Oxazolidinone-quinolone-hybrid antibiotics

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

 

The present invention describes novel compounds in which pharmacophore, hinolan and oxazolidinone, connected by linker group which is stable under physiological conditions, and pharmaceutical antibacterial composition containing these compounds. These connections double action can be used as antimicrobial agents, effective against many known in medicine and veterinary pathogens, including gram-positive aerobic bacteria such as multidrug-resistant staphylococci, streptococci and enterococci, and gram-negative bacteria such as Moraxella catarrhalis and Haemophilus influenzae and anaerobic organisms, such as various species of Bacteroides spp. and Clostridia spp., and acid-fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium spp.

Oxazolidinone-chinolin-hybrid antibiotics described in the literature (see WO 02059116, WO 03002560, WO 03031443, WO 03032962). The main drawback of the compounds known from the prior art, is a poor solubility in water, making it difficult to obtain the corresponding compounds.

The present invention offers new compounds of formula (I), which are used as antimicrobial agents, and are effective against many multidrug-resistant bacteria

where a means alkylenes group, alkenylamine groups who, alkynylamino group, heteroalkyl group, cycloalkenyl group, geteroseksualbnogo group, Allenova group or heteroarenes group, and each of these groups may be substituted,

Q means CR4or N (especially CR4),

X is CR7or N,

Y represents CR6or N,

n is 1, 2 or 3,

m is 1, 2 or 3,

R1means H, F, Cl, Br, I, HE, NH2, alkyl group or heteroalkyl group,

R2denotes H, F or Cl,

R3means H, alkyl group, alkenylphenol group, alkylamino group, heteroalkyl group, cycloalkyl group, geterotsyklicescoe group, aryl group or heteroaryl group, alcylaryl group or heteroallyl group, and each of these groups may be substituted by one, two or more atoms of halogen, such as F or C1, or amino groups,

R4means hydroxy, a group of the formula ORO3R92or S3R10or heteroalkyl group containing at least one group HE, NH2, SO3R10, RHO2R92or COOH or ester group of a natural amino acid or its derivative, and where the group R9independently from one another mean H, alkyl, cycloalkyl, aryl or aralkyl, and R10means H, alkyl, cycloalkyl, the reel or aralkyl,

R5choose from the following groups:

R6means H, F, Cl or OMe,

R7means H, F, Cl, HE, NH2substituted or unsubstituted alkyl group, or substituted or unsubstituted heteroalkyl group, or R3and R7can be linked through alkylenes, alkenylamine or heteroalkyl group, or will be part of cycloalkanones or geteroseksualbnogo group, if R3does not mean N and R7does not mean H, F, HE, NH2or Cl, and

R8means C1-C6heteroalkyl, heteroallyl, heteroalkyl or heterooligomerization group,

or their pharmacologically acceptable salt, MES, hydrate or composition.

The implication is that some of the compounds of formula (I) or (II)referred to in the description of the application may exist in tautomeric forms, of which only one specifically mentioned and displayed in the description, the various geometric isomers (which are usually referred to as CIS/TRANS isomers or often (E) and (Z) isomers or optical isomers due to the presence in the structure of one or more chiral carbon atoms (which usually is about marked in accordance with the rules of Cahn-Ingold-Prelog or R/S system). In addition, some compounds may exist in polymorphic forms. The invention includes all such tautomeric forms, geometric or optical isomers and racemates and diastereomers) and polymorphic forms.

The term "alkyl" means a saturated alkyl group with straight or branched chain, containing from one to ten, preferably from one to six, carbon atoms, such as methyl groups, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 2,2-dimethylbutyl, n-octyl or n-pentyl. Any specified alkyl group substituted by one, two or more substituents, for example, groups F, Cl, Br, I, NH2HE, SH or NO2.

Terms of alkenyl and quinil mean unsaturated alkyl group with straight or branched chain, containing one, two or more double and/or triple links, and alkenyl preferably contains one or two double bonds, and quinil preferably contains one or two triple bond, preferably containing from two to ten, preferably two to six, carbon atoms, such as ethynyl group (vinyl), propenyl (allyl), Isopropenyl, n-pentenyl, butenyl, isoprenyl or hexa-2-enyl, ethinyl, PROPYNYL or butynyl. Any specified Alchemilla or Alchemilla group substituted by one, two or more replace the s, for example, groups F, Cl, Br, I, NH2HE, SH or NO2.

The term heteroalkyl means an alkyl group, alkenyl or quinil above, in which one or more carbon atoms replaced by an atom of oxygen, nitrogen, phosphorus or sulfur, for example an alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy, group alkoxyalkyl, such as methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino, dimethylamino or diethylamino, allylthiourea, such as methylthio, ethylthio or isopropylthio, or cyano. In addition, heteroalkyl could mean one of the above groups containing ketogroup. The term heteroalkyl also means a group derived from carboxy or carboxamido, such as acetyl, propionyl, atomic charges, propionyloxy, acetylamino or propionamido, carboxialkilnuyu group, such as carboxymethyl, carboxyethyl or carboxypropyl, carboxialkilnuyu ether, alkyldiethanolamine, alkoxyimino, alkylaminocarbonyl or alkoxycarbonylmethyl. Any heteroalkyl group specified above, may contain one, two or more substituents, for example F, Cl, Br, I, NH2HE, SH or NO2.

The term cycloalkyl oz is achet saturated or partially unsaturated (containing one, two or more double and/or triple bonds) cyclic group containing one, two or more cycles and from 3 to 14 carbon atoms in the cycle, preferably from 5-6 to ten carbon atoms in the cycle, for example the group cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetralin, cyclopentenyl or cyclohex-2-enyl. Any cycloalkyl group specified above, may contain one, two or more substituents, for example F, Cl, Br, I, HE, NH2SH, N3, NO2, alkyl groups such as methyl or ethyl, heteroalkyl groups such as methoxy, methylamino, dimethylamino or cyano.

The term heteroseksualci means cycloalkyl group specified above, in which one, two or more carbon atoms in the cycle is replaced by one, two or more atoms of oxygen, nitrogen, phosphorus or sulfur or a group S(O)1-2for example , group piperidino, morpholino or piperazine derivatives.

The term aryl means an aromatic cyclic group containing one, two or more cycles and from 5 to 14 carbon atoms in the cycle, preferably from 5-6 to ten carbon atoms in the cycle, such as phenyl group or naphthyl. Any aryl group, mentioned above, may contain one, two or more substituents, for example F, Cl, Br, I, HE, NH2SH, N3, NO2, alkyl groups such as methyl or ethyl, heteroalkyl groups such as methoxy, IU is ylamino, dimethylamino or cyano.

The term heteroaryl means aryl group mentioned above, in which one, two or more carbon atoms in the cycle is replaced by an oxygen atom, nitrogen, boron, phosphorus or sulfur, such as pyridyl group, imidazolyl, pyrazolyl, chinoline, ethenolysis, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazoles, tetrazolyl, pyrazinyl, pyrimidinyl and pyridazinyl.

The term aralkyl (or arylalkyl or alkylaryl) mean groups that include both aryl and alkyl and/or cycloalkyl group.

The term heteroaromatic (or heteroalkyl or heterooligomeric etc.) means aracelio group specified above, in which one, two, three or more carbon atoms replaced by one, two, three or more atoms of oxygen, nitrogen, phosphorus or sulfur or a group S(O)1-2.

Any alkyl, Alchemilla, Alchemilla, heteroalkyl, cycloalkyl, heterocytolysine, aryl, heteroaryl, kalkilya or heteroallyl group, the above substituted by one or more halogen atoms, groups of NH2SH, NO2or HE or unsubstituted alkyl groups, heteroalkyl, aryl, aralkyl, aralkylated, heteroaryl, cycloalkyl or heteroseksualci specified above.

The term "NeoMaster is but substituted" or "substituted" means a group in which one or more hydrogen atoms replaced with a halogen atom, a group NH2SH, NO2or HE, at the group of unsubstituted alkyl, heteroalkyl, aryl, aralkyl, aralkylated, heteroaryl, cycloalkyl or heteroseksualci above.

Preferred and/or preferential variant of the invention are the objects of claims.

Preferred compounds of formula (I)in which R1means N.

In addition, preferred compounds of formula (I)in which R2means F or N.

More preferred compounds of formula (I)in which R3means ethyl, 2-propyl, C3-C6cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), phenyl or pyridyl. All of these groups substituted by one, two, three or more fluorine atoms or by amino groups.

More preferred compounds of formula (I)in which R3means cyclopropyl group.

In addition, preferred compounds of formula (I)in which R7and R3together form a bridging group of the formula-O-CH2-N(Me)- or-O-CH2-CH(Me)-, with the final connection chiral center is (S)-configuration.

More preferred compounds of formula (I)in which R4means hydroxy or a group of the formula OSO3H, ORO3H2The co ORO3H2OSON2CH2COOH or ester of the natural amino acid or its derivative (i.e. a group of the formula-OCOCHR'NH2or its derivative such as ester, amide or alkylamine, where R' is a side chain of natural amino acids such as aspartic acid, glutaric acid, lysine and the like, for example, dimethylaminophenyl, OCOCH2N(CH3)2).

In addition, preferred compounds of formula (I)in which R8means a group of formula-CH2NHCOCH=CHAryl, -CH2O-heteroaryl (especially-oxa-3-oxazol), -CH2NHSO2Me, -CH2NHCOOMe, -CH2NHCOMe, -CH2NHCS2Me, -CH2NHCSMe, -CH2NHCSNH2, -CH2NHCSOMe or-NHCOMe, especially-CH2NHCSMe or-CH2NHCOMe.

Preferred primarily compounds of formula (I)in which R5means structure

More preferred compounds of formula (I)in which R7means H, F, Cl or methoxy group substituted by one, two or three fluorine atoms.

In addition, preferred compounds of formula (I)in which X is N or CH.

More preferred compounds of formula (I)in which Y represents CH or N.

In addition, preferred compounds of formula (I)in which a represents C1-C6alkylen,2-C6albaniles,2-C6al is inlen, C1-C6heteroalkyl, cyclopropyl, epoxide, aziridine, diepoxide, lactam or lactone, and each group may be substituted.

More preferred compounds of formula (I)in which a represents a group of formula-O-B-, where b means With1-C4alkylenes group2-C4alkenylamine group2-C4alkynylamino group or a C1-C4heteroalkyl group, and each group may be substituted by one, two or more hydroxy or amino groups.

Preferred primarily compounds of formula (I)in which a represents a group of formula-CH2CH2-, -Och2-, -Och2CH2-, -SCH2-, -SCH2CH2-, -CH=CH-,, -CH(OH)CH(OH)- or-CH(NH2)CH(OH)-.

Preferred primarily compounds of formula (I), which means CH2or CH2CH2.

Preferred primarily compounds of the formula (II)

where residues have the meanings specified above. In the preferred embodiment, means In CH2or CH2CH2, X is CH, N or C-OMe, and R3means cyclopropyl or X is CR7and R7and R3together form a bridging group of the formula-O-CH2-CH(Me)-, where the final connection is the preferred configuration of chiral what about the center is (S)-configuration, n is 1, 2 or 3, m is 1, 2 or 3, and R4means hydroxy or a group of the formula OSO3H, ORO3H2The co2ORO3H2OSON2CH2COOH or ester of the natural amino acid or its derivative.

Preferred mono-, di - and trinitramine salt (most preferred monosodium salt) of compounds of formula (I) or (II) or mixtures thereof. Preferred primarily mono-, di - or trinitramine salt (most preferred monosodium salt) of compounds of formula (I) or (II)in which R4means ORO3H2or OSO3H, or mixtures thereof.

Preferred primarily sodium salt of the compounds of formula (II)in which R3means cyclopropyl group, X is CH or N, n is 2, m is 2, R4means ORO3H2and means In CH2.

The present invention also relates to pharmaceutically acceptable salts or solvate and hydrate, respectively, and to compositions and formulations of compounds of formula (I) or (II). The present invention describes methods of obtaining pharmaceutically acceptable agents that contain these compounds, and the use of these compounds to obtain pharmaceutically acceptable agents.

The pharmaceutical compositions of the present invention contain at least one connection is a group of formula (I) or (II) as the active agent and optionally carriers and/or diluents and/or adjuvants. In addition, the pharmaceutical compositions of the present invention optionally contain additional known antibiotics.

Examples of pharmacologically acceptable salts of bases of formula (I) or (II) are salts of physiologically acceptable mineral acids, such as hydrochloric acid, Hydrobromic acid, sulphuric acid, phosphoric acid, or organic acids, such as methanesulphonate, para-toluensulfonate, lactic, acetic, triperoxonane, citric, succinic, fumaric, maleic and salicylic acid. Furthermore, the acid compound of formula (I) or (II) may form salts with alkali or alkaline-earth metals, for example, salts of sodium, potassium, lithium, calcium or magnesium, ammonium salts or salts of organic bases, for example salts of methylamine, dimethylamine, trimethylamine, triethylamine, Ethylenediamine, ethanolamine, choline hydroxide, meglumine, piperidine, research, Tris(2-hydroxyethyl)amine, lysine or arginine. The compounds of formula (I) or (II) may form a solvate, especially a hydrate. Hydrating can occur in the process of receiving or due to hygroscopicity initially anhydrous compound of formula (I) or (II). The compounds of formula (I) or (II) may contain asymmetric carbon atoms and may be present in the form of achiral connected to the th, mixtures of diastereomers, mixtures of enantiomers or in the form of optically pure compounds.

In addition, the present invention relates to prodrugs that include a compound of formula (I) or (II) and at least one pharmacologically acceptable protective group which is cleaved under physiological conditions, such as alkoxy, arakaki-, acyl-, SO3H, RHO3H2, acyloxymethyl group (for example, pivaloyloxymethyl), 2-alkyl-2-aryl - or 2-Uralelectromed-2-alcaligenaceae group or alloctype specified above, for example, ethoxy, benzyloxy, acetyl or the atomic charges. Preferred above all prodrugs, representing a compound of formula (I) or (II)where R4means HE modified the hydroxy-group.

As noted above, therapeutic agents which contain the compounds of formula (I) or (II), solvate, salt, or composition, is also included in the scope of the present invention. In General, compounds of formula (I) or (II) to impose a known and acceptable methods known in the prior art, alone or in combination with any other therapeutic agent. Such therapeutic agents can enter one of the following methods: oral way, for example, in the form of tablets, pills, pellets in the shell, pills, semi-solid drugs, soft or hard ka is Sul, for example, soft or hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions or syrups; parenteral means, including intravenous, intramuscular and subcutaneous injection, for example, in the form of injectable solutions or suspensions; rectally way in the form of suppositories; by inhalation or by injection, for example, a powder composition in the form of microcrystals or spray (for example, a liquid aerosol); percutaneous method, for example, using percutaneous delivery (TDS), such as plaster containing the active ingredient, or intranasal way. Upon receipt of such tablets, coated tablets, pills, semi-solid preparations, tablets in the shell, coated tablets and hard, for example, gelatin, capsules, therapeutically effective the product is mixed with pharmaceutically inert inorganic or organic excipients, such as lactose, sucrose, glucose, gelatin, malt, silica gel, starch or its derivatives, talc, stearic acid or its salt, skimmed milk powder, etc. When getting soft capsules as the excipients used, for example, vegetable, mineral, animal or synthetic oils, waxes, fats, polyols. Upon receipt of liquid solutions, emulsions or suspensions or syrups as excipients used, for example, in the and, alcohols, saline, aqueous dextrose, polyols, glycerol, lipids, phospholipids, cyclodextrins, vegetable, mineral, animal or synthetic oils.

Preferred primarily lipids and preferred phospholipids (preferably of natural origin; especially with a particle size of from 300 to 350 nm), preferably in saline phosphate buffer solution (pH 7-8, preferably of 7.4). Upon receipt of the suppositories as excipients can be used, for example, vegetable, mineral, animal or synthetic oils, waxes, fats and polyols. In aerosol compositions are suitable for these purposes, compressed gases, such as oxygen, nitrogen and carbon dioxide. Pharmaceutically suitable agents may also contain additional components, such as preservatives, stabilizers, such as UV-protective agents, emulsifiers, sweeteners, flavoring agents, salts for modifying the osmotic pressure, buffer substances, shell components and antioxidants.

For the person skilled in the art it is evident daily dose for one patient from about 1 mg to about 4000 mg, especially from approximately 50 mg to approximately 3 g, it means that the dose depends on the age and condition of the patient (mammal) and the type of disease that p who belongs to the cure or prevention. The daily dose can be administered as a single dose or divided doses. The average single dose may be about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg and 2000 mg

The compounds of formula (I) and (II) can be synthesized, as shown in the following diagram:

Reaction conditions

Stage 1: CH2Cl2, KOH (50%), 3 h, CT, 97%.

Stage 2: N2Pt/C, 20 h, CT, then Z-Cl (Cbz-Cl), acetone/water, NaHCO3, 12 h, CT, 98%.

Stage 3: n-BuLi, -60°C, 24 h, 80%.

Stage 4: MsCl, triethylamine, CH2Cl2, 100%.

Stage 5: NaN3in DMF, 90°C, the catalyst Bu4NI, 5 h, 90%.

Stage 6: N2Pd(OH)2, THF, Meon, 24 h, and then the Asón, Ac2O CT, 2 h, 70%.

Stage 7: DMF, NaH, 70°C, 12 h, 75%.

Stage 8: H2Pd(OH)2, Meon, THF, 24 h, CT, 100%.

Stage 9: N-methylpyrrolidine, 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid (commercial product), TMS-Cl, base Hunga or2CO3, 80°C, 5 h, 80%.

Examples

Example 1

7-(4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid

Stage 1

Benzyl ether of (4-benzyloxy-3-forfinal)carbamino acid

The solution is 34.9 g of 1-benzyloxy-2-fluoro-4-NIT is benzole (WO 03064413) (MM: 247,28, 141 mmol) and 340 mg of 5% platinum on charcoal in 350 ml of ethyl acetate was stirred in an atmosphere of hydrogen at RT and normal pressure. The results of analysis method GHUR reaction was completed after 20 hours, the Catalyst was separated by filtration through a glass fiber filter and the filtrate was evaporated under reduced pressure to dryness. The oily residue was dissolved in 500 ml of acetone, was added 250 ml of saturated sodium bicarbonate solution and 17.5 g of sodium bicarbonate (MM: 84,01, 208 mmol). The mixture was cooled to 5°C and added dropwise 26,08 g benzylchloride (MM: 170,59, 152 mmole) and the mixture was stirred at room temperature for 2 hours, monitoring the progress of the reaction by TLC (eluent: hexane/ethyl acetate, 3:1). The acetone evaporated, the residue was diluted by adding 500 ml of water and a solid substance was separated by filtration. The crystals were washed with 500 ml of water and dried. Output: 48,05 g, 95,8%. MS (ESI+): AZN 352.5 (M+H)+MC (ESI-): 350,8, (M-H)+.

Stage 2

(5R)-3-(4-Benzyloxy-3-forfinal)-5-hydroxymethylimidazole-2-he

A solution of 17.5 g of benzyl ether (4-benzyloxy-3-forfinal)carbamino acid (MM: 351,38, 50 mmol) in 30 ml of dry tetrahydrofuran was stirred while cooling to -78°C in a bath of dry ice/acetone. Then to the mixture was added dropwise to 22.8 ml of a 2.3 M solution of n-utility (52,5 mmole) in n-hexane and the reaction mixture was stirred at -78°is within 15 minutes Then to the mixture was added a 7.92 g of R(-)-glycidylether (MM: 144,17, 60 mmol) and the reaction mixture was heated to room temperature. The reaction was controlled by the method GHUR, was stopped by adding a saturated solution of ammonium chloride and the mixture was diluted by adding 100 ml of ethyl acetate. The organic layer was washed with 200 ml of water and 200 ml of saline solution. The organic layer was dried over magnesium sulfate, filtered and the filtrate was evaporated under reduced pressure. The residue was led from 200 ml of a mixture of ethyl acetate/hexane, 1:1. A solid substance was separated by filtration and recrystallized from 150 ml of a mixture of ethyl acetate/dichloromethane, 9:1. Colorless crystals were separated by filtration and dried. Yield: 10.4 g, 65.5 per cent. MS (ESI+): 318,1 (M+N)+.

Stage 3

(5S)-5-Azidomethyl-3-(4-benzyloxy-3-forfinal)oxazolidin-2-he

In a solution of 10 g of (5R)-3-(4-benzyloxy-3-forfinal)-5-hydroxymethylimidazole-2-she (MM: 317,32, 31,51 mmole) and 4,78 g of triethylamine (MM: 101,19, 47,26 mmole) in 300 ml of dichloromethane under stirring at 10°C was added 4,32 g methanesulfonanilide (MM: 114,55, 37,82 mmole). The mixture was stirred at room temperature for 1 h, monitoring the course of the reaction by TLC (eluent: ethyl acetate/hexane, 1:1). The reaction was stopped by adding 100 ml of water, the organic layer was washed with 100 ml of brine, dried over magnesium sulfate, filtered and the filtrate is perivale under reduced pressure. The residue was dissolved in 100 ml of dimethylformamide, was added 5,12 g of sodium azide (MM: 65,01, 78,7 mmole) and a catalytic amount of tetrabutylammonium iodide. The suspension was stirred at 90°C during the night, controlling the course of the reaction method GHUR. The dimethylformamide is evaporated under reduced pressure, the residue was dissolved in 200 ml of dichloromethane and the organic layer was sequentially washed with 100 ml water and 100 ml of saline solution. Solution in dichloromethane was dried over magnesium sulfate, filtered and the filtrate was evaporated under reduced pressure. The residue was led from 150 ml of a mixture of ethyl acetate/hexane, 1:1. The crystals were separated by filtration, it was obtained a solid off-white color. Yield: 10.4 g, 97%. MS (ESI+): 343,1 (M+H)+-.

Stage 4

N-[(5S)-{3-(3-Fluoro-4-hydroxyphenyl)}-2-oxoacridine-5-ylmethyl]ndimethylacetamide

A suspension of 10.4 g of (5S)-5-azidomethyl-3-(4-benzyloxy-3-forfinal)oxazolidin-2-she (MM: 342,33, 30,38 mmole) and 1.5 g of 10% palladium on charcoal in 400 ml of a mixture methanol/ethyl acetate, 1:1, was stirred at room temperature in a hydrogen atmosphere for 2 days. The catalyst was separated by filtration through a glass fiber filter and the filtrate was evaporated under reduced pressure. The residue was dissolved in 100 ml of acetic acid was added and 3.72 g of acetic anhydride (MM: 102,09, 36,45 mmole). The solvent was evaporated under reduced pressure, stop the talk was led from a mixture of ethyl acetate/hexane, 1:1, and the received solid off-white color. Output: 6,76 g, 83%. MS (ESI+): 269,4 (M+H)+MC (ESI-): 267,3

(M-H)-.

Stage 5

Benzyl ether of 4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-carboxylic acid

Suspension 22,72 g benzyl ester 1-oxa-6-azaspiro[2.5]octane-6-carboxylic kislota (WO 9803507) (MM: 247,29, 92 mmole), 21,45 g of N-[(5S)-{3-(3-fluoro-4-hydroxyphenyl)}-2-oxoacridine-5-ylmethyl]ndimethylacetamide (MM: 268,246, 80 mmol) and 16,58 g of potassium carbonate (MM: 138,20, 120 mmol) in 150 ml of dimethylformamide was stirred at 100°C for 7 h by controlling the course of the reaction by TLC (eluent: dichloromethane/methanol, 9:1). The dimethylformamide is evaporated under reduced pressure and the residue was dissolved in 600 ml of a mixture of dichloromethane/methanol, 9:1. The organic layer was sequentially washed with 400 ml of water and 400 ml of saline solution. The organic layer was dried over magnesium sulfate, filtered and the filtrate was diluted by adding 250 ml of ethyl acetate. The mixture was concentrated under reduced pressure to a final volume of 400 ml, the Suspension was stirred at room temperature overnight. The crystals were separated by filtration and then washed with 150 ml of ethyl acetate and 100 ml of pentane. Output: 31,65 g, 76.7 per cent. MS (ESI+): 516,8 (M+N)+.

Stage 6

N-[{(5S)-3-[3-Fluoro-4-(4-hydroxypiperidine-4-ylethoxy)phenyl]-2-oxoacetate the in-5-ylmethyl}]ndimethylacetamide

A suspension of 31 g of benzyl ester 4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-carboxylic acid (MM: 515,54, 60,13 mmole) and 2.5 g of 10% palladium on charcoal in 310 ml of methanol and 150 ml of ethyl acetate was stirred in an atmosphere of hydrogen for 4 h, controlling the course of the reaction by TLC (eluent: ethyl acetate). The suspension was diluted with 300 ml of methanol was heated to 40°C. and the catalyst was separated by filtration through a glass fiber filter. The filtrate was concentrated to 150 ml, was diluted by adding 300 ml of ethyl acetate and again has given concerts to 200 ml was Then added 200 ml of diethyl ether and the suspension was stirred while cooling to 0°C. the Solid is separated by filtration and dried. Output: 21,6 g, 94,3%. MS (ESI+): 382,6 (M+N)+.

Stage 7

7-(4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid

A suspension of 71 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo[1,8]naphthiridine-3-carboxylic acid (MM: 282,66, 0.25 mmole), 95 mg of N-[{(5S)-3-[3-fluoro-4-(4-hydroxypiperidine-4-ylethoxy)phenyl]-2-oxoacridine-5-ylmethyl}]ndimethylacetamide (MM: 381,40, 0.25 mmole), 102 mg of triethylamine (MM: 101,19, 1.0 mmol) and 81 mg trimethylchlorosilane (MM: 108,64, 0.75 mmole) in 1 ml N-methylpyrrolidine-2-it was stirred while heating the ri 80°C for 5 h, controlling the course of the reaction by TLC (eluent: dichloromethane/methanol, 9:1). N-Methylpyrrolidine-2-it is evaporated, the residue was dissolved in 20 ml of a mixture of dichloromethane/methanol, 9:1, and the solution was sequentially washed with 10 ml of 0.1 N. hydrochloric acid and 20 ml of saline solution. The organic layer was dried over magnesium sulfate, filtered and the filtrate was evaporated. The residue was dissolved in 10 ml of a mixture of dichloromethane/methanol, 9:1, and diluted by adding 20 ml of ethyl acetate. The precipitation was separated by filtration, it was obtained a solid off-white color. The second portion received at kontsentrirovanii the mother liquor under reduced pressure. Yield: 100 mg, 64%. MS (ESI+): 628,8 (M+N)+, MS (ESI-): 626,8 (M-N)-.

Example 2

7-(4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-phosphonoacetate-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid

Stage 1

7-[4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-(bis-benzyloxycarbonyloxy)piperidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid

In suspension 125 mg of 7-(4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid (MM: 627,60, 0.2 mmole)and 42 mg of tetrazole (MM: 70,05, 0.6 mmole) in 1 ml dichloromethane was added 138 mg dibenzyl-N,N-diisopropylphosphoramidite (MM: 345,42, 0.4 mmole), this has been a slow transformation of the initial suspension in a clear solution. The solution was stirred at room temperature for 2 hours, monitoring the progress of the reaction by TLC (eluent: dichloromethane/methanol, 9:1). The reaction mixture was cooled to 0°C and was added to 0.6 ml of 0.5 M solution of meta-chlorbenzoyl acid in dichloromethane. The mixture was stirred at room temperature for 2 h and was diluted by adding 20 ml of dichloromethane. The organic layer is successively washed with 20 ml saturated sodium bicarbonate solution, 20 ml of saline solution and dried over magnesium sulfate. The suspension was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol, 9:1), to receive solid off-white color. Yield: 158 mg, 89%. MS (ESI+): 889,3 (M+H)+MC (ESI-): 887,0 (M-H)-.

Stage 2

7-(4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-phosphonoacetate-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid

Suspension 158 mg of 7-[4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-(bis-benzyloxycarbonyloxy)piperidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthas who ridin-3-carboxylic acid (MM: 887,84, 0,177 mmole) and 20 mg of 20% palladium hydroxide on activated carbon in 20 ml of a mixture of dichloromethane/methanol/water, 6:3:1, was stirred at room temperature in a hydrogen atmosphere for 3 hours, the Catalyst was separated by filtration through a glass fiber filter, the solvent was evaporated under reduced pressure and the residue was dissolved in 10 ml of methanol. The solution was diluted by adding 20 ml of water, there was observed the formation of a white precipitate. A solid substance was separated by filtration and dried. Yield: 85 mg, 68%. MS (ESI+): 709,0 (M+N)+, MS

(ESI-): 706,5 (M-N)-.

Example 3

7-[4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-(2,6-diaminohexanoic)piperidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid

Stage 1

tert-Butyl ether 4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-carboxylic acid

The specified connection was received during the interaction of a 3.83 g of tert-butyl methyl ether 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid (WO 0204462) (MM: 213,28, 18 mmol) and £ 4.02 g of N-[(5S)-{3-(3-fluoro-4-hydroxyphenyl)}-2-oxoacridine-5-ylmethyl]ndimethylacetamide (MM: 268,246, 15 mmol) in the presence of 3.1 g of potassium carbonate (MM: 138,20, 22.5 mmole) in 30 ml of dimethylformamide, similarly to that described in example 1, stage 5. O is d: 4,89 g, 67%. MS (ESI+): 482,6 (M+N)+.

Stage 2

tert-Butyl ether 4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-(2,6-bis-benzyloxycarbonylamino)piperidine-1-carboxylic acid

In a suspension of 96 mg of tert-butyl ester 4-{4-[5-(5S)-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-carboxylic acid (MM: 481,52, 0.2 mmole), 195 mg of Z-Lys(Z)-OH (MM: 414,46, 0.4 mmole) and 49 mg of 4-dimethylaminopyridine (MM: 122,17, 0.4 mmole) in 2 ml of dichloromethane under stirring at room temperature was added 115 mg hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (MM: 191,70, 0.6 mmole) and the reaction mixture was stirred over night. The mixture was diluted by adding 20 ml of ethyl acetate, the organic layer was sequentially washed with 10 ml of 1 N. hydrochloric acid, 20 ml water and 20 ml of brine, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol, 9:1), it was obtained a colorless viscous oil. Yield: 150 mg, 88%. MS (ESI+): 878,8 (M+N)+.

Stage 3

Hydrochloride 4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}piperidine-4-silt ether of 2,6-bis-benzyloxycarbonylamino acid

200 mg of tert-butyl ester 4-{4-[5-(5S)-(acetamidomethyl)-2-oxoacridine-3-yl]-2-CFT is phenoxymethyl}-4-(2,6-bis-benzyloxycarbonylamino)piperidine-1-carboxylic acid (MM: 977,97, 0.22 mmole) was dissolved in 4 ml of a 1.25 M solution of dry HCl in methanol. The reaction mixture was stirred at 40°C for 2 h, the solvent was removed by distillation under reduced pressure, to receive solid off-white color. Output: 178 mg, Quant. MS (ESI+): 778,8 (M+N)+.

Stage 4

7-[4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-(2,6-bis-benzyloxycarbonylamino)piperidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid

The specified connection was received when interacting 62 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo[1,8]naphthiridine-3-carboxylic acid (MM: 282,66, 0.25 mmole), 178 mg of the hydrochloride of 4-{4-[5-(5S)-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}piperidine-4-silt ether of 2,6-bis-benzyloxycarbonylamino acid (MM: 814,31, 0.22 mmole) and 48 mg of trimethylchlorosilane (MM: 108,64, of 0.44 mmole) in the presence of 90 mg of triethylamine (MM: 101,19, to 0.88 mmole) in 1 ml N-methylpyrrolidine-2-it is the same as described in example 1, step 7. Yield: 94 mg, 42%. MS (ESI+): 1025,3 (M+N)+.

Stage 5

7-[4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-(2,6-diaminohexanoic)piperidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid

A suspension of 94 mg of 7-[4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-the l]-2-forfinancial}-4-(2,6-bis-benzyloxycarbonylamino)piperidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid (MM: 1024,05, 0,091 mmole) and 20 mg of 20% palladium hydroxide on activated carbon in 20 ml of a mixture of dichloromethane/methanol/water, 6:3:1, was stirred at room temperature in a hydrogen atmosphere for 4 hours, the Catalyst was separated by filtration through a glass fiber filter, the solvent was evaporated under reduced pressure and the residue was dissolved in 10 ml of methanol. The solution was diluted by adding 20 ml of water, there was observed the formation of a white precipitate. A solid substance was separated by filtration and dried. Yield: 29 mg, 43%. MS (ESI+): 757,0 (M+N)+, MS

(ESI-): 755,2.

Example 4

Mono-[4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-1-(6-carboxy-8-cyclopropyl-3-fluoro-5-oxo-5,8-dihydro[1,8]naphthiridine-2-yl)piperidine-4-yl]ester of succinic acid

Stage 1

4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-1-tert-butoxycarbonylamino-4-silt/benzyl W succinic acid

825 mg tert-butyl ester 4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-carboxylic acid (MM: 481,52, 1,71 mmole), 1.07 g monobenzyl ester of succinic acid (MM: 208,21, 5,14 mmole) and 0.63 g of 4-dimethylaminopyridine (MM: 122,17, 5.1 mmole) in 10 ml of dichloromethane was stirred at room temperature in the presence of 1.3 g of the hydrochloride of N-(3-dimethyl isopropyl)-N'-ethylcarbodiimide (MM: 191,70, 6.8 mmole) in the same way as described in example 3, stage 2, to receive the specified connection. Yield: 820 mg, 70%. MS (ESI+): 673,3 (M+N)+.

Stage 2

4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}piperidine-4-silt/benzyl W succinic acid

820 mg of 4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-1-tert-butoxycarbonylamino-4-silt/benzyl of diapir succinic acid (MM: 671,72, of 1.23 mmole) was dissolved in 4 ml triperoxonane acid and the reaction mixture was stirred at room temperature for 1 h the Solvent is evaporated, the residue was dissolved in 30 ml of a mixture of dichloromethane/methanol, 9:1, and the organic layer was sequentially washed with 30 ml of saturated sodium bicarbonate solution and 30 ml of brine, dried over magnesium sulfate, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol (+2% triethylamine), 95:5). Yield: 420 mg, 60%. MS (ESI+): 572,7 (M+N)+.

Stage 3

4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-1-(6-carboxy-8-cyclopropyl-3-fluoro-5-oxo-5,8-dihydro[1,8]naphthiridine-2-yl)piperidine-4-silt/benzyl W succinic acid

The specified connection was obtained in the interaction of 113 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo[18]naphthiridine-3-carboxylic acid (MM: 282,66, 0.4 mmole), 230 mg of 4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}piperidine-4-silt/benzyl of diapir succinic acid (MM: 571,60, 0.4 mmole) and 87 mg of trimethylchlorosilane (MM: 108,64, 0.8 mmole) in the presence of 161 mg of triethylamine (MM: 101,19, 1.6 mmole) in 2 ml of N-methylpyrrolidine-2-it is the same as described in example 1, step 7. Yield: 25 mg, 7.6 percent. MS (ESI+): 819 (M+N)+MC (ESI-): 817,8.

Stage 4

Mono-[4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-1-(6-carboxy-8-cyclopropyl-3-fluoro-5-oxo-5,8-dihydro[1,8]naphthiridine-2-yl)piperidine-4-yl]ester of succinic acid

22 mg of 4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-1-(6-carboxy-8-cyclopropyl-3-fluoro-5-oxo-5,8-dihydro[1,8]naphthiridine-2-yl)piperidine-4-silt/benzyl W succinic acid (MM: 817,80, 0.026 mmole) and 2 mg of 20% palladium hydroxide on activated carbon in 20 ml of a mixture of tetrahydrofuran/methanol, 1:1, was first made in the same way as described in example 3, stage 5. Yield: 16 mg, 81%. MS (ESI+): 729 (M+N)+, MS (ESI-): 727 (M+N)-.

Example 5

7-(4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

In a solution of 60 g of N-[{(5S)-3-[3-fluoro-4-(4-hydroxypiperidine-4-ylethoxy)phenyl]-2-oksaoksa alidin-5-ylmethyl}]ndimethylacetamide (C 18H24FN3O5MM: 381,40, of) 0.157 mol) and 26,87 ml ethyldiethanolamine (MM: 129,25, of) 0.157 mol) in 300 ml of N-methylpyrrolidine-2-she added 67,81 g of a complex of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid/boron diacetate (MM: 410,57, 0,165 mol) and the mixture was stirred at 80°C for 5 h N-Methylpyrrolidine-2-he was evaporated under reduced pressure, the residue was dissolved in 300 ml of methanol and through the resulting solution at 10°C for 30 min was passed a stream of dry hydrogen chloride. The solution was stirred at room temperature until formation of yellow precipitate. The transformation of a complex of boron in the free acid was controlled by the method GHUR. The mixture was diluted with 300 ml of ethyl acetate, the solid was separated by filtration and washed with 100 ml of ethyl acetate/methanol, 8:2, and 100 ml of ethyl acetate. Solid yellow dried, when it got to 86.4 g of product which was dissolved in 200 ml of dimethylsulfoxide at 40°C and the yellow solution was added with stirring to 1000 ml of water. Solid yellow substance was separated by filtration, washed with water and dried. Output: 73g, to 74.5%. MS (ESI+): 627,8 (M+N)+, MS (ESI-): 625,8 (M+N)-.

Example 6

7-[4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-(bis-benzyloxycarbonyloxy)piperidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroxy the Lin-3-carboxylic acid

To a suspension of 35 g of 7-(4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (MM: 626,61, 55,85 mmole) and 6,45 g tetrazole (MM: 70,05, 92,15 mmole) in 700 ml of dichloromethane under stirring at room temperature was added a solution of 31.8 g of dibenzyldithiocarbamate (MM: 345,42, 92,15 mmole) in 20 ml of dichloromethane and the mixture was stirred for 1 h, monitoring the course of the reaction by TLC (eluent: dichloromethane/methanol, 9:1). The mixture was washed at 0°C. 200 ml of 1 N. hydrochloric acid and 100 ml saturated sodium bicarbonate solution. The aqueous layer was again extracted with 200 ml dichloromethane. The combined organic layers were concentrated to a volume of 500 ml and at room temperature was added to 13.2 ml of 70% solution of tert-butylhydroperoxide in water (MM: 90,12, 95 mmol). The reaction mixture was stirred for 30 min, diluted with 500 ml of dichloromethane, the organic layer was washed with 200 ml of 1 N. hydrochloric acid and 300 ml of brine, dried over magnesium sulfate, filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in 400 ml dichloromethane and diluted with 400 ml n-hexane. The mixture was concentrated (300 mbar, the temperature in the bath to 40°C) up to a volume of 400 ml. Viscous oil decantation and dissolved in 400 ml of boiling methanol. The solution is the end of what was tarawali under reduced pressure to a volume of 300 ml and was stirred at RT over night. The suspension was cooled to 0°C and separated solid substance. Output: 27,60 g, 55.6 per cent. MS (ESI+): 888,3 (M+N)+, MS (ESI-): 885,8 (M+N)-.

Example 7

7-(4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-phosphonoacetate-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

27 g of 7-[4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-(bis-benzyloxycarbonyloxy)piperidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (MM: 886,85, 30,44 mmole) is suspended in 600 ml of acetonitrile was added 53 ml of 33% solution of anhydrous Hydrobromic acid in acetic acid. The yellow suspension was diluted by adding 150 ml of acetic acid and was heated at 45°C for 3 h, and the results GHWR/MS indicated completion of reaction. The viscous suspension was added with stirring to 1.5 liters of water. The crystals off-white color was separated by filtration, washed with 300 ml of water, 150 ml of ethanol and 150 ml of ether. The solid is suspended in 1.3 l of water was added 35 ml (35 mmol) of 1 M sodium hydroxide solution. The solid was dissolved in a solution of yellow-brown color was added 15 g of activated charcoal and the mixture was filtered. The filtrate was extracted with three portions of 200 ml with a mixture of dichloromethane/methanol, 95:5. The water layer is obavljale 40 ml of 1 M HCl and the product was crystallized under stirring. A solid substance was separated and dried. Output: 17.3 g, 80,4%. MS (ESI+): 609,7 (M+N)+, MS (ESI-): 607,8 (M+N)-.

Example 8

7-(4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

The specified connection was obtained in the interaction of 114 mg of N-[{(5S)-3-[3-fluoro-4-(4-hydroxypiperidine-4-ylethoxy)phenyl]-2-oxoacridine-5-ylmethyl}]ndimethylacetamide (MM: 381,40, 0.3 mmole), 127 mg of diacetilactis 1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid (Sakurai Nobuhiro, Sano Mitsuharu, Hirayama Fumihiro, Kuroda Tsuyoshi on, Uemori Satoru, Bioorg. Med. Chem. Lett., 8, 16, 2185-2190 (1998)) (MM: 423,137, 0.3 mmole) in the presence of 38 mg ethyldiethanolamine (MM: 129,25, 0.3 mmole) in 1 ml N-methylpyrrolidine-2-it is the same as described in example 5. Yield: 137 mg, 69.5 per cent. MS (ESI+): 658,2 (M+N)+, MS (ESI-): 655,8 (M+N)-.

Example 9

7-(4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

The specified connection was obtained in the interaction of 114 mg of N-[{(5S)-3-[3-fluoro-4-(4-hydroxypiperidine-4-ylethoxy)phenyl]-2-oxoacridine-5-ylmethyl}]ndimethylacetamide (MM: 381,40, 0.3 mmole), 121 mg of 1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroxy the Lin-3-carboxylate/boron diacetate (WO 03032962, MM: 405,15, 0.3 mmole) in the presence of 77 mg ethyldiethanolamine (MM: 129,25, 0.6 mmole) in 2 ml of N-methylpyrrolidine-2-it is the same as described in example 5. Yield: 117 mg, 61.2 per cent. MS (ESI+): 639,8 (M+N)+, MS (ESI-): 637,5 (M+N)-.

Example 10

9-(4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6N-1-oxa-3A-azafenidin-5-carboxylic acid

A solution of 140 mg of 9,10-debtor-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazin-6-carboxylic acid (MM: 281,22, 0.5 mmole), 191 mg of N-[{(5S)-3-[3-fluoro-4-(4-hydroxypiperidine-4-ylethoxy)phenyl]-2-oxoacridine-5-ylmethyl}]ndimethylacetamide (MM: 381,40, 0.5 mmole) and 129 mg ethyldiethanolamine (MM: 129,25, 1 mmol) in 1 ml N-methylpyrrolidine-2-it was stirred at 80°C for 24 h the Solvent vypaivali under reduced pressure, the residue was dissolved in methanol and added 10 ml of a 1.2 M solution of anhydrous hydrogen chloride in methanol. The methanol is evaporated, the residue triturated in ethyl acetate, the solid was separated and twice was led from a mixture of dichloromethane/ethanol. Yield: 88 mg, 27%. MS (ESI+): 643,7 (M+N)+, MS (ESI-): to 641.5 (M+N)-.

Example 11

7-(3-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-3-hydroxypyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carbon whom I acid

Stage 1

Benzyl ester 1-oxa-5-azaspiro[2.4]heptane-5-carboxylic acid

To a solution of benzyl ester 3-methyleneindoline-1-carboxylic acid (WO 9624593) in 5 ml dichloromethane was added 2.16 g of sodium bicarbonate (MM: 84,01, 26,28 mmole) and 2,47 g 80% meta-chloroperbenzoic acid (MM: 172,57, 11,48 mmole) and the reaction mixture was stirred at room temperature for 3 hours, the Reaction mixture was diluted by adding 20 ml of saturated solution of sodium sulfite and 45 ml of dichloromethane. The organic layer was sequentially washed with 30 ml of saturated sodium bicarbonate solution and saline. The organic layer was dried over magnesium sulfate. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/n-hexane, 1:1), to receive solid off-white color. Yield: 440 mg, 57%. MS (ESI+): 234,1 (M+H)+.

Stage 2

Benzyl ether of 3-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-3-hydroxypyrrolidine-1-carboxylic acid

To a solution of 420 mg of N-[(5S)-{3-(3-fluoro-4-hydroxyphenyl)}-2-oxoacridine-5-ylmethyl]ndimethylacetamide (MM: 268,246, and 1.56 mmole) in 2 ml of dimethylformamide were added 83 mg of sodium hydride and the suspension was stirred at room temperature for 1 h Then the mixture was added 440 mg of benzyl ester 1-oxa-5-azaspiro[2.4]heptane-5-carboxylic acid (MM: 233,26, 1.88 m is Olya) in 1 ml DMF and the mixture was stirred at 70°C for 3 hours The dimethylformamide is evaporated under reduced pressure, the residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol (+1% NH3), 95:5), the received powder off-white color. Output: 630 mg, 80%. MS (ESI+): 502.5 (M+N)+.

Stage 3

N-{(5S)-3-[3-Fluoro-4-(3-hydroxypyrrolidine-3-ylethoxy)phenyl]-2-oxoacridine-5-ylmethyl}ndimethylacetamide

Suspension 660 mg benzyl ester 3-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-3-hydroxypyrrolidine-1-carboxylic acid (MM: 501,51, 1,31 mmole) and 20 mg of 10% palladium on activated carbon in 20 ml of a mixture of ethyl acetate/methanol, 1:1, was stirred for 12 h in an atmosphere of hydrogen. The catalyst was separated by filtration through a glass fiber filter, the filtrate was evaporated under reduced pressure, it was obtained a colorless oil. Output: 400 mg, 83,2%. MS (ESI+): 368,4 (M+N)+.

Stage 4

7-(3-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-3-hydroxypyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid

The specified connection was received when interacting 39 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo[1,8]naphthiridine-3-carboxylic acid (MM: 282,66, 0.24 mmole), 99 mg of N-{(5S)-3-[3-fluoro-4-(3-hydroxypyrrolidine-3-ylethoxy)phenyl]-2-oxoacridine-5-ylmethyl}ndimethylacetamide (MM: 367,38, 0.24 mmole) in the presence of 101 mg of triethylamine is (MM: 101,19, 1.0 mmol) and 80 mg of trimethylchlorosilane (MM: 108,64, 0.75 mmole) in 2 ml of N-methylpyrrolidine-2-it is the same as described in example 1, step 7. Yield: 70 mg, 46%. MS (ESI+): 614,7 (M+N)+, MS (ESI-): 612,7 (M+N)-.

Example 12

7-(3-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-3-hydroxypyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

The specified connection was obtained in the interaction of 106 mg of N-{(5S)-3-[3-fluoro-4-(3-hydroxypyrrolidine-3-ylethoxy)phenyl]-2-oxoacridine-5-ylmethyl}ndimethylacetamide (MM: 367,38, to 0.29 mmole), 119 mg of the complex (7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid/boron diacetate (MM: 410,57, to 0.29 mmole) in the presence of 75 mg ethyldiethanolamine (MM: 129,25, of 0.58 mmole) in 2 ml of N-methylpyrrolidine-2-it is the same as described in example 5. Yield: 19 mg, 11%. MS (ESI+): 613,5

(M+N)+, MS (ESI-): 611,5(M+N)-.

Example 13

7-(3-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-3-hydroxypyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

The specified connection was received when interacting 143 mg N-{(5S)-3-[3-fluoro-4-(3-hydroxypyrrolidine-3-ylethoxy)phenyl]-2-oxoacridine-5-ylmethyl}ndimethylacetamide (MM: 367,38, to 0.39 mmole), 165 mg of 1-cycloprop the l-6,7-debtor-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid/diacetilactis (MM: 423,137, to 0.39 mmole) in the presence of 100 mg of ethyldiethanolamine (MM: 129,25, to 0.78 mmole) in 2 ml of N-methylpyrrolidine-2-it is the same as described in example 5. Output: 143 mg, 57%. MS (ESI+): 643,7 (M+N)+, MS (ESI-): 641,7 (M+N)-.

Example 14

7-(3-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-3-hydroxypyrrolidine-1-yl)-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

The specified connection was received when interacting 48 mg of N-{(5S)-3-[3-fluoro-4-(3-hydroxypyrrolidine-3-ylethoxy)phenyl]-2-oxoacridine-5-ylmethyl}ndimethylacetamide (MM: 367,38, of 0.13 mmole), 53 mg of 1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate/boron diacetate (MM: 405,15, of 0.13 mmole) in the presence of 33 mg ethyldiethanolamine (MM: 129,25, of 0.26 mmole) in 1 ml of N-methylpyrrolidine-2-it is the same as described in example 5. Yield: 41 mg, 50%. MS (ESI+): 625,8 (M+N)+, MS (ESI-): 623,8 (M+N)-.

Example 15

9-(3-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-3-hydroxypyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6N-1-oxa-3A-azafenidin-5-carboxylic acid

The specified connection was received when interacting 110 mg 9,10-debtor-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazin-6-carboxylic acid (MM: 281,22, to 0.39 mmole), 143 mg of N-{(5S)-3-[3-fluoro-4-(3-hydroxypyrrolidine-ylethoxy)phenyl]-2-oxoacridine-5-ylmethyl}ndimethylacetamide (MM: 367,38, to 0.39 mmole) and 100 mg of ethyldiethanolamine (MM: 129,25, to 0.78 mmole) in 2 ml of N-methylpyrrolidine-2-it is the same as described in example 10. Yield: 103 mg, 42%. MS (ESI+): 629,8 (M+N)+.

Example 16

7-(4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxyether-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Stage 1

tert-Butyl ether 4-Meilenstein-1-carboxylic acid

In a solution of 1 g of methyltriphenylphosphonium (MM: 357,22, and 2.79 mmole) in 20 ml of tetrahydrofuran at -78°C was added to 1.22 ml of a 2.3 M solution of n-utility in n-hexane (2.8 mmole) and the reaction mixture was stirred at -78°C for 10 min and then at 0°C for 1 h, the Suspension was cooled to -78°C. and then was added a solution of 595 mg tert-butyl ester 4-oxazepan-1-carboxylic acid (WO 2000044376) (MM: 213,279, 2,78 mmole) in 10 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 1.5 h, the reaction was stopped by adding 30 ml of a saturated solution of ammonium chloride and the mixture was diluted with 30 ml of ethyl acetate. The organic layer was sequentially washed with 30 ml water and 30 ml brine, dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, the residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:1). Output: 487 mg, 83%. NMR (CDCl3): δ of 1.35 (s, 9H, tert-bot.), of 1.6 (m, 2H, -CH2-), and 2.14 (m, 2H), 2,33 (m, 2H), 3,29 (m, 4H, N-CH2), of 4.67 (m, 2H, vinyl-CH2).

Stage 2

tert-Butyl ester 1-oxa-6-azaspiro[2,6]nonan-6-carboxylic acid

The specified connection was received when interacting tert-butyl ester 4-Meilenstein-1-carboxylic acid (MM: 211,307, at 1.73 mmole) and 1.36 g of 80% meta-chloroperbenzoic acid (MM 72,57, 6,05 mmole) in the presence of 1.16 g of sodium bicarbonate (MM: 84,01 for 13.8 mmole) in 5 ml of dichloromethane in the same way as described in example 11, step 1. Yield: 250 mg, 63%. MS (ESI+): 228,8 (M+N)+, 127,8 (M-(CH3)3SOSO).

Stage 3

tert-Butyl ether 4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxyether-1-carboxylic acid

The specified connection was obtained in the interaction of 247 mg of tert-butyl methyl ether 1-oxa-6-azaspiro[2.6]nonan-6-carboxylic acid (MM: 227,31, a 1.08 mmole), 296 mg of N-[(5S)-{3-(3-fluoro-4-hydroxyphenyl)}-2-oxoacridine-5-ylmethyl]ndimethylacetamide (MM: 268,246, 80 mmol) and 228 mg of potassium carbonate (MM: 138,20, 1.65 mmole) in 150 ml of dimethylformamide analogously to that described in example 1, stage 5. Output: 334 mg, 62%. MS (ESI+): 496,8 (M+N)+, 440,8 (M-(CH3)3+N)+.

Stage 4

N-{(5S)-3-[3-Fluoro-4-(4-hydroxyether-4-ylethoxy)phenyl]-2-oxoacridine-5-ylmethyl}ndimethylacetamide

A solution of 334 mg of tert-butyl ester 4-{4-[(5S)-5-(acetyl shall Enomatic)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxyether-1-carboxylic acid (MM: 495,55, 0,674 mmole) in 3 ml of a 1.25 M solution of anhydrous hydrogen chloride in methanol was stirred at 35°C for 4 hours

The solvent is evaporated under reduced pressure, the residue was dissolved in 4 ml of water and the aqueous layer was neutralized to pH 7 by adding saturated sodium bicarbonate solution. The water evaporated and the residue was dissolved in 30 ml of dichloromethane/methanol, 9:1. The insoluble salt was separated by filtration, the filtrate was evaporated to dryness, to receive solid off-white color. Output: 266 mg, Quant. MS (ESI+): 395,8 (M+H)+, MS (ESI-): 440,6 (M+NAO-).

Stage 5

7-(4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxyether-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

The specified connection was obtained in the interaction of 150 mg of N-{(5S)-3-[3-fluoro-4-(4-hydroxyether-4-ylethoxy)phenyl]-2-oxoacridine-5-ylmethyl}ndimethylacetamide (MM: 395,43) and 163 mg of the complex (7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid/boron diacetate (MM: 410,57, 0,397 mmole) in the presence of 98 mg ethyldiethanolamine (MM: 129,25, 0,758 mmole) in 2 ml of N-methylpyrrolidine-2-it is the same as described in example 5. Yield: 70 mg, 28.8 per cent. MS (ESI+): 641,7 (M+N)+.

Example 17

7-(4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxyether-1-yl)-1-cyclopropyl-6-fluoro-4-the CSR-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid

The specified connection was obtained in the interaction of 98 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo[1,8]naphthiridine-3-carboxylic acid (MM: 282,66, 0,348 mmole), 138 mg of N-{(5S)-3-[3-fluoro-4-(4-hydroxyether-4-ylethoxy)phenyl]-2-oxoacridine-5-ylmethyl}ndimethylacetamide (MM: 395,43, 0,348 mmole), 140 mg of triethylamine (MM: 101,19, of 1.39 mmole) and 113 mg of trimethylchlorosilane (MM: 108,64, the 1.04 mmole) in 1 ml N-methylpyrrolidine-2-it is the same as described in example 1, step 7. Yield: 150 mg, 77%. MS (ESI+): 642,7 (M+N)+, MS (ESI-): 640,7 (M+N)-.

Example 18

Sodium salt of 7-(4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-phosphonoacetate-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

183 g of the compound obtained as described in example 7, was dissolved at room temperature in 400 ml of dry DMSO, and the solution so obtained was added 60 g preparation of (fuller's earth, the mixture was filtered, the filter residue was washed with 50 ml of dry DMSO. The combined filtrates were mixed in a nitrogen atmosphere with another portion of 50 ml of dry DMSO and 2000 ml of dry acetone. In this solution at room temperature was added dropwise to 47.1 g of 2-ethylhexanoate sodium (97% solution in ethyl acetate, i.e. a 250 ml). Then, the resulting suspension was stirred for 1 h and at room temperature was added 2750 ml of ethyl the ETA. The resulting suspension was stirred for another 1 h, the precipitated crystals were separated by filtration, washed with ethyl acetate (10×500 ml) to remove DMSO and dried under vacuum. If the crystals contained a residual amount of DMSO and/or ethyl acetate, then suspended in acetone/water (99:1) for 24 h the Mixture was filtered, the filter residue was washed with acetone/water (99:1, 2×500 ml) and dried on the vacuum filter for 12 hours Then the solid was dried in vacuum. Yield: 90%.

Example 19

tert-Butyl ether 4-{4-[5S-(acetamidomethyl)-2-oxoacridine-3-yl]-2-perforating}-4-hydroxypiperidine-1-carboxylic acid

In the example described is a method of obtaining structural blocks by the reaction Sonogashira.

Stage 1

Benzyl ether of (4-bromo-3-forfinal)carbamino acid

To a solution of 4-bromo-3-foronline (50.0 g, to 0.263 mol, 1 EQ.) in acetone (660 ml) was added with stirring sodium bicarbonate (27,63 g, 0,329 mol, 1.25 EQ.) and a saturated solution of sodium bicarbonate (333 ml). The resulting mixture was cooled to 15°C and in small portions was added benzylchloride (39 ml, 0,276 mole, of 1.05 equiv.) at this temperature the reaction mixture is maintained not higher than 22°C. the Mixture was stirred at room temperature for 90 minutes and the acetone was removed in vacuum. The aqueous layer was AKST who was agarawala with ethyl acetate (3×150 ml), the combined organic layers were washed with a saturated solution of sodium chloride, dried over MgSO4was filtered , the solvent evaporated and to the residue was added n-hexane. The mixture was stirred at room temperature for 30 min, the crystals were separated by filtration and washed with hexane, to receive the first portion of solids. The filtrate was evaporated and the solid at 0°C was mixed with heptane and stirred for 30 minutes the Mixture was filtered, to receive the second portion of solids, which was combined with the first portion, to receive 85,3 g of solid substance (yield).).

Stage 2

(5R)-3-(4-Bromo-3-forfinal)-5-hydroxymethylimidazole-2-he

In anhydrous tert-butanol (25,0 g of 0.53 mol, 2.07 EQ.) in anhydrous THF (170 ml) at -30°C under nitrogen atmosphere was added utility (2.3 M solution in n-hexane, 118.3 ml 0,272 mol, 1.06 EQ.). The mixture was stirred at -30°C for 30 min and then slowly warmed up to 0°C. After 30 min at 0°C portions to the mixture was added benzyl ester (4-bromo-3-forfinal)carbamino acid (83 g, 0,256 mol, 1 EQ.), keeping the temperature no higher than 0°C, and the resulting mixture was stirred at 0°C for another 30 minutes Then cooled in an ice bath, to the mixture was added R(-)-glycidylether (39,7 ml, in 0.288 mol, of 1.12 EQ.) and slowly heated to room temperature. The mixture was extracted with a feast upon the authorized solution of sodium chloride, the organic phase was dried over MgSO4was filtered and the filtrate was evaporated. The crude product is recrystallized from ethyl acetate (yield: 64,1 g, 86.4 per cent).

Stage 3

3-(4-Bromo-3-forfinal)-2-oxoacridine-(5R)-ymetray ether methanesulfonate acid

Cooled in an ice bath, a solution of (5R)-3-(4-bromo-3-forfinal)-5-hydroxymethylimidazole-2-it (54,0 g, 0,186 mol, 1 EQ.) triethylamine (51,8 ml, 0,372 mol, 2 EQ.) in anhydrous DHM (420 ml) at 0°C was added methanesulfonamide (27.4 ml, 0,354 mol, 1.9 equiv.) the resulting mixture was slowly heated to room temperature and then was stirred for 3 hours Then the mixture was washed with 10% sodium hydrogen carbonate solution, there was observed the formation of a precipitate. A solid substance was separated by filtration and washed DHM. Filtrate and wash fractions were dried over MgSO4was filtered and the solvent evaporated. The obtained solid is suspended in diethyl ether, separated by filtration, washed with ice diethyl ether, and dried, to receive and 68.5 g (yield amount.) the end product.

Stage 4

(5R)-Azidomethyl-3-(4-bromo-3-forfinal)oxazolidin-2-he

A suspension of 3-(4-bromo-3-forfinal)-2-oxoacridine-(5R)-Eletropaulo ether methanesulfonate acid (68,5 g, 0,186 mol, 1 EQ.), tetrabutylammonium iodide (China 0,686 g, 0,00186 mol, 0.01 EQ.) and of sodium azide (a 24.57 g, 0,378 mole 2,03 EQ.) in anhydrous DMF (500 ml) under nitrogen atmosphere was stirred at 80°C during the night. The reaction Smeg cooled, the DMF is evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated sodium chloride solution, dried over MgSO4was filtered and the filtrate was evaporated, it was given to 58.6 g (yield amount.) product in the form of a solid white color.

Stage 5

(5R)-Aminomethyl-3-(4-bromo-3-forfinal)oxazolidin-2-he

A mixture of (5R)-azidomethyl-3-(4-bromo-3-forfinal)oxazolidin-2-it (10,5 g of 33.3 mmole, 1 EQ.), triphenylphosphine (12,6 g, 48 mmol, 1,44 EQ.) and water (7.8 ml, 433 mmole, 13 EQ.) in THF (180 ml) was stirred at 80°C. After completion of the reaction the mixture was cooled and the solvents evaporated in vacuo. The residue was purified by chromatography (eluent: ethyl acetate to remove the derivatives of triphenylphosphine, then diclomelan/methanol, 9:1), to receive 9,63 g (yield amount.) product in the form of a solid white color.

Stage 6

(5S)-N-[(4-Bromo-3-forfinal)-2-oxoacridine-5-ylmethyl]ndimethylacetamide

(5R)-aminomethyl-3-(4-bromo-3-forfinal)oxazolidin-2-ONU (9,63 g of 33.3 mmole, 1 EQ.) was added acetic acid (9 ml, 156 mmol, 4,68 EQ.) and acetic anhydride (9 ml, 95,3 mmole, 2,86 EQ.) and the resulting suspension was stirred at room temperature for 1 h Then the solvent is evaporated in a high vacuum, thus obtained product (11,03 g, Quant.) in a solid beige color.

Stage 7

tert-Butyl EF the p 4-oxopiperidin-1-carboxylic acid

To hydrate hydrochloride 4-piperidone (3,9 g, 25.4 mmole, 1 EQ.) in water/dioxane (50 ml, 1:1) solution was added VOS2(Of 6.02 g, 27.6 mmole, 1.1 EQ.) in dioxane (25 ml), and adding observed exothermic reaction. After completion of the reaction, the reaction mixture was stirred at room temperature for 4 hours, the Dioxane is evaporated, the residue was extracted with ethyl acetate, the extract was dried over MgSO4was filtered and the filtrate was evaporated, the thus obtained product (of 5.06 g, Quant.) in a solid white color.

Stage 8

tert-Butyl ester 4-hydroxy-4-trimethylsilylethynyl-1-carboxylic acid

To a solution of TMS-alkyne (6,03 ml, 42,4 mmole, of 1.26 EQ.) in THF (124 ml) at -78°C under nitrogen atmosphere was added n-utility (2.3 M solution in n-hexane, 16.0 ml, 36.8 mmole, 1.1 EQ.), the resulting mixture was stirred at -78°C for 30 min, and then at -78°C was added a solution of tert-butyl methyl ether 4-oxopiperidin-1-carboxylic acid (6.7 g, a 33.6 mmole, 1 EQ.) in THF (30 ml). The reaction mixture was stirred at -78°C for 15 min and then slowly warmed up to room temperature. After 30 min the reaction was stopped by adding 10% solution of sodium hydrosulphate. The two phases were separated, the aqueous layer was extragonadal with ethyl acetate, the combined organizacje layers were washed with saline and dried over magnesium sulfate. After the oxygen is the generation received sufficient net balance of light yellow (7 g, 70%)which was used without further purification.

Stage 9

tert-Butyl ether 4-ethinyl-4-hydroxypiperidine-1-carboxylic acid

A mixture of tert-butyl ester 4-hydroxy-4-trimethylsilylethynyl-1-carboxylic acid (7 g, 23.5 mmole, 1 EQ.) and potassium carbonate (1.0 g, 7,25 mmole, 0.3 EQ.) in the Meon (30 ml) was stirred at room temperature for 6 hours the Solvent was removed under reduced pressure and the residue suspended in diethyl ether. The suspension was washed with a saturated solution of ammonium chloride and water, dried over MgSO4was filtered and the filtrate was evaporated, the thus obtained product (4.5 g, 86%) as a solid white color.

Stage 10

tert-Butyl ether 4-{4-[5S-(acetamidomethyl)-2-oxoacridine-3-yl]-2-perforating}-4-hydroxypiperidine-1-carboxylic acid

PdCl2(P(C6H5)3)2(297 mg, 0,422 mmole, 0.1 EQ.) and 148 mg of copper iodide(I) (160 mg, 0,78 mmole, 0.2 EQ.) was stirred at RT in an argon atmosphere. Then to the mixture was added (5S)-N-[(4-bromo-3-forfinal)-2-oxoacridine-5-ylmethyl]ndimethylacetamide (1.40 g, 4,22 mmole, 1 EQ.), tert-butyl ether 4-ethinyl-4-hydroxypiperidine-1-carboxylic acid (1.24 g, 5.5 mmole, 1.3 EQ.) in anhydrous DMF (20 ml) and Diisopropylamine (10 ml) and the mixture was stirred at RT for 30 minutes To initiate the reaction mixture was stirred under heating at 50°C in accordance with is their night. Then to the mixture was added diethyl ether and water, the layers were separated and the aqueous layer was extragonadal diethyl ether. The combined organic layers were washed with a saturated solution of sodium chloride, dried over MgSO4was filtered and the filtrate was evaporated. The residue was purified by chromatography (eluent: ethyl acetate to remove residual triphenylphosphine, then dichloromethane/Meon), received the product (1.55 g, 77%) as a solid gray color.

Example 20

tert-Butyl ester 4-(3-{4-[5S-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinal}acryloyl)piperazine-1-carboxylic acid

In the example described is a method of obtaining structural blocks in the Heck reaction.

Stage 1

tert-Butyl ether piperazine-1-carboxylic acid

To a solution of piperazine (20 g to 0.23 mol, 2 EQ.) in dichloromethane (800 ml) with stirring at RT was added a solution of di-tert-BUTYLCARBAMATE (24 g, of 0.11 mol, 1 EQ.) in 200 ml of dichloromethane and the mixture was stirred at RT over night. Then the mixture was filtered and the filtrate was evaporated. To the residue was added diethyl ether, the mixture was filtered and to the filtrate was added to n-heptane. The suspension was filtered and the filtrate was evaporated, the thus obtained product (19 g, 43.9 per cent) in the form of a solid white color.

Stage 2

tert-Butyl ether 4-acryloyldimethyl-1-carboxylic acid

In the OHL is established in an ice bath, a solution of tert-butyl methyl ether piperazine-1-carboxylic acid (2 g, 9.8 mmole, 1 EQ.) triethylamine (1.4 ml, 9.8 mmole, 1 EQ.) in dichloromethane (50 ml) under stirring at 0°C was added dropwise akriloilkhlorida (0.8 ml, 9.8 mmole, 1 EQ.), the mixture was stirred and warmed up to room temperature for 2 hours Then the mixture was added 1 M hydrochloric acid (50 ml), the layers were separated, the organic phase is washed with a saturated solution of sodium bicarbonate (2×50 ml) and saturated sodium chloride solution (50 ml), dried over MgSO4was filtered and the solvent evaporated. The residue was purified by chromatography (eluent: ethyl acetate/n-hexane, 1:1), to receive the product (1.26 g, 49%) as a solid white color.

Stage 3

tert-Butyl ester 4-(3-{4-[5S-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinal}acryloyl)piperazine-1-carboxylic acid

(5S)-N-[(4-Bromo-3-forfinal)-2-oxoacridine-5-ylmethyl]ndimethylacetamide (1,998 g, 6.0 mmol, 1 EQ.), tert-butyl ether 4-acryloyldimethyl-1-carboxylic acid (1.6 g, 6.6 mmole, 1.1 EQ.), triphenylphosphine (105 mg, 0.4 mmole, 0,067 equiv.) the palladium(II) acetate (134 mg, 0.6 mmole, 0.1 EQ.), diisopropylethylamine (10 ml), potassium carbonate (829 mg, 6 mmol, 1 EQ.) in DMF (15 ml) was stirred at 140°C for 4 h, the Solvent evaporated, the residue was dissolved in dichloromethane, washed with water, dried over MgSO4and the solvent evaporated. The residue was purified by chromatography (eluent: ethyl acetate to remove astatke is triphenylphosphine, then dichloromethane/Meon), received the product (1.3 g, 46%) as a solid gray color.

Example 21

tert-Butyl ester 4-(3-{4-[5S-(acetamidomethyl)-2-oxoacridine-3-yl]-2-fervency}-2-hydroxypropionic)piperazine-1-carboxylic acid

In the example described is a method of obtaining structural blocks using the disclosure epoxy cycle in the presence of phenol.

Stage 1

tert-Butyl ether 4-oxiranylmethyl-1-carboxylic acid

In anhydrous THF (50 ml) at -78°C in an atmosphere of argon was added a solution of anhydrous tert-butylhydroperoxide (5.5 M solution in nonane, 2,07 ml, 11,38 mmole, 1.5 EQ.). In the resulting solution at -78°C was added utility (2.3 M solution in n-hexane, to 3.36 ml, 8.4 mmole, 1.1 EQ.) and the mixture was stirred at the same temperature for a further 5 minutes and Then at -78°C was added dropwise a solution of tert-butyl methyl ether 4-acryloyldimethyl-1-carboxylic acid (1,96 g of 7.64 mmole, 1 EQ.) in anhydrous THF (20 ml). The resulting mixture was slowly heated to room temperature and was stirred for 16 hours Then the mixture was added sodium sulfite (1.5 g, 12 mmol, 1.55 equiv.) and was stirred for 15 minutes the Mixture was diluted with diethyl ether (50 ml), filtered through celite and the filtrate was evaporated. The residue was purified by chromatography (eluent: ethyl acetate/n-hexane, 4:1)was economocal product (0.39 g, 19%) as a solid white color.

Stage 2

tert-Butyl ester 4-(3-{4-[5S-(acetamidomethyl)-2-oxoacridine-3-yl]-2-fervency}-2-hydroxypropionic)piperazine-1-carboxylic acid

To a solution of N-[(5S)-{3-(3-fluoro-4-hydroxyphenyl)}-2-oxoacridine-5-ylmethyl]ndimethylacetamide (stage 4, example 1, in 0.104 g of 0.39 mmole, 1 EQ.) and K2CO3(of 0.081 g, 0,585 mmole, 1.5 EQ.) in DMF (2 ml) was added under stirring tert-butyl ether 4-oxiranylmethyl-1-carboxylic acid (0.1 g, of 0.39 mmole, 1 EQ.), the mixture was heated up to 80°C and was stirred for 4 h Then the mixture was cooled to room temperature, was added dichloromethane/methanol (10 ml, 9:1), the organic layer was washed with water (2×10 ml) and a saturated solution of sodium chloride, dried over MgSO4was filtered and the solvent evaporated. The residue was purified by chromatography (eluent: dichloromethane/methanol, 9:1), to receive the product (0.08 g, 39%) as a solid white color.

Example 22

tert-Butyl ester 4-(2-{4-[5S-(acetamidomethyl)-2-oxoacridine-3-yl-2-fervency}acetyl)piperazine-1-carboxylic acid

In the example described is a method of obtaining structural blocks by alkylation of the phenolic group.

Stage 1

tert-Butyl ester 4-(2-bromoacetyl)piperazine-1-carboxylic acid

In a mixture of tert-butyl methyl ether piperazine-1-carboxylic key is lots (4.0 g, 21,47 mmole, 1 EQ.) and diisopropylethylamine (12,05 g, 92,5 mmole, 4.3 EQ.) in dichloromethane (108 ml) under stirring and cooling in an ice bath was added dropwise bromoacetamide (a 4.86 ml, 21,47 mmole, 1 EQ.). The resulting mixture was washed with water (I ml) and a saturated solution of sodium chloride (100 ml), dried over MgSO4was filtered and the solvent evaporated. The residue was purified by chromatography (eluent: ethyl acetate/n-hexane, 1:1), to receive the product (2,72 g, 41%) as a solid orange oil.

Stage 2

tert-Butyl ester 4-(2-{4-[5S-(acetamidomethyl)-2-oxoacridine-3-yl]-2-fervency}acetyl)piperazine-1-carboxylic acid

To a solution of N-[(5S)-{3-(3-fluoro-4-hydroxyphenyl)}-2-oxoacridine-5-ylmethyl]ndimethylacetamide (stage 4, example 1, about 1.75 g, 6.5 mmole, 1 EQ.) and potassium carbonate (at 1,138 g, 9,75 mmole, 1.5 EQ.) in DMF (32 ml) was added with stirring, tert-butyl ester 4-(2-bromoacetyl)piperazine-1-carboxylic acid (2.0 g, 6.5 mmole, 1 EQ.), the mixture was heated to 80°C., stirred for 30 min, cooled and added to dichloromethane/methanol (100 ml, 9:1). Then the organic layer was washed with water (2×10 ml) and a saturated solution of sodium chloride, dried over MgSO4was filtered and the solvent evaporated. The residue was purified by chromatography (eluent: dichloromethane/methanol, 9:1), to receive the product (1,72 g, 55%) as a solid brown color.

The use of the 23

tert-Butyl ester 4-(2-{4-[5S-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinal}ethyl)-4-hydroxypiperidine-1-carboxylic acid

In the example described is a method of obtaining structural blocks recovery triple bond.

To a solution of tert-butyl ester 4-{4-[5S-(acetamidomethyl)-2-oxoacridine-3-yl]-2-perforating}-4-hydroxypiperidine-1-carboxylic acid (example 19) (0.95 g, 2 mmole, 1 EQ.) in methanol/ethyl acetate (20 ml, 1:1) was added with stirring 10% Pd/C (100 mg), and then the mixture was first made using a balloon with hydrogen. After completion of the reaction, 10% Pd/C was removed by filtration through celite, the filter residue was washed with methanol/ethyl acetate (2×10 ml, 1:1), the filtrate and the washing fractions were evaporated, when it got hard enough pure substance of white color (0.96 g, Quant.), which was used without further purification.

A General method of removal of the protective tert-Budilnik groups

To the resulting amine (1 EQ.) at room temperature was added hydrogen chloride (1.25 M solution in methanol, 4.0 equiv.) the mixture was stirred at room temperature or heated at 40°C. to complete the reaction, cooled and podslushivaet to pH 10 by addition of saturated solution of sodium bicarbonate. The resulting mixture was evaporated, the residue was dissolved in dichloromethane/methanol, 9:1. Then the flask is about the mixture was placed in an ultrasonic bath, voiced for 5 min, and then filtered. The filtrate was evaporated, the thus obtained product was used without additional purification for condensation with quinolone groups.

Example 24

7-(4-{4-[5S-(acetamidomethyl)-2-oxoacridine-3-yl]-2-perforating}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

The specified connection was obtained using the General method of removal of the tert-butilkoi protective groups specified above, with the formation of the amine. Then, the resulting amine are condensed with the corresponding quinoline according to the method described in example 5, with two stages was obtained the desired product with a yield of 8%.

Example 25

7-(4-{4-[5S-(acetamidomethyl)-2-oxoacridine-3-yl]-2-perforating}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid

The specified connection was obtained using the General method of removal of the tert-butilkoi protective groups specified above, with the formation of the amine. Then, the resulting amine are condensed with the corresponding quinoline according to the method described in example 1, stage 7, with two stages was obtained the desired product with a yield of 15%.

Example 26

7-[4-(3-{4-[5S-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinal}and relail)piperazine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

The specified connection was obtained using the General method of removal of the tert-butilkoi protective groups specified above, with the formation of the amine. Then, the resulting amine are condensed with the corresponding quinoline according to the method described in example 5, with two stages was obtained the desired product with a yield of 15%.

Example 27

7-[4-(3-{4-[5S-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinal}acryloyl)piperazine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid

The specified connection was obtained using the General method of removal of the tert-butilkoi protective groups specified above, with the formation of the amine. Then, the resulting amine are condensed with the corresponding quinoline according to the method described in example 1, stage 7, with two stages was obtained the desired product with a yield of 11%.

Example 28

7-[4-(3-{4-[5S-(acetamidomethyl)-2-oxoacridine-3-yl]-2-fervency}-2-hydroxypropionic)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

The specified connection was obtained using the General method of removal of the tert-butilkoi protective groups specified above, with the formation of the amine. Then, the resulting amine are condensed with the corresponding quinoline according to the method described in example in two stages was obtained the desired product with a yield of 5%.

Example 29

7-[4-(3-{4-[5S-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-fervency}-2-hydroxypropionic)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid

The specified connection was obtained using the General method of removal of the tert-butilkoi protective groups specified above, with the formation of the amine. Then, the resulting amine are condensed with the corresponding quinoline according to the method described in example 1, stage 7, with two stages was obtained the desired product with a yield of 4%.

Example 30

7-[4-(2-{4-[5S-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-fervency}acetyl)piperazine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

The specified connection was obtained using the General method of removal of the tert-butilkoi protective groups specified above, with the formation of the amine. Then, the resulting amine are condensed with the corresponding quinoline according to the method described in example 5, with two stages was obtained the desired product with a yield of 20%.

Example 31

7-[4-(2-{4-[5S-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-fervency}acetyl)piperazine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid

Specify the second compound was obtained using the General method of removal of the tert-butilkoi protective group, the above, with the formation of the amine. Then, the resulting amine are condensed with the corresponding quinoline according to the method described in example 1, stage 7, with two stages was obtained the desired product with a yield of 18%.

Example 32

7-[4-(2-{4-[5S-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinal}ethyl)-4-hydroxypiperidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

The specified connection was obtained using the General method of removal of the tert-butilkoi protective groups specified above, with the formation of the amine. Then, the resulting amine are condensed with the corresponding quinoline according to the method described in example 5, with two stages was obtained the desired product with a yield of 10%.

1. The compounds of formula (I)

where a means alkylenes group, alkynylamino group, alkynylamino group, heteroalkyl group, cycloalkenyl group, geteroseksualbnogo group, Allenova group or heteroarenes group, and each of these groups may be substituted,
Q means CR4,
X represents CR7or N
Y represents CR6or N
n is 1, 2 or 3,
m is 1, 2 or 3,
R1means H, F, Cl, Br, I, HE, NH2, alkyl group or heteroalkyl group,
R2denotes H, F or Cl,
R3means H, and kilou group, alkenylphenol group, alkylamino group, heteroalkyl group, cycloalkyl group, geterotsyklicescoe group, aryl group, heteroaryl group, alcylaryl group or heteroallyl group, and each of these groups may be substituted by one, two or more halogen atoms or amino groups,
R4means hydroxy, a group of the formula OPO3R92or OSO3R10or heteroalkyl group containing at least one HE, NH2, SO3R10, PO3R92or COOH group or ester group of a natural amino acid or its derivative, and where the group R9independently from one another mean H, alkyl, cycloalkyl, aryl or aralkyl, a R10means H, alkyl, cycloalkyl, aryl or aralkyl,
R5choose from the following groups:


R6means H, F, Cl or OMe,
R7means H, F, Cl, HE, NH2substituted or unsubstituted alkyl group, or substituted or unsubstituted heteroalkyl group, or R3and R7can be linked through alkylenes, alkenylamine or heteroalkyl group, or will be part of cycloalkanones Il is geteroseksualbnogo group, if R3does not mean N and R7does not mean H, F, HE, NH2or Cl, a
R8means1-C6heteroalkyl, heteroallyl, heteroalkyl or heterooligomerization group, or a pharmacologically acceptable salt, MES, hydrate.

2. Compounds according to claim 1, where R1means N.

3. Compounds according to claim 1, where R2means F or N.

4. Compounds according to claim 1, where R3means ethyl, 2-propyl, C3-C6pilooski, phenyl or pyridyl, each of these groups may be substituted by one, two, three or more fluorine atoms or by amino groups.

5. Compounds according to claim 1, where R3means cyclopropyl group.

6. Compounds according to claim 1, where R7and R3together form a bridging group of the formula-O-CH2-N(Me)- or-O-CH2-CH(Me)-, with the final connection chiral center is preferably in the (S)-configuration.

7. Compounds according to claim 1, where R7means H, F, Cl or methoxy group which may be substituted by one, two or three fluorine atoms.

8. Compounds according to claim 1, where X is N or CH.

9. Compounds according to claim 1, where R4means hydroxy or a group of the formula OSO3H, OPO3H2The co2ORO3H2OSON2CH2COOH or ester of the natural amino acid or its derivative.

10. Connection p., where R denotes a group of the formula
-CH2NH=CH-aryl, -CH2Heteroaryl, -CH2NHSO2Me, -CH2NHCOOMe, -CH2NHCOMe, -CH2NHCS2Me, -CH2NHCSMe, -CH2NHCSNH2, -CH2NHCSOMe or-NHCOMe.

11. Compounds according to claim 1, where R5means the following structure:

12. Compounds according to claim 1, where Y represents CH or N.

13. Compounds according to claim 1, where a represents1-C6alkylen,2-C6albaniles,2-C6akinyan,1-C6heteroalkyl, cyclopropyl, epoxide, aziridine, diepoxide, lactam or lactone, and each of these groups may be substituted.

14. Compounds according to claim 1, where a represents a group of formula-CH2CH2-, -Och2-, -Och2CH2-, -SCH2-, -SCH2CH2-, -CH=CH-, -C≡C-, -CH(OH)CH(OH)- or-CH(NH2)CH(OH)-.

15. The compounds of formula (I) according to claim 1 in the form of mono-, di - or trinational salt or a mixture thereof, particularly mono-, di - or trinacria salt of the compounds of formula (I), where R4means ORO3H2or OSO3H, or their mixture.

16. Pharmaceutical composition having antimicrobial activity containing a compound according to any one of claims 1 to 15, and optionally carriers and/or adjuvants and/or diluents.

17. The use of compounds according to any one of claims 1 to 15 to obtain drugs, the purpose is different for treatment of bacterial infections.

18. The use of the pharmaceutical composition according to item 16 to obtain drugs for the treatment of bacterial infections.



 

Same patents:

FIELD: organic chemistry, chemistry of polymers, chemical technology.

SUBSTANCE: invention relates to using hydroxylamine esters for decreasing molecular mass of polypropylene, propylene copolymers or polypropylene mixtures. Method involves addition to propylene polymers subjected for destruction at least one hydroxylamine ester chosen from group including compound of the formula (IA): wherein n means 1; Ra means aliphatic carboxylic acid acyl radical comprising from 2 to 18 carbon atoms; R'1, R'2 and R'3 mean independently of one another hydrogen atom or methyl group; G means aliphatic carboxylic acid acyl-acyl radical comprising from 1 to 18 carbon atoms or aromatic carboxylic acid acyl-acyl radical comprising from 7 to 18 carbon atoms of the formula (IB): wherein n means 1; Ra means aliphatic carboxylic acid acyl radical comprising from 2 to 18 carbon atoms; each R'1, R'2 and R'3 means independently of one another hydrogen atom or methyl group; G1 means hydrogen atom, (C2-C18)-alkanoyl; G2 means hydrogen atom, (C1-C8)-alkyl, aliphatic carboxylic acid acyl-acyl radical comprising from 1 to 18 carbon atoms of the formula (IC): wherein n means 1; Ra means aliphatic carboxylic acid acyl radical comprising from 2 to 18 carbon atoms; each R'1, R'2 and R'3 means independently of one another hydrogen atom or methyl group; G means (C2-C8)-alkylene, (C4-C22)-acyloxyalkylene or aliphatic carboxylic acid acyl radical comprising from 1 to 18 carbon atoms and this mixture is heated to temperature below 280°C. Addition of hydroxylamine esters results to increasing the destruction degree of used polypropylene polymer that is reflected by the melt efflux velocity value in comparison with this index of the parent polymer.

EFFECT: improved method for molecular mass decreasing.

3 cl, 15 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-hydroxypiperidine of the general formula (I): wherein R means (a): -C(O)(CH2)nC(O)OH; (b): wherein R1 means -N(R2)(R3); each R2 and R3 means hydrogen atom, lower alkyl or cyclic tertiary amine; (c): -P(O)(OH)2 or (d): -C(O)(CH2)n and -NHC(O)(CH2)nN(R2)(R3) wherein n means a whole number 1-4. Indicated compounds can be used as prodrugs in preparing medicinal agents used in treatment of diseases associated with blocking agents for receptors of subtype NMDA.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 1 tbl, 20 ex

The invention relates to novel oligomeric aliphatic phosphites or phosphonites; to compositions containing an organic material, mainly polymeric material and new oligomeric aliphatic phosphites or phosphonites, and also to their use for stabilizing organic materials against oxidative, thermal and induced light of destruction

FIELD: chemistry; pharmacology.

SUBSTANCE: there are disclosed compounds composed as to formula , where n and m stand for integer 1 to 3; z stands for integer 0 to 1; R is chosen from hydrogen, hydroxy or alkoxy; R2 stands for hydrogen; R3 and R4 are independently chosen from the group consisting of hydrogen, halogen; R5 is chosen from the group consisting of halogen, alkyl; R6 represents alkyl; E is chosen from the group specified in item 1 of formula of invention, A is chosen from N and C(R11), X is chosen from C, a stands for double bond and b stands for single bond; and Y is chosen from N(R1) provided when Y stands for N(R1), X stands for C, where R1 is chosen from C3-C6-cyclolkyl, phenyl; provided if A stands for C(R11), X stands for C, and Y stands for N(R1), then R11 and R1 can be bonded thus forming morpholinyl.

EFFECT: compounds possess antibacterial activity and are suitable as antibacterial means for treating bacterial infections in humans and animals.

13 cl, 10 tbl

FIELD: medicine.

SUBSTANCE: in the formula I or it pharmaceutically comprehensible salt: m it is peer 3; n it is peer from 0 to 2; all R1 independently mean H; R2 means aryl, unessentially replaced 1-2 assistants chosen from group, including halogen, and C1-C12alcoxy; R3 means H, C1-C12alkyl; p it is peer 2 or 3; R5, R6, R7 and R8 independently mean H, C1-C12alkyl, or one of R5 and R6 together with one of R7 and R8 and the atoms located between them can form a 4-7-termed heterocyclic ring, or R7 and R8 together with atom of nitrogen to which they are attached, can form a 5-7-termed heterocyclic ring; or one of R5 and R6 together with R3 and the atoms located between them can form a 5-7-termed heterocyclic ring. Bonds I possess selective opposing activity in the relation of 5-NT6 receptor.

EFFECT: possibility to use bond in a pharmaceutical composition for treatment of CNS and gastroenteric tract.

16 cl, 8 dwg, 2 tbl, 10 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a method for preparing derivatives of benzoxazine and describes a method for preparing compound represented by the formula . Method involves of compound represented by the formula (I): with compound represented by the formula (II-1-a): in the presence of a base to form compound represented by the formula (III-1-a): followed by reduction of this compound to compound represented by the formula (IV-a): , interaction of this compound with compound represented by the following formula: to form compound represented by the formula (V-a): and the following treatment of this compound in the presence of a base to obtain compound represented by the formula (VI-a): , treatment of this compound with compound of boron trifluorine and its conversion by this manner to the boron chelate compound represented by the following formula: followed by reaction of this compound with 4-methylpiperazine to obtain compound represented by the following formula: followed by cleavage and elimination of boron chelate of this compound. In each of above given formulas X1, X2 and X3 represents independently halogen atom; R1 represents a leaving group; R3 represents hydrogen atom or carboxyl-protecting group; R4 represents hydroxyl-protecting group; each R5 and R6 represents independently alkyl group comprising 1-6 carbon atoms; R7 represents carboxyl-protecting group; Y represents alkoxy-group comprising 1-6 carbon atoms, halogen atom or dialkylamino-group (wherein alkyl groups can be similar or different and each represents alkyl group comprising 1-6 carbon atoms). Also, invention describes variants above described method, methods for preparing intermediate compounds and intermediate compound. Invention provides industrially favorable methods for preparing intermediate compounds that are useful for preparing compounds with antibacterial properties.

EFFECT: improved preparing methods, valuable properties of compounds.

96 cl, 102 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of aminomethylpyrrolidine of the formula (I) , their salts or hydrates wherein R1 represents aryl with from 6 to 10 carbon atoms or heteroaryl wherein heteroaryl is a five-membered ring or a six-membered ring and comprises from 1 to 2 heteroatoms taken among nitrogen, oxygen and sulfur atom; aryl and heteroaryl can comprise one or more substitutes taken among the group consisting of halogen atom or (C1-C6)-alkoxyl; each radical among R2, R3, R4, R5, R6, R7 and R8 represents hydrogen atom (H) independently; Q represents incomplete structure representing by the following formula: wherein R9 means (C3-C6)-cyclic alkyl that can be substituted with halogen atom; R10 means hydrogen atom (H); R11 means hydrogen atom (H), NH2; X1 means halogen atom; A1 represents incomplete structure representing by the formula (II): wherein X2 means hydrogen atom (H), halogen atom, halogenmethoxyl group, (C1-C6)-alkyl or (C1-C6)-alkoxyl group; X2 and above indicated R9 can be combined to form the ring structure and inclusion part of the main skeleton and such formed ring comprises oxygen, nitrogen or sulfur atom as a component atom of the ring and the ring can comprise (C1-C6)-alkyl as a substitute; Y means hydrogen atom (H). Compounds of the formula (I) elicit an antibacterial effect and can be used for preparing a therapeutic agent.

EFFECT: valuable medicinal properties of compounds.

2 tbl, 61 ex

The invention relates to new chemical compounds, namely new condensed heterocyclic systems - 2-3-dihydropyrido[1,2,3-de]-1,4-benzoxazine (1)

The invention relates to new, containing in the 3-position of the indole ring is substituted piperazinylcarbonyl the rest of 1.7-bellrowan derivatives of indole and their salts, to the way they are received, as well as containing these compounds, pharmaceutical compositions and the intermediate product to obtain these compounds

The invention relates to antimicrobial compound used as a drug for humans and animals, and fish

FIELD: pharmacology.

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

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

26 cl, 49 ex, 2 tbl

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 3,11b-cys-dihydrotetrabenazene of general formula (1) or to its antipode . Invention also relates to composition, to pharmaceutical composition, to application of 3,11b-cys-dihydrotetrabenazene, to method of obtaining 3,11b-cys-dihydrotetrabenazene by i. 1, to compounds of formula (II), (III), as well as to ester of Mosher's acid and 3,11b-cys-dihydrotetrabenazene.

EFFECT: obtaining novel biologically active compounds possessing activity as inhibitor of vesicular carrier of monoamines VMAT2.

23 cl, 12 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula IId and their pharmacologically acceptable salts. In formula IId M represents -CH- or -N-; R2c bonded with carbon atom of 5-member ring and is selected from hydrogen and methyl; R2d is bonded with carbon atom from 6-member ring and selected from hydrogen and fluorine; one of R2a and R2b represents methoxy, and other is Q1X1, where X1 represents -O-, and values of other radicals are given in formula IId, to pharmaceutical composition, inhibiting antiogenesis and/or reducing vessel permeability, which contains as active component compound of formula IId, to application of invention compounds for preparation of medication and to compounds of 7-benzyloxy-4(4-fluorine-2-methylindol-5-iloxy)-6-methoxyquinazoline and 4-(4-fluorine-2- methylindol -5-yloxy)-7-hydroxy-6-methoxyquinazo-line.

EFFECT: development of effective method of obtaining quinazoline compounds.

12 cl, 54 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to application of derivatives of 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidine of formula [I] as active ingredient for preparation of medication possessing anti-tumor activity, as well as to novel compounds of formula [I'], their pharmaceutically acceptable salts, hydrates and solvates. In formula[I] or [I'] values X1 and X2 are respectively selected from nitrogen atom and carbon atom, group is respectively selected from or . Other radical values are given in invention formula.

EFFECT: compounds can be applied for treatment and prevention of diseases induced by undesirable cell proliferation, such as cancer, rheumatism, etc.

32 cl, 11 tbl, 4 ex

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