology ether of ethylene glycol; sulfoxidov, such as dimethyl sulfoxide; esters such as ethyl acetate; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone, and also water. These solvents may be used in mixture. The preferred solvent includes water.

Ammonia is used in this is the reaction, includes ammonia water, and so forth. The quantity of ammonia used is the number of moles of the compounds of General formula [11], multiplied by the amount of from 1 to 100, preferably from 1 to 30.

The reaction can be performed at a temperature in the range from room temperature to 150°C, preferably from 50 to 100°C, over a period of time from 30 minutes to 120 hours.

(3-4)

The compound of the formula [13] can be obtained by oxidation of compounds of formula [12]. The reaction may be carried out by the methods described in "Advanced Organic Chemistry"by Jerry March, the 4thedition, John Wiley & Sons, INC., 1992, p.1167-1171; and "Comprehensive Organic Transformations" by Richard C. Larock, VCH Publishers, INC., 1989, p.604-614; or in any way consistent with them.

The solvent used in the reaction may be any solvent so far as it does not affect the course of the reaction. Examples include halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; ethers, such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol, dimethyl ether of diethylene glycol, diethyl ether of diethylene glycol and onomatology ether of ethylene glycol; sulfoxidov, such as dimethyl sulfoxide; esters such as ethyl acetate; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; acids such as acetic acid is, as well as water. These solvents may be used in mixture. The preferred solvent includes tetrahydrofuran.

The oxidizing agent used in this reaction includes, for example, dimethylsulfoxide, chromium trioxide, manganese dioxide and chlorine chromel. The preferred oxidizing agent comprises manganese dioxide.

The amount of oxidizing agent used in the reaction, represents the number of moles of the compounds of General formula [12], multiplied by the amount of from 1 to 30, preferably from 1 to 5.

The reaction can be performed at a temperature of from -78 to 200°C, preferably from 0 to 100°C, over a period of time from 30 minutes to 48 hours.

(3-5)

The compound of General formula [15] can be obtained by the interaction of the compounds of General formula [14] with the compound of the formula [13] in the presence of a reducing agent. The reaction may be carried out by methods described in WO 02/50061, WO 02/56882, "Advanced Organic Chemistry"by Jerry March, the 4thedition, John Wiley & Sons, INC., 1992, p.898-900; and "Comprehensive Organic Transformations" by Richard C. Larock, VCH Publishers, INC., 1989, p.421-425; or in any way consistent with them.

The solvent used in this reaction may be any solvent so far as it does not affect the course of the reaction. Examples include alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; halogenated hydrocarbons, such as meth is Lenhard, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol, dimethyl ether of diethylene glycol, diethyl ether of diethylene glycol and onomatology ether of ethylene glycol; sulfoxidov, such as dimethyl sulfoxide; esters such as ethyl acetate; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone, and water. These solvents may be used in mixture. The preferred solvent includes methanol.

The reducing agent used in this reaction includes, for example, hydride complexes such as alumalite lithium, triacetoxyborohydride sodium, cyanoborohydride sodium and borohydride sodium borane, sodium, and sodium amalgam. You can also alternatively use electrolytic recovery, where as the cathode using copper or platinum; catalytic reduction, in which the use of Raney Nickel, platinum oxide or palladium-mobile, and you can use the restore to use the zinc/acid". The preferred reducing agent includes borohydride sodium. Borohydride sodium can be used in solid form or in solution.

The number of compounds of General formula [14] and vos is canonites, used in the reaction, represent the amount of from 1 to 50, preferably from 1 to 5, multiplied by the number of moles of the compounds of General formula [13].

The reaction can be performed at a temperature of from -30 to 150°C, preferably from 0 to 100°C, over a period of time from 10 minutes to 120 hours.

(3-6)

The compound of General formula [16] can be obtained by protecting aminogroup compounds of General formula [15]. The reaction can be performed, for example, by the method described in "Greene's Protective Groups in Organic Synthesis" by M. Wuts and W. Greene, 4thedition, John Wiley & Sons, INC., 2006, p.696-926, or in any way consistent with him.

(3-7)

The compound of General formula [17] can be obtained by removing the protecting compounds of General formula [16]. The reaction can be performed, for example, by the method described in "Greene's Protective Groups in Organic Synthesis" by M. Wuts and W. Greene, 4thedition, John Wiley & Sons, INC., 2006, p.696-926; or in any way consistent with him.

[Method 4]

where R4defined above.

(4-1)

The compound of General formula [18] can be obtained by the interaction of the compounds of General formula [17] with a compound of General formula [7]. The reaction can be carried out in accordance with the method of obtaining 3-5.

(4-2)

The compound of the formula [20] can be obtained by removing the protecting compounds of General formula [18], with subsequent crystallization in rez is ltate neutralization. The reaction of the removal of protection can be realized, for example, by the method described in "Greene's Protective Groups in Organic Synthesis" by M. Wuts and W. Greene, 4thedition, John Wiley & Sons, INC., 2006, p.696-926, or in any way consistent with him.

The solvent used in this reaction may be any solvent so far as it does not adversely affect the course of the reaction. Examples include mixed solvents of water and organic solvents, and water.

The organic solvent includes, for example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol, dimethyl ether of diethylene glycol, diethyl ether of diethylene glycol and onomatology ether of ethylene glycol; sulfoxidov, such as dimethyl sulfoxide; esters such as ethyl acetate; ketones, such as acetone and 2-butanone; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone. These solvents may be used in mixture. Preferred solvents include mixed solvents of water and alcohols, and water; this water is more preferable is.

When using mixed solvents of water and organic(s), solvent(s), the ratio of water to organic(them) to the solvent(s) (water/organic solvent) is preferably in the range from 100/0 to 50/50, more preferably from 100/0 to 80/10.

The reaction can be performed at a temperature from -20 to 120°C, preferably from 10 to 80°C, over a period of time from 10 minutes to 120 hours.

The method of receiving according to the present invention has properties such as (1) high output, (2) no need for column chromatography on silica gel (3) and, consequently, low waste, (4) non-use of toxic or unstable reagents, and therefore applicable as a method of industrial production.

In the methods of obtaining 1-4 compounds of formula[3], [7], [12] and [13], as well as compounds of the General formula[2], [5], [6], [8], [10], [11], [15], [16], [17] and [18] can be isolated and subjected to cleaning, but can be used without allocating, by the following reaction.

When the compound of the present invention represented by the formula [20], is used as a pharmaceutical product, usually used in the preparation of the medicinal product pharmaceutical auxiliary agents such as a filler, a carrier and a diluent, can be mixed as is bademosi. The pharmaceutical preparations can be administered orally or parenterally, according to the conventional technique. You can enter them in a standard dosage form in the form of tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, liquids/fluids, drugs in the form of pellets, suppositories, ophthalmic solutions, nasal drops, ear drops, plasters, ointments or injections. The route of administration, dosage and frequency of injection can be selected appropriately according to the age, weight of the patient and the symptoms of the disease. The connection in the form of a pharmaceutical product usually can be entered orally or parenterally (for example, introduction by injection, intravenous drip, or rectum) in the dose component for the adult patient from 0.01 to 1000 mg/kg, from one to several times a day.

The compound of the present invention represented by the formula [20], reveals considerable antibacterial activity against gram-positive bacteria, including resistant bacteria, such as multidrug-resistant Staphylococcus aureus, multidrug-resistant pneumococci, and vancomycin-resistant Enterococcus, gram-negative bacteria, anaerobic or atypical mycobacteria.

More specifically, the compound of the present invention finds significant antibacterial ActiveState microorganisms, choose from Staphylococcus aureus (Staphylococcus aureus Smith, Staphylococcus aureus FDA 209P, Staphylococcus aureus F-3095 (multidrug-resistant Staphylococcus aureus)), Staphylococcus aureus F-2161 (multidrug-resistant Staphylococcus aureus), Streptococcus pneumococci (Streptococcus pneumoniae IID553, Streptococcus pneumoniae D-1687 (QRSP), Streptococcus pneumoniae D-4249 (MDRSP)), Enterococcus faecalis (Enterococcus faecalis ATCC29212, Enterococcus faecalis IID682, Enterococcus faecalis D-2648 (VCM-R), Enterococcus faecalis EF-210 (VanA type VRE)Enterococcus faecium (Enterococcus faecium NBRC 13712, Enterococcus faecium EF-211 (VanA type VRE)), Corynebacterium diphtheriae (Corynebacterium diphtheriae ATCC 27010), Escherichia coli (Escherichia coli NIHJ), Serratia marcescens (Serratia marcescens IID5218), Haemophilus influenzae (Haemophilus influenzae ATCC 49247), Moraxella catarrhalis (Moraxella catarrhalis ATCC 25238), Pseudomonas aeruginosa (Pseudomonas aeruginosa IFO3445), Enterobacter cloacae (Enterobacter cloacae IID977), Citrobacter freundii (Citrobacter freundii NBRC 12681), Gardnerella vaginalis (Gardnerella vaginalis ATCC 14018), Neisseria gonorrhoeae (Neisseria gonorrhoeae ATCC 19424), Peptostreptococcus asaccharolyticus (Peptostreptococcus asaccharolyticus ATCC 14963), Propionibacterium acnes (Propionibacterium acnes JCM 6425), Clostridium perfringens (Clostridium perfringens ATCC 13124), Bacteroides fragilis (Bacteroides fragilis ATCC 25285), Porphyromonas gingivalis (Porphyromonas gingivalis JCM 8525), Prevotella intermedia (Prevotella intermedia JCM 7365), Fusobacterium nucleatum (Fusobacterium nucleatum JCM 8532), Legionella pneumophilia (Legionella pneumophilia ATCC 33153, Legionella pneumophilia subsp. pneumophilia ATCC 33155, Legionella pneumophilia subsp. pneumophilia ATCC 33215, Legionella pneumophilia subsp. fraseri ATCC33216) and Mycoplasma pneumoniae (Mycoplasma pneumoniae ATCC 15531).

The compound of the present invention represented by the formula [20], detects a sufficient degree of security. The degree of safety is assessed through a large set of tests that select from a variety of those who tov on the security, including, for example, the test for cytotoxicity; test for selectivity whose target is DNA gyrase man and microorganisms; test for selectivity whose target is topoisomerase IV man and microorganisms; hERG test, the study of multiple-dose toxicity; test for inhibition of the activity of cytochrome P450 (CYP); test for metabolism-dependent inhibition; in vivo micronucleus test in mice and in vivo USD test rat liver.

The compound of the present invention represented by the formula [20], has significant metabolic stability. Metabolic stability is assessed through a wide set of tests to choose from a variety of stability tests, including, for example, the test on the metabolic stability of human liver microsomes and test for metabolic stability S9 person.

The applicability of the compounds of the present invention represented by the formula [20]described next with reference to the following examples test.

EXAMPLE TEST 1

Test the susceptibility

As the compounds of the present invention were selected compound of example 16.

The compound of the present invention was dissolved in dimethyl sulfoxide and was measured antibacterial activity (MIC) method of cultivation nutrient medium of microtitre, recomendada the major Japanese society of chemotherapy.

The study used the bacteria Staphylococcus aureus (S.aureus Smith, FDA209P, F-3095), Enterococcus faecalis (E.faecalis D-2648) and Escherichia coli (E. coli NIHJ).

Bacterial cells were grown overnight on agar Mueller-Hinton: MHA plates at 35°C suspended in sterilized saline solution to obtain the equivalent to McFarland standard No. 0.5 in. To obtain the inoculum cell suspension was diluted ten times. Approximately 0,005 ml of inoculum was inoculable in cation-regulated nutrient medium Mueller-Hinton (CAMHB), 100 μl of the cell containing the test substance, and left at 35°C for cultivation during the night. The lowest concentration of test substance at which no observed bacterial growth with the naked eye, was defined as MIC.

The results are shown in table 1.

[Table 1]
MIC(mcg/ml)
S.aureus Smith0,0625
S.aureus FDA209P0,0313
S.aureus F-30950,0313
E.faecalis D-26480,25
E. coli NIHJ 0,125

The compound of the present invention shows significant antibacterial activity against different bacterial strains.

SAMPLE TEST 2

Test hygroscopicity

As the compounds of the present invention were selected compound of example 16. As comparative compounds were selected compound of comparative example 1.

The compound of the present invention and a comparative compound was stored for three weeks at room temperature and relative humidity, which constitutes 97%. As a result, the compound of the present invention represented powder, which had no obvious changes. On the other hand, comparative connection broke as a result of absorption of moisture from the atmosphere.

The compound of the present invention showed high stability.

EXAMPLE TEST 3

Solubility

As the compounds of the present invention were selected compound of example 16.

The compound of the present invention was added in an excessive amount to 0.2 mol/l solution of phosphate buffer (pH 6.5). The mixture was shaken in a thermostatic vibrator (25°C) within 48 hours and centrifuged. The supernatant was filtered through a filter with pore size of 0.45 μm, whereby measured rastvorimosti using high-speed liquid chromatography. As a result, the solubility in 0.2 mol/l phosphate buffer solution (pH 6.5) was 21.2 mg/ml

EXAMPLE

The present invention is described referring to the following examples, however without restricting it to these examples.

Each abbreviated symbol means the following.

Boc: tert-butoxycarbonyl; Bn: benzyl; Bu: butyl; Me: methyl; THP: tetrahydro-2H-Piran-2-yl; DMSO-d6: deuterated dimethyl sulfoxide

Example 1

To a solution of 0.11 kg of sodium hydroxide in 1000 ml of water was added 1.4 kg 12% aqueous solution of sodium hypochlorite and 0.40 kg of 2-chloro-5-fioricetonline. The mixture was stirred for 2 hours 30 minutes at room temperature. The reaction mixture was heated to 45°C and stirred for 4 hours. The reaction mixture was cooled to room temperature and was added ethyl acetate and 6 mol/l hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, was added anhydrous magnesium sulfate and activated charcoal, and the mixture was stirred for 30 minutes at room temperature. The insoluble substance was filtered, and the solvent evaporated under reduced pressure to obtain 0,29 kg of 2-chloro-5-herperidin-3-amine as a brown solid.

1H-NMR(CDCl3) δ value: 4,22(2H, s), 6,79(1H, DD, J=9,3, 2.7 Hz), to 7.67(1H, is, J=2.7 Hz)

Example 2

To a suspension of 25.0 g of 2-chloro-5-herperidin-3-amine, 3.8 g of chloride bis(tricyclohexylphosphine)palladium(II) and 1.5 g of 2-(decret-butylphosphino)biphenyl in 75 ml of butyl acrylate was added to 44.1 g diisopropylethylamine; wherein at room temperature was added dropwise 15.7 g of formic acid. A mixture of 3 hours and boiled under reflux. To the reaction mixture at 100°C was added 32,1 g diisopropylethylamine and 11.5 g of formic acid and the mixture is 5 hours and boiled under reflux. The reaction mixture was cooled to 80°C, there was added 50 ml of toluene and 75 ml of water; and the resulting mixture was cooled to room temperature. A solid product was obtained by filtration and washed using consistently toluene and water, to obtain 18.0 g of 7-fluoro-3,4-dihydro-1,5-naphthiridine-2(1H)-it is in the form of a white solid.

1H-NMR(DMSO-d6) δ value: 2,60(2H, t, J=7,7 Hz)of 3.00(2H, t, J=7,7 Hz), 7,03(1H, DD, J=9,8, 2.7 Hz), 8,07(1H, d, J=2.7 Hz), and 10.3(1H, sh)

Example 3

A mixed solution of 150 ml of butyl acetate and 73 ml of butyl acrylate was boiled under reflux by heating for 45 minutes under nitrogen atmosphere. The reaction mixture was cooled to 30°C and there was added 50.0 g of 2-chloro-5-herperidin-3-amine, 3.8 g of palladium(II)acetate, with 44.8 g of triphenylphosphine and 36.6 g of sodium carbonate. A mixture of 13 hours boiled with bratim fridge in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, there was added 150 ml of water and 700 ml of butyl acetate; and the mixture was stirred for 1 hour. The insoluble substance was filtered, and the filter cake was washed using 50 ml of butyl acetate. The filtrate and wash liquid were combined. The organic layer was separated and 800 ml of solvent evaporated under reduced pressure. To the obtained precipitate was added dropwise 300 ml of cyclohexane and 30 ml of toluene; the mixture was cooled to 5°C. the Solid product was obtained by filtration and washed using a mixed solution of toluene/cyclohexane (1:2) and toluene to obtain of 57.8 g of butyl (2E)-3-(3-amino-5-herperidin-2-yl)acrylate as a yellow solid.

1H-NMR(CDCl3) δ value: to 0.96(3H, t,J=7,3 Hz), to 1.38 to 1.48(2H, m), 1,64-1,72(2H, m), 4,10(2H, sh), is 4.21(2H, t, J=6.6 Hz), 6,72(1H, DD, J=9,8, and 2.3 Hz), 6,86(1H, d, J=15.1 Hz), 7,71(1H, d, J=15.1 Hz), 7,94(1H, d, J=2,3 Hz)

Example 4

To a suspension of 9.1 g of butyl (2E)-3-(3-amino-5-herperidin-2-yl)acrylate and 0.9 g of 10% palladium on carbon carrier in 30 ml of methanol was added 4 ml of formic acid and added dropwise under ice cooling was added 15 ml of triethylamine. The reaction mixture is 2 hours and stirred at 60°C. the Reaction mixture was cooled to room temperature, insoluble matter was filtered, and the filter cake was washed using 30 ml of toluene. The filtrate and the wash liquid is awn United, and the solvent evaporated under reduced pressure. To the precipitate obtained was added 30 ml of toluene. A mixture of 2 hours and 30 minutes was stirred at 100°C. To the reaction mixture at 45°C was added dropwise 30 ml of water and the mixture was cooled to 5°C. the Solid product was obtained by filtration and washed successively with water and toluene to obtain 5.7 g of 7-fluoro-3,4-dihydro-1,5-naphthiridine-2(1H)-it is in the form of a white solid.

1H-NMR(DMSO-d6) δ value: 2,60(2H, t, J=7,7 Hz)of 3.00(2H, t, J=7,7 Hz), 7,03(1H, DD, J=a 9.9, 2.6 Hz), 8,07(1H, d, J=2,6 Hz), and 10.3(1H, sh)

Example 5

To a suspension of 49.8 g of potassium phosphate in 90 ml of dimethyl sulfoxide was added 30.0 g of 7-fluoro-3,4-dihydro-1,5-naphthiridine-2(1H)-she and 39.7 g of 2-bromo-1,1-dimethoxyethane. A mixture of 3 hours and stirred at 100°C. To the mixture was added to 7.7 g of potassium phosphate and 6.1 g of 2-bromo-1,1-dimethoxyethane and a mixture of 1 hour and stirred at the same temperature. The reaction mixture was cooled to room temperature and was added 120 ml of water and 120 ml of toluene. The mixture was brought to pH 8.5 with acetic acid and was added 3.0 g of activated charcoal. The insoluble substance was filtered, and the filter cake was washed using 30 ml of toluene and 30 ml of water. The filtrate and wash liquid were combined, the organic layer was separated, and the aqueous layer was extracted with 60 ml of toluene. The organic layer and the extract were combined, to evaporate dissolve Italy under reduced pressure. There was added 90 ml dibutylamino ether, and the mixture was cooled to -3°C. the Solid product was obtained by filtration and washed using consistently disutility ether and water to get 30,8 g of 1-(2,2-dimethoxymethyl)-7-fluoro-3,4-dihydro-1,5-naphthiridine-2(1H)-it is in the form of a light yellow solid.

1H-NMR(CDCl3) δ value: 2,73-and 2.83(2H, m), 3,07-3,14(2H, m), 3,44(6N, C)3,93(2H, d, J=5.4 Hz), br4.61(1H, t, J=5.4 Hz), was 7.45(1H, DD, J=10,5, 2.4 Hz), of 8.06(1H, d, J=2.4 Hz)

Example 6

To a suspension of 5.0 g of 1-(2,2-dimethoxymethyl)-7-fluoro-3,4-dihydro-1,5-naphthiridine-2(1H)-she, of 5.3 g of N-bromosuccinimide and 3.0 g of potassium carbonate in 30 ml of chlorobenzene, in the atmosphere of nitrogen at 50-60°C three times every hour was added 0.12 g of 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile). After stirring the reaction mixture at the same temperature for 1 hour there was added 10 ml of water. The mixture is brought to a pH of 12.6, using 20% sodium hydroxide solution. The organic layer was separated and washed with 15 ml of water. The aqueous layer was extracted with 15 ml of toluene. The organic layer and the extract were combined, to evaporate the solvent under reduced pressure. To the precipitate obtained was added 2 ml of chlorobenzene and 6 ml of cyclohexane. The mixture was stirred for 30 minutes under ice cooling. A solid product was obtained by filtration and washed with cyclohexane to obtain 4.1 g of 1-(2,2-dimethoxymethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it is as light yellow solid.

1H-NMR(CDCl3) δ value: 3,44(6N, (C), 4,30(2H, d, J=5.3 Hz)and 4.65(1H, t, J=5.3 Hz), 6.87 in(1H, d, J=9.8 Hz), 7,71(DD, 1H, J=10,6, 2.4 Hz), 7,92(1H, d, J=9.8 Hz), to 8.41(1H, d, J=2.4 Hz)

Example 7

To a suspension of 158 g of 1-(2,2-dimethoxymethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she 1.26 l 2-butanone at room temperature was added 79 ml of hydrochloric acid concentration of 12 mol/L. of a Mixture of 3 hours and boiled under reflux. After cooling the reaction mixture to 10°C solid product was obtained by filtration and washed with 2-butanone to obtain 152 g of monohydrate (7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde hydrochloride as a pale yellow solid.

1H-NMR(DMSO-d6) δ value: at 5.27(2H, s),to 6.88(1H, d, J=9.9 Hz), 7,99-of 8.04(2H, m), 8,58(1H, d, J=2.4 Hz), 9,68(1H, s)

Example 8

To a suspension of 14.3 g of koiwai acid in 57 ml of tetrahydrofuran was added 11 ml of 3,4-dihydro-2H-Piran and 77 mg of the monohydrate of p-toluenesulfonic acid. The mixture was stirred 6 hours at room temperature. To the mixture was added 1 ml of an aqueous solution of sodium hydroxide concentration of 0.5 mol/l Solvent evaporated under reduced pressure, to obtain and 26.8 g of 5-hydroxy-2-((tetrahydro-2H-Piran-2-yloxy)methyl)-4H-Piran-4-it is in the form of a light yellow solid.

To a solution of the obtained 5-hydroxy-2-((tetrahydro-2H-Piran-2-yloxy)methyl)-4H-p the RAS-4-it in 45 ml of N,N-dimethylformamide was added 45 ml of toluene, to 20.8 ml of 1-bromo-2-chlorethane and 41.6 g of potassium carbonate and the mixture was stirred for 4 hours at 60°C. the Mixture was left to stand at room temperature during the night; and the solvent evaporated under reduced pressure. To the obtained precipitate was added to 107 ml of water and a mixture of 90 ml of ethyl acetate/17 ml of toluene. The organic layer was separated, and the aqueous layer was extracted using a mixture of 90 ml of ethyl acetate/17 ml of toluene. The organic layer and the extract were combined and the solvent evaporated under reduced pressure to obtain 26.7 g of 5-(2-chloroethoxy)-2-((tetrahydro-2H-Piran-2-yloxy)methyl)-4H-Piran-4-she as a brown oily substance.

1H-NMR(DMSO-d6) δ value: 1,52-1,71(4H, m), 1,73-to 1.79(1H, m), 1,80-of 1.88(1H, m), of 3.56(1H, dddd, J=11,1, 4,4, 4,2, 1,4 Hz), with 3.79(2H, t, J=6.0 Hz), 3,80-of 3.85(1H, m), 4,27(2H, t, J=6.0 Hz), or 4.31-4,37(1H, m), 4,49-4,55(1H, m), to 4.73(1H, t, J=3,4 Hz), of 6.52(1H, s), of 7.75(1H, s)

Example 9

To a solution of 314 g of 5-(2-chloroethoxy)-2-((tetrahydro-2H-Piran-2-yloxy)methyl)-4H-Piran-4-it is in 630 ml of methanol was added 6.3 ml of concentrated hydrochloric acid and the mixture was stirred 6 hours at room temperature. To the reaction mixture was added 13 ml of 28% ammonia water and the solvent evaporated under reduced pressure to obtain 240 g of 5-(2-chloroethoxy)-2-(hydroxymethyl)-4H-Piran-4-it (crude product) as a brown oily substance.

10.6 g polychemoresistance substance was purified column chromatography on silica gel [silica gel: KANTO CHEMICAL CO., INC., silica gel 60; eluate: a mixture of chloroform/methanol = 95:5], to obtain 7.0 g of 5-(2-chloroethoxy)-2-(hydroxymethyl)-4H-Piran-4-it is in the form of a light brown solid.

1H-NMR(CDCl3) δ value: 3,05(1H,s), with 3.79(2H, t, J=5,9 Hz), 4,25(2H, t, J=5,9 Hz), 4,50(2H, s), 6,53(1H, t, J=0.9 Hz), of 7.75(1H, s)

Example 10

To 229 g of 5-(2-chloroethoxy)-2-(hydroxymethyl)-4H-Piran-4-it (crude product) was added 572 ml of 28% ammonia water. The mixture was stirred for 7 hours at 85°C and left to stand at room temperature over night. The reaction mixture was extracted 4 times with 500 ml of 2-propyl. The organic layer was immediately combined and the solvent evaporated under reduced pressure to obtain 90,5 g (2,3-dihydro-(1,4)like(2,3-c)pyridin-7-yl)methanol as a brown oily substance.

1H-NMR(CDCl3) δ value: 4,25-to 4.38(4H, m), to 4.62(2H, s)6,76(1H, s), 8,11(1H, s)

Example 11

To a solution of 111 g of (2,3-dihydro-(1,4)like(2,3-c)pyridin-7-yl)methanol in 1110 ml of tetrahydrofuran was added 164 g of manganese dioxide. The mixture was stirred 5 hours at 70°C and was stirred at room temperature overnight. The reaction mixture was subjected to filtration through celite and the filter cake was washed with 500 ml of tetrahydrofuran. The filtrate and wash liquid were combined, to evaporate the solvent at below the nom pressure. The precipitate was recrystallized from 750 ml of 2-propanol to obtain a 53.5 g of 2,3-dihydro-(1,4)like(2,3-c)pyridine-7-carbaldehyde as a pale yellow solid.

1H-NMR(CDCl3) δ value: to 4.38(4H, s), 7,51(1H, s), 8,31(1H, s), 9,92(1H, s)

Example 12

A solution of 3.0 g of 2,3-dihydro-(1,4)like(2,3-c)pyridine-7-carbaldehyde and 3.4 g of 4-amino-1-benzylpiperidine in 30 ml of methanol was stirred for 50 minutes at room temperature and was added dropwise a solution of 0.34 g of sodium borohydride in 30 ml of 0.01 mol/l sodium hydroxide/methanol, while cooling with ice. The mixture is then 2 hours and was stirred under ice cooling was added dropwise 6 ml of concentrated hydrochloric acid at a temperature of 10°C or below and 1 hour 30 minutes mixed. A solid product was obtained by filtration, to be 6.8 g of 1-benzyl-N-(2,3-dihydro-(1,4)like(2,3-c)pyridine-7-ylmethyl)piperidine-4-amine of trihydrochloride in the form of a white solid.

1H-NMR(D2O) δ value: 1,93-2,03(2H, m), 2,48(2H, d, J=13.3 Hz), 3,13-is 3.21(2H, m), 3,62-to 3.73(3H, m), 4,37(2H, s), 4,43-of 4.49(4H, m), 4.53-in-4,58(2H, m), 7,35(1H, s), 7,49-EUR 7.57(5H, m), 8,30(1H, s)

Example 13

To a solution of 6.8 g of 1-benzyl-N-(2,3-dihydro-(1,4)like(2,3-c)pyridine-7-ylmethyl)piperidine-4-amine of trihydrochloride in a mixture of 20 ml of water/11 ml of tetrahydrofuran under ice cooling was added 8 ml of 20% is one solution of sodium hydroxide and then there was added to 3.3 g of di-tert-BUTYLCARBAMATE. The mixture was stirred for 8 hours at room temperature there was added 11 ml of ethyl acetate. The organic layer was separated, and there was added to 5.1 g of silica gel (Chromatorex-NH, FUJI SILYSIA CHAMICAL LTD.). The mixture was stirred 1 hour at room temperature and filtered by passing through 2.6 g of silica gel (Silica gel 60N, KANTO CHEMICAL CO., INC). For washing used 35 ml of ethyl acetate. The filtrate and wash water were combined and the solvent evaporated under reduced pressure to obtain 6.3 g of tert-butyl(1-benzylpiperidine-4-yl)(2,3-dihydro-(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate as a pale yellow foam.

1H-NMR(CDCl3) δ value: 1,32-1,54(N, m, 1,55-of 1.74(4H, m), 1,92-2,07(2H, m), 2,87(2H, d, J=11.5 Hz), 3,44(2H, s), 4,07-4,18(1H, m), 4,22-4,32(4H, m), 4,33-4,48(2H, m), 6,72(1H, s), 7,20-7,24(1H, m), 7,27-7,31(4H, m), of 8.04(1H, s)

Example 14

To a solution of 5.9 g of tert-butyl(1-benzylpiperidine-4-yl)(2,3-dihydro-(1,4)like(2,3-c)pyridine-7-ylmethyl)carbamate in 30 ml of methanol was added 1.2 g of 5% palladium on a carbon carrier and the mixture was stirred for 7 hours at 60°C in hydrogen atmosphere. The mixture was subjected to filtration on celite and to the filtrate was added 40 ml of ethyl acetate and 30 ml of an aqueous solution of sodium hydroxide with a concentration of 0.5 mol/L. Organic layer was washed with saturated sodium chloride solution, dried using sodium sulfate, and the solvent evaporated under reduced pressure. Receiving the hydrated precipitate was recrystallized from a mixture of 5 ml of ethyl acetate/15 ml of heptane, to obtain 3.0 g of the monohydrate of tert-butyl((2,3-dihydro-(1,4)like(2,3-c)pyridin-7-yl)methyl)(piperidine-4-yl)carbamate as a white powder.

1H-NMR(CDCl3) δ value: 1,39(N, C), 1,48-of 1.53(2H, m), 1,63 by 1.68(2H, m), 2,61-of 2.66(2H, m), 3,07-3,10(2H, m), 4.26 deaths-of 4.38(7H, m), of 6.75(1H, s), with 8.05(1H, s)

Example 15

To a solution of 5.0 g of the monohydrate of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(piperidine-4-yl)carbamate in 40 ml of N-methyl-2-pyrrolidone was added 3.5 g of monohydrate (7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde hydrochloride and the mixture was stirred for 1 hour at room temperature. To the mixture under ice cooling was added separately 5 portions of 4.3 g of triacetoxyborohydride sodium over a period of 80 minutes and the mixture is 1 hour and 40 minutes was stirred under ice cooling. After heating to room temperature, to the mixture was added 20 ml of water and the pH brought to 11.5 using 20% aqueous sodium hydroxide solution. To the mixture at 70-80°C was added 20 ml of N-methyl-2-pyrrolidone and the mixture was stirred for 2 hours 30 minutes at the same temperature. The reaction mixture was cooled to room temperature and the solid product was obtained by filtration and washed with water to be 6.5 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate as a light brown solid.

H-NMR(CDCl3) δ value: of 1.30 and 1.80(13H, m), 2,08-of 2.27(2H, m), 2,56-to 2.65(2H, m), 2,93 totaling 3.04(2H, m), as 4.02-4,19(1H, m), 4,23-4,49(8H, m), of 6.73(1H, s), at 6.84(1H, d, J=9.9 Hz), 7,47(1H, DD, J=10,2, 2.3 Hz), 7,87(1H, d, J=9,9 Hz), with 8.05(1H, s), to 8.41(1H, d, J=2.3 Hz)

Example 16

To a suspension of 25.0 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 50 ml of water was added dropwise 18 ml of concentrated hydrochloric acid at 28-39°C. the Reaction mixture was stirred for 3 hours 30 minutes at 40-50°C, cooled to room temperature, was added 17 ml of 20% aqueous the sodium hydroxide solution and 25 ml of water and heated to 60°C. the Mixture was brought to pH 3 using concentrated hydrochloric acid was added 25 ml of water. The insoluble substance was filtered at 50°C. the Precipitate on the filter was washed using 25 ml of water. The filtrate and wash liquid were combined and heated to 40°C, was added to 13.5 ml of 20% aqueous solution of sodium hydroxide, 150 ml of 2-butanone and 25 ml of water and heated under reflux to dissolve the solid. The reaction mixture was cooled to 10°C and the solid product obtained by filtration, washed with water, to be 19.3 g of the monohydrate of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it is in the form of light deltoro solids.

1H-NMR(CDCl3) δ value: 1,35 of 1.50(2H, m), 1,90(2H, d, J=12,2 Hz)to 2.18(2H, dt, J=11,5, 2.2 Hz), 2,46 at 2.59(1H, m)of 2.64(2H, t, J=7,1 Hz), 2,95(2H, d, J=12.0 Hz), with 3.79(2H, s), 4.26 deaths-4,34(6N, m), for 6.81(1H, s), 6,85(1H, d, J=9.8 Hz), 7,56(1H, DD, J=10,2, 2.4 Hz), 7,88(1H, DD, J=9,8, 0.5 Hz), 8,10(1H, s), to 8.41(1H, d, J=2.4 Hz)

Example 17

A solution of 3.03 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 45 ml triperoxonane acid was stirred 1 hour 30 minutes at room temperature. The reaction mixture was cooled with ice, was added 30 ml of water and 30 ml of ethyl acetate and brought to pH 10 with 2 mol/l aqueous solution of sodium hydroxide. The organic layer was separated, and the aqueous layer was extracted 7 times with ethyl acetate. The organic layers were combined and the solvent was concentrated under reduced pressure to 10 ml, and then the insoluble substance was filtered. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on unmodified silica gel [eluate; a mixture of chloroform/methanol = 92:8], recrystallized from 3 ml of ethyl acetate, to obtain 0,611 g of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she (dehydrate) as a pale yellow solid.

1H-NMR(CDCl3) δ value: of 1.39 to 1.47(2H, m), 1,87-of 1.93(2H, m), 2,1(2H, t, J=10,8 Hz), 2.49 USD is 2.55(1H, m)of 2.64(2H, t, J=7,1 Hz), 2,92 are 2.98(2H, m), with 3.79(2H, s), 4.26 deaths-the 4.29(2H, m), 4,29-4,34(4H, m), PC 6.82(1H, s), 6,85(1H, d, J=9.6 Hz), 7,55(1H, d, J=9.6 Hz), 7,88(1H, d, J=9.6 Hz), 8,10(1H, s), to 8.41(1H, d, J=2.3 Hz)

Anal. calculated for (Anal. Calcd.) C23H26FN5O3: C, 62,86; H, 5,96; H, 15,94; N, 15,94; F, 4,32

Found: C, 62,58; H, of 5.92; N, 15,80, F, 4,21

Comparative example 1

To a suspension of 0.30 g of tert-butyl (2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)ethyl)piperidine-4-yl)carbamate in 2 ml of 2-propanol was added to 0.23 ml of concentrated hydrochloric acid and the resulting mixture was stirred 1 hour 50 minutes while heating under reflux. The reaction mixture was cooled to 5°C and a solid substance was obtained by filtration, to be 0.28 g of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she trihydrochloride in the form of a light yellow solid.

1H-NMR(D2O) δ value: 2,00-of 2.16(2H, m), 2,52-2,61(2H, m), 3,23-to 3.35(2H, m), 3,61-to 3.67(2H, m), 3,69-of 3.80(1H, m), 3,98-4,07(2H, m), 4,46-4,51(2H, m)to 4.52(2H, s), 4,55-4,63(2H, m), 4,71-4,96(2H, m), of 6.99(1H, d, J=9.8 Hz), 7,44(1H, s), 7,93-to 7.99(1H, m), 8,10(1H, d, J=9.8 Hz), at 8.36(1H, s), to 8.57(1H, d, J=2.2 Hz)

Example obtain 1

To a suspension of 3.00 g of 7-fluoro-1,5-naphthiridine-2(1H)-she 5,04 g of potassium phosphate in 12 ml of dimethylsulfoxide was added at room Tempe is the atur 4.68 g of 2-bromo-1,1-diethoxyethane and the resulting mixture was stirred for 4.5 hours at 94°C. The reaction mixture was cooled and was added 21 ml of water and 12 ml cyclopentylmethyl ether. The mixture was brought to pH 5.8 using hydrochloric acid with a concentration of 12 mol/L. Then the insoluble substance was filtered, and the precipitate on the filter was washed twice in 3 ml cyclopentylmethyl ether. The organic layers obtained filtrate and wash liquid were separated, and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain 3.11 g of 1-(2,2-diatexite)-7-fluoro-1,5-naphthiridine-2(1H)-it is in the form of a light yellow oily substance.

1H-NMR(CDCl3) δ value: 1,12(6N, t, J=7,1 Hz), 3,47-3,55(2H, m), 3,74-3,82(2H, m), the 4.29(2H, d, J=5,1 Hz), 4,78(1H, t, J=5.4 Hz), 6,86(1H, d, J=9.8 Hz), 7,82(1H, DD, J=10,6, 2.4 Hz), 7,92(1H, d, J=9.8 Hz), to 8.41(1H, d, J=2.4 Hz)

Example of getting 2

To 480 ml of 2-butanone was added 30 ml of hydrochloric acid with a concentration of 12 mol/L. the Mixture was heated to 70°C and was added dropwise a solution of 60 g of 1-(2,2-diatexite)-7-fluoro-1,5-naphthiridine-2(1H)-she's in 60 ml of 2-butanone, followed by boiling under reflux for 2 hours. After cooling the reaction mixture to 25°C solid product was obtained by filtration and washed with 2-butanone to get to 50.3 g of the monohydrate hydrochloride (7-fluoro-2-oxo-1,5-naphthiridine-1(2H)-yl)acetaldehyde in view of the light-yellow solid.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 shows the powder x-ray diffraction monohydrate 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it.

APPLICABILITY IN the PRODUCTION environment

The monohydrate of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-c)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she of the present invention (1) has strong antibacterial activity and a high degree of security, (2) does not detect diffusion, as a result of absorption of moisture from the air, or hygroscopicity, (3) easy to handle, (4) it is obtained when using solvent safe for the human body, (5) it is produced under conditions that are unloaded to the environment, and (6) it is possible to obtain in mass production, thus it is applicable as gross pharmaceutical product.

1. The monohydrate of 1-(2-(4-((2,3-dihydro(1,4)like(2,3-C)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it.

2. The method of obtaining monohydrate 1-(2-(4-((2,3-dihydro(1,4)like(2,3-C)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-it is represented by the formula
[Formula 19]

which is characterized by interaction
(1) derived naphthiridine, submitted the wow formula
[Formula 7]

and get on the interaction of pyridine derivative represented by the formula
[Formula 1]

with an ester of acrylic acid with the formation of a derivative of acrylic acid represented General formula
[Formula 2]

where R1represents an alkyl group;
then restore/cyclist derived acrylic acid, to obtain the derived dihydronaphthalene represented by the formula
[Formula 3]

acting further on the received derived dihydronaphthalene compound represented the General formula
[Formula 4]

where L1represents a leaving group; Y represents a protected carbonyl group,
to obtain the derived dihydronaphthalene submitted to the General formula
[Formula 5]

where Y is defined above,
oxidizing the resulting derived dihydronaphthalene to derive naphthiridine submitted to the General formula
[Formula 6]

where Y is defined above; and
then removing the protection derived naphthiridine using (2) piperidine derivative represented General formula
[The form is but 17]

where R4is aminosidine group,
and get on interaction derived koiwai acid, present a General formula
[Formula 8]

where R2is hydroxylamino group,
with a compound represented the General formula
[Formula 9]

where L2represents a leaving group; X represents a leaving group, to obtain the derived koiwai acid, present a General formula
[Formula 10]

where R2and X is defined above,
then removing the protection derived koiwai acid, to obtain the derived koiwai acid, present a General formula
[Formula 11]

where X is defined above,
then influencing derived koiwai acid with ammonia to obtain the pyridine derivative represented by the formula
[Formula 12]

then oxidizing the obtained derivative of pyridine with the formation of a pyridine derivative represented by the formula
[Formula 13]

then acting on the obtained derivative of pyridine piperidine derivative represented General formula
[Formula 14]
where R3is aminosidine group,
to get a piperidine derivative represented General formula
[Formula 15]

where R3defined above,
protecting the next aminogroup to get a piperidine derivative represented General formula
[Formula 16]

where R4defined above; R3defined above,
and then removing the protection derived piperidine education
(3) derived naphthiridine submitted to the General formula
[Formula 18]

where R4defined above,
and then removing the protection derived naphthiridine.

3. A method of obtaining a piperidine derivative represented General formula
[Formula 29]

where R4is aminosidine group,
characterized
interaction derived koiwai acid, present a General formula
[Formula 20]

where R2is hydroxylamino group, with a compound represented the General formula
[Formula 21]

where L2represents a leaving group; X represents a leaving group, with the formation of the derived koiwai acid represented General formula is th
[Formula 22]

where R2and X is defined above,
then remove the protection derived koiwai acid, to obtain the derived koiwai acid, present a General formula
[Formula 23]

where X is defined above,
then acting on the derived koiwai acid with ammonia to obtain the pyridine derivative represented by the formula
[Formula 24]

then oxidizing the obtained derivative of pyridine with the formation of a pyridine derivative represented by the formula
[Formula 25]

then acting on the obtained derivative of pyridine piperidine derivative represented General formula
[Formula 26]

where R3is aminosidine group,
to get a piperidine derivative represented General formula
[Formula 27]

where R3defined above,
then protecting aminogroup to get a piperidine derivative represented by the formula
[Formula 28]

where R4defined above; R3defined above,
and then removing the protection derived piperidine.

4. The method of receiving according to claim 2 or 3, where R3is aralkyl the second group; R4represents an acyl group or alkoxycarbonyl group.

5. A method of obtaining a pyridine derivative represented by the formula
[Formula 34]

which is characterized by the interaction of the derived koiwai acid, present a General formula
[Formula 30]

where R2is hydroxylamino group,
with a compound represented the General formula
[Formula 31]

where L2represents a leaving group; X represents a leaving group, to obtain the derived koiwai acid, present a General formula
[Formula 32]

where R2and X is defined above,
then removing the protection derived koiwai acid, to obtain the derived koiwai acid, present a General formula
[Formula 33]

where X is defined above,
and then influencing derived koiwai acid with ammonia.

6. A method of obtaining a pyridine derivative represented by the formula
[Formula 36]

which is characterized by the interaction of the derived koiwai acid, present a General formula
[Formula 35]

where X represents a leaving g is the UPP,
with ammonia.

7. Derived koiwai acid, present a General formula
[Formula 37]

where R2arepresents a hydrogen atom, tetrahydropyranyloxy or tetrahydrofuranyl group; withdrawing group, X represents a halogen atom.

8. Antibacterial containing monohydrate, 1-(2-(4-((2,3-dihydro(1,4)like(2,3-C)pyridine-7-ylmethyl)amino)piperidine-1-yl)ethyl)-7-fluoro-1,5-naphthiridine-2(1H)-she.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline compounds of formula (I) and physiologically acceptable acid addition salts and N oxides thereof, wherein R denotes a polycyclic group of formula (R) wherein * indicates the quinolinyl radical binding site; A denotes (CH2)a, where a equals 0, 1, 2 or 3; B denotes (CH2)b, where b equals 0, 1, 2 or 3; X' denotes (CH2)x where x equals 0, 1, 2 or 3; Y denotes (CH2)y where y equals 0, 1, 2 or 3; provided that a+b=1, 2, 3 or 4, x+y=1, 2, 3 or 4, and a+b+x+y=3, 4, 5, 6 or 7; Q denotes N; R1 denotes hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, phenyl-C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, where phenyl rings in last two said groups are unsubstituted or carry 1, 2 or 3 substitutes selected from halogen, C1-C4-alkyl or C1-C4-halogenalkyl; R2 denotes hydrogen; R3 denotes hydrogen; p=0, 1 or 2; R4, if present, denotes C1-C4-alkyl and is bonded with X and/or Y, if p=2, two radicals R4, which are bonded with adjacent carbon atoms of X or Y, together can also denote a straight C2-C5-alkylene; q=0; n=0; m=0; X denotes S(O)2; which is located in position 3 of quinoline; Ar denotes a radical Ar1, wherein Ar1 is a phenyl, wherein the phenyl can be unsubstituted or can carry 1 substitute Rx wherein Rx denotes halogen, CN, C1-C6-alkyl, C1-C6-halogenalkyl, C1-C6-alkoxy, C1-C6-halogenalkoxy, C1-C6-alkylthio, C1-C6-halogenalkylthio, NRx1 Rx2, wherein Rx1 and Rx2 independently denote hydrogen, C1-C6-alkyl, or Rx1 and Rx2 together with a nitrogen atom form an N-bonded 5-, 6- or 7-member saturated heteromonocyclic ring or an N-boned 7-, 8-, 9- or 10-member saturated heterobicyclic ring, which are unsubstituted or carry 1, 2, 3 or 4 radicals selected from C1-C4-alkyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treatment using the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel quinoline derivatives are obtained, which respond to modulation of the serotonin 5-HT6 receptor.

23 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 , where X and T are N or C, Q is a (3-7)-member aromatic ring which contains 0-3 nitrogen atoms as ring members, and which is optionally benzo-condensed and is substituted with oxo; C1-C6-alkyl; halogen- C1-C6-alkyl; hydroxy-C1-C6-alkyl; C1-C6-alkoxy; C6-C10-aryl; or a (3-7)-member heteroaryl containing 1-3 oxygen atoms, P is C1-C6-alkyl, optionally substituted with a halogen, and R is a group selected from: (i) -C1-C6-alkyl-R1, (ii) -NR2R3, (iii) -O-R4, (iv) -S-R5, (v) -C (=O))-R6, (vi) optionally substituted (3-7)-member heteroaryl containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (vi) optionally substituted (3-7)-member heteroatom containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (vii) optionally substituted, saturated or partially unsaturated, separate or condensed (3-10)-member heterocyclic ring containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (viii) azido; where each R1, R2, R3, R4, R3, R6, is as described in the claim. The invention also relates to a pharmaceutical composition for preventing and treating a vascular disease, which contains a compound of formula 1.

EFFECT: compounds of formula 1 with inhibitory activity with reference to aggregation of thrombocytes.

7 cl, 7 dwg, 2 tbl, 519 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where: A is CA1; E is CE1; W is (CH2)n; Y is (CH2)P; n and p are independently equal to 0 or 1; R1 is a phenyl which is substituted with a phenyl {which is optionally substituted with a halogen, hydroxy, CH(O), CO2H, C1-4alkyl, C1-4alkyl-(N(C1-4alkyl)2), C1-4alkyl(NH2), C1-4alkyl(NH(C1-4alkyl)), C1-4hydroxyalkyl, CF3, C1-4alkylthio, C1-4alkyl(heterocyclyl) or C1-4alkylNHC(O)O(C1-4alkyl)} or a heterocyclyl; and the heterocyclyl is optionally substituted with C1-6alkyl; R2 is NHC(O)R3; and R3 is C1-4alkyl {substituted with NR7R8 or a heterocyclyl}, C3-7cycloalkyl (optionally substituted with a NR43R44 group) or a heteroaryl; where R7, R8, R43 and R44 are as defined in claim 1; wherein the heteroaryl is optionally substituted with a halogen, C1-4alkyl, CF3, C1-4alkoxy, OCF3, heterocyclyl or an amino(C1-4alkyl) group; R7 and R8 are independently C1-6alkyl; A1, E1 and G1 are independently hydrogen or halogen; unless otherwise stated, the heterocyclyl is optionally substituted with C1-6alkyl; R25 is C1-6alkyl; R50 is hydrogen or C1-6alkyl (optionally substituted with a NR51R52 group); R30, R36, R40, R42 or R44 is independently hydrogen, C1-6alkyl(optionally substituted with hydroxy, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl (which is optionally substituted with hydroxy) or NR45R46), C3-7cycloalkyl (optionally substituted with a hydroxy(C1-6alkyl) group) or a heterocyclyl (optionally substituted with C1-6alkyl); R29, R35, R39, R41, R43, R45, R46 and R51 are independently hydrogen or C1-6alkyl; where the heterocyclyl is a non-aromatic 5- or 6-member ring containing one or two heteroatoms selected from a group comprising nitrogen and oxygen; and where the aryl is phenyl or naphthyl; and where the heteroaryl is an aromatic 5- or 6-member ring, optionally condensed with another ring (which can be carbocyclic and aromatic or non-aromatic), having one or two heteroatoms selected from a group comprising nitrogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a PDE4-mediated disease state.

10 cl, 81 dwg, 15 tbl, 375 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrole nitrogen-containing heterocyclic derivatives of formula (I) or their pharmaceutically acceptable salts:

,

wherein: X means C, N; each R1,R2 means H; R3 means C1-10alkyl; R4 means -[CH2CH(OH)]rCH2NR9R10, -(CH2)nNR9R10; provided X means N, R5 is absent, each R6, R7, R8 means H, halogen; provided X means C, each R5, R6, R7, R8 means H, halogen, hydroxyC1-10alkyl, C1-10alkyl, phenyl, 6-member heteroaryl with one N, -OH, -OR9, -NR9R10, -(CH2)nCONR9R10, -NR9COR10, -SO2R9 and -NHCO2R10, wherein said phenyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, C1-10alkoxyl, halogen; each R9, R10 means H, C1-10alkyl wherein C1-10alkyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, phenyl, halogenophenyl, -OH, C1-10alkoxy, OH- C1-10alkyl; or R9 and R10 together with an attached atom form a 5-6-member heteroring which may contain one O; n is equal to 2- 6; z is equal to 1-2; r is equal to 1-6;.

EFFECT: compounds may be used as protein kinase inhibitors.

14 cl, 2 tbl, 67 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of antibiotics, which represent compounds of formula (I) and their pharmaceutically acceptable salts, where U, V, W, X, R1, R2, R3, R4, R5, R6, A, B, D, E, G, m and n are determined in description. Invention also relates to pharmaceutical composition, containing said compounds and their application for obtaining medication for prevention or treatment of bacterial infections.

EFFECT: obtaining useful antimicrobial agents, efficient against various pathogens of people and animals.

23 cl, 1 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to anhydrous crystalline vinflunine salts of general formula (I) prepared with 1 or 2 equivalents of a pharmaceutically acceptable inorganic or organic acid. . In formula (I) [The acid] represents hydrobromic, lactic or fumaric acid for a group of water-soluble crystalline salts, as well as para-toluenesulphonic, benzoic, mandelic and para-hydroxybenzoic acid for a group of relatively water-insoluble crystalline salts.

EFFECT: preparing the anhydrous crystalline vinflunine salts.

8 cl, 8 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel azaindole derivatives, having JAK-2 and JAK-3 kinase inhibiting activity, or pharmaceutically acceptable salts thereof. In formula (I): R3 denotes H; X1 denotes N or CR4; R2 denotes H, COOH, COOR' or CONHR'; R4 denotes H, F, R, OH, OR', COR', COOH, COOR', CONH2 or CN; or R2 and R4, taken together, form a benzene ring optionally substituted with 1-2 R10; R' denotes C1-3-alkyl or C1-3-alkenyl, each optionally substituted 1-2 R5; each R5 is independently selected from CN, unsubstituted C1-2alkyl, or two groups R5 together with a carbon atom with which they are bonded form a cyclopropyl ring; each R10 is independently selected from halogen, OCH3 or OH; R1 denotes or , R is H or denotes C1-2alkyl, optionally substituted with 1-3 R11; R6 denotes C1-4alkyl, optionally substituted with 1-5 R12; values of radicals R7 -R9, ring A, R11 -R14. The invention also relates to a pharmaceutical composition containing said compounds and a method of treating or reducing severity of a pathological condition such as allergy, asthma, amyotrophic lateral sclerosis, multiocular sclerosis, graft rejection, rheumatoid arthritis, solid malignant tumour, haematologic malignant disease, leukaemia, lymphoma and myeloproliferative disorders.

EFFECT: high efficiency of using the compounds.

41 cl, 6 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to substituted imidazopyridine derivatives of general formula (I) or enantiomers, diastereomers and tautomers and pharmaceutically acceptable salts thereof, in which A denotes -NH-, -CH2-, -CH2-CH2- or a bond; X denotes phenyl, phenyl condensed with a saturated heterocyclic 5- or 6-member ring, where the heterocyclic ring can contain one or two heteroatoms selected from O and N, and where the heterocyclic ring can further be substituted with an oxo group, a 6-member saturated heterocyclyl containing O as a heteroatom, a 5-6-member heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, and where each phenyl and heteroaryl is possibly substituted with 1 to 2 R14 and/or 1 substitute R4b and/or 1 substitute R5; R1 and R2 are independently selected from the following groups: C1-6-alkyl and C1-6-alkylene-C3-7-cycloalkyl, and where each alkyl is possibly substituted with a OH group, or R1 and R2 together with the nitrogen atom with which they are bonded form a 5-6-member ring which is possibly substituted with one substitute selected from C1-6-alkyl and O-C1-6-alkyl; R4b denotes C(O)NH2, C(O)OH, C(O)NH-C1-6-alkyl, C(O)N-(C1.6-alkyl)2, SO2-C1-6-alkyl, oxo group, and where the ring is at least partially saturated, NH2, NH-C1-6-alkyl, N-(C1-6-alkyl)2; R5 denotes a 6-member heteroaryl containing N as a heteroatom; R3 denotes -(CR8R9)n-T; R8 and R9 are independently selected from the following groups: H and C1-6-alkyl; n equals 1, 2, 3, 4, 5 or 6; T denotes or NR12R13; R10 denotes H, NH2, OH, C1-6-alkyl, possibly substituted with one OH, a halogen atom, NH(C1-6-alkyl) or N(C1-6-alkyl)2; q equals 1 or 2; Y denotes CH2, NR11 or O; R11 denotes H, or C1-6-alkyl; R12 and R13 are independently selected from the following groups: H, C1-6-alkyl, C1-6-alkynyl, (CH2)0-2-C3-7-cycloalkyl, and C1-6-alkylene-O- C1-6-alkyl, where C1-6-alkyl is possibly substituted with one halogen; R14 denotes a halogen atom, CN, C1-6-alkyl, possibly substituted with 1-3 substitutes selected from halogen atom, OH, O- C1-6-alkyl, O-C(O)C1-6-alkyl, O- C1-6-alkyl, possibly substituted with one substitute selected from OH, O- C1-6-alkyl, and O-C(O) C1-6-alkyl, or OH. The invention also relates to a pharmaceutical composition based on the compound of formula (I).

EFFECT: novel imidazopyridine derivatives are obtained, which can be used as melanocortin-4 receptor modulators.

17 cl, 8 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (aza)indole derivatives of formula

wherein the values T, X1-X3, R1, Q, Y, J are presented in clause 1 of the patent claim.

EFFECT: compounds possess xanthine oxidase inhibitory action that enables using it in a pharmaceutical composition for treating a disease specified in a group consisting of hyperuricemia, gouty tophus, gouty arthritis, renal diseases associated with hyperuricemia and nephrolithiasis.

19 cl, 62 tbl, 332 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to particular compounds, which demonstrate inhibiting activity with respect to ERK, whose structure formula is given in description, to their pharmaceutically acceptable salts, based on them pharmaceutical composition and their application for treatment of cancer, mediated by ERK activity.

EFFECT: obtaining compounds, which demonstrate inhibiting activity with respect to ERK.

5 cl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof: (I) where R1, R2 and R3, which are identical or different, denote H, lower alkyl; R4, R5, R6, R7 and R8, which are identical or different, denote H, lower alkyl, halogen, nitro, -X-OR0, -X-NR10R11, -X-NR0C(O)R10, -X-O-halogen lower alkyl, -X-O-X-phenyl; or R6 and R7 are combined to form -O-lower alkylene-O-; R, which is identical or different, denotes H, lower alkyl; R10, R11, which are identical or different, denote H, lower alkyl; X, which is identical or different, denotes a bond, lower alkylene.

EFFECT: compounds exhibit type 5 17βHSD inhibiting activity, which enables their use in producing a pharmaceutical composition and in a method of inhibiting type 5 17βHSD.

15 cl, 11 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted pyrazolopyrimidines derivatives of formula , wherein Y1, Y2, Y3, Y4 represent N or C-, wherein at least, two groups of Y1-Y4 represent carbon atom, R1 represents chlorine or bromine, R2-R7 represent, e.g. hydrogen, methyl or ethyl; and R10 and R11 independently represent, e.g. hydrogen or C1-C6alkyl, their optical isomers and pharmaceutically acceptable salts. Also, the invention refers to using said compounds for treating and preventing a number of acute and chronic mGluR5 related neurological disorders, such as, e.g. pains of various character, dyskinesia, Parkinson's disease, anxiety disorder, Alzheimer's disease and others, a pharmaceutical composition containing specified compounds and methods for preparing them.

EFFECT: compounds are strong mGluR5 modulators.

21 cl, 2 tbl, 274 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclohexylamine derivatives of formula (I), having inhibiting properties towards at least one monoamine transporter, such as serotonin transporter, dopamine transporter or norepinephrine transporter, or a combination of two or more transporters. The compounds can be used to treat and/or prevent central nervous system disorders such as pain, depression, anxiety, schizophrenia, sleep disorder etc. In formula (I) , n equals 0 or 1; s equals 1, 2 or 3, m equals a whole number from 0 to 12; Ar is

or where Y and Z are (i) both halogen; or (ii) one of Y and Z is CF3 or OCF3 and the other is hydrogen; Y1, Z1, Y2 and Z2 each independently denotes H or a halogen; each X independently denotes H, halogen, CF3, OR5, (C1-C4)alkyl, optionally substituted with halogen or OH, or NR6R7; each R1 and R2 independently denotes H or (C1-C6)alkyl; and each R3 and R4 independently denotes H or (C1-C9)alkyl optionally substituted with OH; where each R5 independently denotes H, (C1-C4)alkyl or phenyl; and each R6 and R7 independently denotes H or (C1-C4)alkyl; where at least two of R1, R2, R3, R4 and X together with atoms to which they are bonded are optionally bonded to form a 5-6-member ring, where the 5-6-member ring is selected from: a) R3 and R4 together with a nitrogen atom to which they are bonded optionally form a pyrrolidine, piperidine, piperazine or morpholine ring, which is optionally substituted with (C1-C4)alkyl; b) when R3 is H or lower alkyl, X and R4 together with atoms to which they are bonded optionally form a 1,3-oxazine ring; c) two X substitutes together with a carbon atom to which they are bonded optionally form a 1,3-dioxolane ring; and d) when R1 and R3 denote hydrogen, R2 and R4 together with atoms to which they are bonded optionally form a 5- or 6-member saturated heterocyclic ring containing one nitrogen atom.

EFFECT: high efficiency of using the compounds.

29 cl, 36 dwg, 11 tbl, 6 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to novel compounds - tetrahydronaphthyridine derivatives of formula (I) or their pharmaceutically acceptable salts, where R1 represents C1-6alkoxycarbonyl group optionally substituted with 1-5 substituents, etc; R2 represents C1-6alkyl group; R3 represents hydrogen or and all; R4 represents C1-4alkylene group; R5 represents optionally substituted unsaturated 5-8-member heterocyclic group containing 1-4 heteroatoms independently selected from oxygen and nitrogen atoms; R6, R7 and R8 represent independently hydrogen atom, hydroxygroup, cyanogroup, C1-6alkyl group, C1-6alkoxygroup, mono- or di- C1-6alkylcarbamoyl group or mono- or di- C1-6alkylaminogroup, optionally substituted with 1-6 substituents independently selected from halogen atom, C1-6alkoxygroup and aminogroup; R10 represents optionally substituted with 1-2 substituents phenyl group; which possess inhibiting activity with respect to cholesteryl ester transfer protein (CETP).

EFFECT: novel tetrahydronaphthyridine derivatives and method of obtaining them.

12 cl, 408 ex, 38 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzodiazine of the formula (1), which possess properties of inhibiting proliferative action and can be used during treatment of hyper-proliferative diseases like cancer. In formula (I) G1 and G2 each independently representing a halogen; X1 -R1 selected C1-C6-alkoxy, X2 represents a simple bond; Q1 represents a non-aromatic saturated 3-7-member monocyclic heterocyclic ring with 1 circular heteroatom of nitrogen and not necessarily 1 or 2 heteroatoms, selected from nitrogen, oxygen and sulphur, where Q1 does not necessarily have 1, 2 or 3 substitute groups, which can be similar or different , selected from cyano, carbamoyl, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkyl-sulfinyl C1-C6-alkyl-sulfonyl, N-C1-C6-alkyl-carbamoyl N,N-di-[C1-C6-alkyl]carbamoyl, C1-C6-alkanoyl, sulfamoyl, N-C1-C6-alkyl-sulfamoyl, N,N-di-[C1-C6-alkyl-]sulfamoyl, carbamoyl C1-C6-alkyl, N-C1-C6-alkyl-carbamoylC1-C6-alkyl, N,N-di-[C1-C6-alkyl]carbamoylC1-C6-alkyl, sulfamoylC1-C6-alkyl, N-C1-C6-alkyl-sulfamoylC1-C6-alkyl, N,N-di-[C1-C6-alkyl]sulfamoylC1-C6-alkyl, C1-C6-alkanoylC1-C6-alkyl, or from the group with the formula: Q2 -X3-, where X3 represents CO and Q2 represents a non-aromatic saturated 3-7-member monocyclic heterocyclic ring with 1 circular nitrogen heteroatom and not necessarily 1 or 2 heteroatoms, selected from nitrogen and sulphur, and where. Q2 does not necessarily have 1, 2 or 3 substitute groups, which can be similar or different, selected from halogens, C1-C4-alkyl, and where any C1-C6-alkyl and C2-C6-alkaloid groups within the limits of Q1 does not necessarily have one or more substitute groups, which can be similar or different, selected from hydroxy and C1-C6-alkyl and/or not necessarily a substitute selected from cyano, C1-C6-alkoxy, C2-C6-alkanoxy and NRaRb, where Ra represents hydrogen or C1-C4-alkyl and Rb represents hydrogen or C1-C4-alkyl, or Ra and Rb together with a nitrogen atom, to which they are attached, they form a 4-, 5- or 6- member non-aromatic saturated monocyclic heterocyclic ring with 1 circular heteroatom of nitrogen and not necessarily 1 or 2 heteroatoms, selected from nitrogen, oxygen and sulphur, which not necessarily have 1 or 2 substitutes, which can be similar or different, on the available carbon atom, and selected from halogens and C1-C3-alkilenedioxy.

EFFECT: obtaining new derivatives benzodiazine, which possess properties of inhibiting proliferative action and can be used during the treatment of hyper-proliferative diseases such as cancer

27 cl, 73 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

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

SUBSTANCE: invention relates to novel substituted derivatives of noscapine of the general formula (1) or its racemates, optical isomers, or their pharmaceutically acceptable salts and/or hydrates possessing anticarcinogenic activity, and to a pharmaceutical composition as tablets, capsules or injection formulations placed into pharmaceutically acceptable package, ant to methods for their synthesis, and to a method for inhibition of proliferation by their using. In compounds of the formula (1) R1 represents a substitute of amino-group chosen from alkyl; R2 represents a substitute of cyclic system chosen from possibly substituted alkyl wherein substitutes are chosen from possibly substituted amino-group or azaheterocycle comprising possibly oxygen (O), sulfur (S) or nitrogen (N) atoms as an additional heteroatom, and added to alkyl group by nitrogen atom, possibly substituted aryl possibly substituted and possibly condensed heteroaryl comprising at least one heteroatom chosen from nitrogen, sulfur and oxygen atoms, possibly substituted sulfamoyl. Except for, invention relates to 3-(9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, 3-(9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, 5-(4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-9-carbaldehyde (or -9-carbonitrile, or -9-sulfonyl chloride, or -9-carboxylic acid) and 3-(9-methoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, and method for their synthesis. Also, invention relates to combinatory and focused libraries.

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

20 cl, 5 tbl, 9 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

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

32 cl, 1 tbl, 132 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to experimental medicine and pharmacology, namely a method for preparing lithium salt of comenic acid (lithium comenate) by mixing a comenic acid solution heated up to temperature max. 80±2°C, with lithium carbonate or hydroxide solution in the stoichiometrically-defined amounts, and colouring the solution in yellow and reducing pH of the solution to 4.6 or 10.0 respectively, and recovering luthium salt of comenic acid from the solution by water distillation under vacuum. For this purpose, lithium salt of comenic acid is suggested to be used in the amount of 2 mg per 1 kg of body weight once daily for 3 days.

EFFECT: invention refers to the agents for preventing and treating neurodegenerative diseases caused by an brain oxidative damage.

2 cl, 2 dwg, 5 tbl

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