Derivatives of khinoksalinona, methods for their preparation, pharmaceutical tool based on them

 

(57) Abstract:

Describes new derivatives of khinoksalinona formula I, where the values of R1, R5- R8specified in paragraph 1 of the formula that has affinity for AMPA receptors. Also describes the method of production thereof, and pharmaceutical tool based on them. 4 S. and 2 C.p. f-crystals, 1 PL.

The invention relates to a derivative of khinoksalinona used in medicines and the way they are received.

It is known that derivatives of cinoxacin have affinity to Quiqualat - receptors and affinity suitable as pharmaceuticals for the treatment of diseases of the Central nervous system. Proposed according to the invention, the compounds correspond to the formula (I):

< / BR>
where R1represents -(CH2)n-CR2H- (CH2)m-Z; and

R5, R6, R7and R8are identical or different and denote hydrogen, (C1-C6)-alkyl. CF3, nitro group, halogen, NR9R10, cyano group; SOpR11; SO2NR12R13; SO3H; SO3(C1- C6) - alkyl or or14;

and

R2denotes hydrogen or (R16; "n", "m" and "q" each denote 0, 1, 2 or 3; Z represents POXY, OPOXY, OR17, NR18R19, NH-COR20, NH-SO2-R21, SO2R22, CO2R23, halogen, cyano-group, or tetrazole;

R11denotes H, (C1-C6)-alkyl, phenyl;

"p" represents 0, 1 or 2;

R12, R13, R17and R23denote hydrogen or (C1-C4)-alkyl;

R14denotes H or, if necessary, 1-3 times substituted by halogen (C1-C6)-alkyl;

R20and R21denote (C1-C6) -alkyl, if necessary substituted with halogen phenyl or heteroaryl;

R22denotes hydroxyl, (C1-C6-alkoxy or NR24R25;

X and Y are identical or different and denote hydroxyl, (C1-C6-alkoxy, (C1-C4)-alkyl or NR18R19;

R9and R10are identical or different and denote hydrogen, CO-(C1-C6)-alkyl, phenyl or (C1-C6)-alkyl, which if necessary can be replaced by (C1-C4-alkoxyl or, if necessary, mono - or disubstituted by (C1-C4)-alkyl amino group; or together with the nitrogen atom oily form an unsaturated 5-membered heterocycle, which may contain 1-3 N-atoms and may be substituted;

R15and R16, R18and R19are identical or different and denote hydrogen, (C1-C4)-alkyl, phenyl or together with the nitrogen atom form a 5-7-membered saturated, a heterocycle, which may contain another nitrogen atom, sulfur or oxygen, and may be substituted, or form an unsaturated 5-membered heterocycle, which may contain 1-3 N-atoms and may be substituted;

R24and R25are identical or different and denote hydrogen, (C1-C4) -alkyl or together with the nitrogen atom form a saturated 5 to 7 membered heterocycle, which can contain another oxygen atom, sulfur or nitrogen;

as well as their isomers, or salts;

moreover, if R2represents hydrogen and Z represents the POXY or CO2R23, R5- R8not represent hydrogen, and if R2represents hydrogen, Z represents the POXY or CO2R23and R5, R6, R7or R8denote CF3, No2, halogen, NH2or methyl, then there is a disubstituted compounds of formula (I); and if R1means metaphosphate acid and R6denotes a cyano group or a substituted will oznachaet metaphosphate acid and R6means CF3or NO2and R7denotes an imidazole, R5and R8at the same time cannot signify hydrogen; and if R1denotes-CH2-COOH and R5denotes hydrogen, R6and R7at the same time cannot denote halogen or methyl.

Compounds of General formula (I) include also the possible tautomeric forms and cover E - or Z - isomers, or, if there is a chiral center, the racemates or enantiomers.

The substituents are preferably in position 6 and/or 7.

Under the alkyl every time you need to understand linear or branched alkyl residue, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. -butyl, pentyl, isopentyl, hexyl, preferably C1-C4-alkyl residues.

Under the halogen every time you need to understand fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine and bromine.

If R9and R10, R15and R16, R18and R19, R24and R25together with the nitrogen atom form a saturated a heterocycle, it represents, for example, piperidine, pyrrolidine, morpholine, thiomorpholine, hexahydroazepin or piperazine. The heterocycle may be 1-3 times Zam is Holin, or phenylpiperazin.

If R9and R10, R15and R16; R18and R19together with the nitrogen atom form an unsaturated heterocycle, it is necessary, for example, to call the imidazole, pyrazole, pyrrole and triazole, which can be one of the twice substituted by cyano group, a C1-C4-alkyl, phenyl or CO2-(C1-C6)-alkyl.

If the compound of formula I contains an acid function, as suitable salts of physiologically acceptable salts with organic and inorganic bases, such as, for example, soluble salts of alkali and alkaline earth metals and N-methyl-glucamine, dimethylglycine, ethyl glucamine, lysine, 1,6-hexadien, ethanolamine, glucosamine, sarcosine, serinol, three-hydroxy - methylaminomethyl, aminopropanol, Sovak-base, 1-amino - 2,3,4-butanetriol.

If the compound of formula I contains a primary function, suitable physiologically acceptable salts with organic and inorganic acids as HCl, H2SO4, phosphoric acid, citric acid, tartaric acid and others.

As the heteroaryl residue R20and R21take into account the six-membered heteroaromatic compounds as pyridine, pyrazin>19, SO3H or tetrazol that position 5,6,7 and/or 8-substituted C1-C6-alkyl, CF3, nitro group, halogen, SOpR11, SO2NR12R13or NR9R10.

Especially preferred derivatives of phosphonic acid and carboxylic acid, which can be one of the twice substituted. Particularly preferred derivatives of phosphonic acid in position 5-8 replaced twice. Preferred substituents are in particular NR9R10and CF3.

The compounds of formula (I) and their physiologically acceptable salts on the basis of their affinity for AMPA-receptors are applicable in the quality of medicines. Based on your profile of actions proposed according to the invention compounds are suitable for treating diseases that are caused by hyperactivity of excitatory amino acids, such as glutamate or aspartate. Since the new compounds act as antagonists of excitatory amino acids and have a high specific affinity for AMPA receptors, the fact that they displace radioactively labeled specific agonist (RS)-amino-3 - hydroxy-5-methyl-4-isoxazoline (AMR) of AM is proving amino acids, in particular AMPA receptors.

According to the invention, the compounds can be used to treat neurological and psychiatric disorders that are excited by overstimulating AMPA-receptor. Neurologic diseases which can be treated functionally and oseltamivir, are, for example, neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, chorea Huntington, amyotrophic lateral sclerosis and Olivo-cerebellopontine degeneration. According to the invention, the compounds can be applied for the prevention of postischemic cell death (Zelluntergangs), cell death after brain injury; stroke, hypoxia, anoxia and hypoglycemia and for the treatment of senile dementia, multi-infarct dementia, epilepsy and muscle spasms. To psychiatric diseases include state of fear, schizophrenia, migraine, pain status, and treatment of sleep disorders and prohibiting symptoms (Entzugssymptomatik) after misuse of medication, as in the prohibition of the use of alcohol, cocaine, benzodiazepine or opiate.

To apply the proposed according to the invention compounds as medicines can be brought to the form formats and parenteral pharmaceutical, organic or inorganic, inert carriers, such as water, gelatin, gum Arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. Pharmaceutical preparations may be in solid form, e.g. as tablets, pills, suppositories, capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary they contain, additionally, auxiliary substances, such as preservatives, stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or buffers.

For parenteral use is suitable in particular injectable solutions or suspensions, especially aqueous solutions of the active compounds in polyhydroxyserratane castor oil.

As systems-carriers can be used as surface-active auxiliary substances, such as salts of Gallic acids or animal or vegetable phospholipids, but also mixtures thereof, as well as liposomes or their components.

For oral administration especially suitable tablets, pills or capsules containing talc and/or hydrocarbon carriers or binders, such as lactose, corn or cartouche need added sweetener.

The dose of the biologically active substances can be changed depending on the route of administration, age and weight of the patient, type and severity of curable diseases and similar factors. The daily dose is 0.5-1000 mg, preferably 50-200 mg, and the dose can be administered in one dose or take in the view is divided into 2 or more daily doses.

Getting proposed according to the invention the connection is carried out using known methods. In particular, the compounds of formula (I) can be obtained by the fact that

a) compound of formula (II):

< / BR>
where R1- R8have the above significance, cyclist with oxalic acid or a reactive derivative of oxalic acid; or

b) the compound of formula (III):

< / BR>
where R1have the above values and one of the substituents R5', R6', R7'or R8'represents tsepliaeva group, nucleophile replace; and, if necessary, then amyraut ester group; or atrificial ester to acid group or lidiruyut acid group; or restore the nitro-group to the amino group; or alkylate or acelerou amino group; or amino-group exchange is about ether; or alcohol is transferred to a halide; or the halogen nucleophile replace; or nitrile transferred to tetrazole; or share isomers; or get salt.

Cyclization to compounds of formula (I) is performed with the use of oxalic acid in a known manner, single-stage, in an acidic medium or with a reactive derivative of oxalic acid in one stage or in two stages. The preferred two-stage method, in which the diamine is injected into the interaction of with a derivative of oxalic acid as the acid chloride incomplete complex ester of oxalic acid, or reactive derivative imidazoline oxalic acid in polar solvents, such as cyclic or acyclic ethers or halogenated hydrocarbons, for example, tetrahydrofuran, diethyl ether or methylene chloride, in the presence of a base, such as organic amines, such as triethylamine, pyridine, base hunga or dimethylaminopyridine. Subsequent cyclization can be carried out in a basic or acidic, preferably, however, in an acidic medium and in the reaction mixture as the agent of dissolution can add the alcohol.

Suitable bases for the two-stage slag, as hydrocarbons or ethers.

As tseplyaesh groups in a variant of the method b), and upon receipt of the parent compounds of formula (II) suitable Halogens like fluorine, chlorine, bromine, iodine, or O-mesilate, O-tosylate, On-triplet or O-nonflat. Nucleophilic substitution is done according to known literature methods in the presence of a base and favor him through activating electroanatomic group, as, for example, nitro group, cyano group, trifluoromethyl, preferably in the O-position.

As a suitable nucleophiles, for example, primary and secondary amines; N-containing, unsaturated or saturated heterocycles; cyanide; alcoholate; thiolate and others. The interaction can be performed in polar solvents, such as alcohols, halogenated hydrocarbons, dimethylacetamide, acetonitrile or water, or without solvent. As grounds suitable inorganic bases, as the hydroxides or carbonates of alkali or alkaline earth metals, or organic bases, as cyclic, alicyclic and aromatic amines, as DBU, base Hunya, pyridine or dimethylaminopyridine. As the basis in the case of amines can be used by the nucleophile in excess of Oia amine, if necessary, you can work in an autoclave under pressure.

Further, if necessary, the saponification of the ester group can perform basic or acidic by the way, what hydrolyzing at elevated temperatures up to the boiling temperature of the reaction mixture, in the presence of acids as highly concentrated aqueous hydrochloric acid, if necessary in a solvent, such as, for example, triperoxonane acid or alcohols. Esters of phosphonic acid hydrolyzing, preferably by heating in concentrated aqueous acid, such as concentrated hydrochloric acid, if necessary with the addition of alcohol, or by treatment with trimethylsilylethynyl in inert solvents, such as acetonitrile, and subsequent treatment with water.

The etherification to complex ether carboxylic acids or phosphonic acids conduct itself in a known manner using the appropriate alcohol under acid catalysis or in the presence of an activated derivative of the acid. As an activated derivative of the acid take into account, for example, the acid chloride acid, imidazole acid or acid anhydride. In the case of phosphonic acids esterification to complex air AK p-toluensulfonate.

The amidation is carried out with the use of free acids or their reactive derivatives such as acid chlorides, mixed anhydrides, imidazolides or azides, by introducing them into interaction with the corresponding amines at room temperature.

The restoration of the nitro group to the amino group carried out catalytically in polar solvents at room temperature or at elevated temperature. As catalysts suitable metals, such as Raney Nickel, or catalysts based on noble metals, such as palladium or platinum, if necessary media. Instead of hydrogen can be used in a known manner also the ammonium formate. Reducing agents, as the chloride of tin(II) or chloride titanium(III), can be applied as well as complex metal hydrides, possibly in the presence of salts of heavy metals. As a reducing agent is also applicable for iron. The reaction is carried out then in the presence of acid, for example acetic acid, or ammonium chloride, if necessary with the addition of a solvent such as water. It may be preferable to the introduction of the ester group before carrying out the reaction. If there are multiple nitro groups in the forefront of the placed by using Na2S.

If it is desirable alkylation of amino group, you can alkilirovanii conventional methods, for example, using alkylhalogenide or option Mitsonubo by interaction with alcohol in the presence of triphenylphosphine and a complex ester of azodicarboxylic acid, or amine is subjected to reductive aminating with aldehydes or ketones, in case of necessity sequentially with two different carbonyl compounds, and get mixed derivatives (see literature, for example, Verardo, and others, Syntesis 1993, 121; Syntesis 1991, 447; Kawaguchi, syntesis 1985, 701; Micovic, etc., Syntesis 1991, 1043.

The acylation of the amino group to carry out the usual way, for example, using galodamadruga acid or acid anhydride, in the presence of a base, as dimethylaminopyridine, in solvents, such as methylene chloride, tetrahydrofuran, or pyridine, or the option Schotten-Baumann in aqueous solution at alkaline pH values.

The introduction of the cyano group can be accomplished through reaction of Sandmeyer, for example, the intermediate formed from amino-compounds with NITRILES diazonium salts can be administered during interaction with cyanides of alkali metals in the presence of copper cyanide(I).

Introduction g of the intermediate formed with NITRILES diazonium salts enter into interaction with the chloride or copper bromide (I) in the presence of an appropriate acid, as hydrochloric acid or Hydrobromic acid, or potassium iodide. When using complex organic ester of nitrous acid, the halogen can be entered, for example, by adding methylaniline or tetrabromomethane, in a solvent, such as dimethylformamide.

Introduction fluorine is carried out, for example, by reaction Balz - Shiemann when using tetrafluoroborate the page.

The introduction of NO2group is carried out by way of a number of known methods of nitration. For example, you can netravati using detroitmetroairport in inert solvents, such as halogenated hydrocarbons, or in sulfolane, glacial acetic acid or acetonitrile. The introduction of NO2groups can also be carried out, for example, using nitrouse acid in concentrated sulfuric acid as solvent at temperatures in the range 0-30oC.

The introduction of halogen carried out by known methods of halogenation, as, for example, by electrophilic aromatic substitution.

For example, you can idiopath using iodine or adnovate acid by Wirth and others (Liebigs Ann. Chem., 634, 84, (1960)) or using N-iodine-succinimide, in solvents, such as tetrahydrofuran, di the ways, for example, by reaction with trimethylsilanol, if necessary, with the addition of alkali metal iodide, in an inert solvent as acetonitrile, at temperatures from 0oC to the boiling point of the solvent.

The introduction of tetrazole carried out by reacting a corresponding nitrile with an azide, such as trimethylsilane, attestation acid or sodium azide, if necessary, with the addition of a source of protons, as, for example, ammonium chloride or triethylammonium, in polar solvents, such as dimethylformamide, dimethylacetamide or N - organic, at temperatures up to the boiling point of the solvent.

The conversion of alcohol into the halogen is carried out using golodnikov acids, as thionyl chloride or tribromide phosphorus, with the solvent or without him. As a possible solvent, halogenated hydrocarbons such as methylene chloride, or ethers.

The mixture of isomers is possible to separate by conventional methods, such as crystallization, chromatography or salt formation, the enantiomers, respectively, E/Z - isomers.

Obtaining salts carried out in the usual way, the fact that a solution of compound Timoti are in solution, and the precipitate is separated, or the usual process solution.

If the starting compounds is not described, these are known or get similar to well-known compounds, for example, according to the application of WIPO 93/08171 or according to methods described here.

The following examples should clarify the proposed according to the invention method.

Obtaining parent compounds

Example 1. A).

2,05 g mono - tert-butoxycarbonylmethylene together with 1.25 g (0,86 ml) of 4 - fluoro-3-nitro-1-trifluoromethyl-benzene is heated for 30 minutes at a bath temperature of 50oC. the mass hardens. Then chromatographic through silica gel using a mixture of methylene chloride with ethanol in a ratio of 10:1. Obtain 2.2 g of [1-(N-Carbo-tert.- butoxy-2-N-(2-nitro-4-triptoreline)] -Ethylenediamine.

B). N-(2-Nitro-4-triptoreline)Ethylenediamine

2.2 g of 1-N-Carbo - tert-butoxy-2-N-(2-nitro-4-triptoreline)-Ethylenediamine in 60 ml of ethanol is heated with 60 ml of 1N. hydrochloric acid for 2 hours at 110oC. After concentrating obtain 1.77 g of N-(2 - nitro-4-triptoreline)Ethylenediamine as hydrochloride.

C). [N-1-(Benzoyl)-N-2-(2-nitro-4-triptoreline)] Ethylenediamine
mg of triethylamine and then with 295 g of benzoyl chloride. After stirring for 2 hours at room temperature, extracted twice with water. The organic phase is dried, filtered and concentrated. Obtain 690 mg of [N-1-(benzoyl)-N-2-(2-nitro-4 - triptoreline)]Ethylenediamine. Similarly get:

[N-1-(methanesulfonyl)-N-2-(2-nitro-4-triptoreline)] Ethylenediamine; N-1-(4-chloro-benzoylamine)-N-2-(2-nitro-4 - triptoreline)-Ethylenediamine;

N-1-(nicotineamide)-N-2-(2-nitro-4-triptoreline)- Ethylenediamine; N-1-(phenylcarbonylamino)-N-2-(2-nitro-4-triptoreline)- Ethylenediamine.

Example 2. A).1-(2-Nitro-4-triptoreline)-2 - methoxyethane

3.75 g of 2-Methoxyethylamine and 10.5 g of 4-fluoro-3-nitro-1 - cryptomelane in 200 ml of water with 10 g of sodium carbonate are heated at a bath temperature of 100oC for 2 hours. When cooled, the precipitated product, which can be distinguished by sucking (9.8 g). The aqueous mother liquor is acidified with 4n. hydrochloric acid and extracted with three times 100 ml of ethyl acetate. The combined organic extracts dried, filtered and concentrated. Get another 2.7, the Total output is 12.5 g of 1-(2-nitro-4-triptoreline)amino-2-methoxyethane.

Example 3. A)

1.1 g of 2,4-Deformirovannoe with 2.8 g farout through silica gel using a mixture of methylene chloride with ethanol in a ratio of 10: 1. Obtain 1.6 g of diethyl ether N-(2-nitro-5 - forfinal)aminomethylphosphonic acid.

Similarly receive: diethyl ether

N-(2-nitro-4-forfinal)aminomethylphosphonic acid;

diethyl ether 1-[N-(2-nitro-4-forfinal)amino]acanthostega acid;

diethyl ether 1-[N-(2-nitro-5-forfinal)amino]acanthostega acid;

diethyl ether 1-(2-nitro-4-triptoreline)-4 - methoxypropiophenone acid.

B)

331 mg Diethyl ether N - benzophenonetetracarboxylic acid injected with 40 mg of Aliquat 336 and 209 mg of 2-methoxy-1-brometea and at 0oC is mixed with 280 mg of powdered potassium hydroxide, and then stirred for 3.5 hours at room temperature. The mixture is mixed with methylene chloride and 180 mg of silica gel, briefly stirred and sucked off. The concentrated filtrate chromatographic through silica gel using a mixture of cyclohexane to ethyl acetate in the ratio of 1:1. Obtain 180 mg of diethyl ether 2-(N - benzofuranyl)-4-methoxy-papapostolou acid.

C).

2.0 g of Diethyl ether 2-(N-benzofuranyl)-4-labels-supraperiosteal acid in 30 ml of 1N. HCl and 30 ml of diethyl ether is stirred for 3 hours at Kamniska phase contains benzophenone, and its cast. The aqueous phase is concentrated to dryness, treated with 15 ml of saturated solution of sodium chloride, neutralized with Na2CO3and extracted with three times 50 ml of methylene chloride. The organic phase is dried, filtered and concentrated, receiving 800 mg of diethyl ether 2-amino-4-methoxy - papapostolou acid.

Example 4. A).

790 mg of Diethyl ether N-(2-nitro-5-forfinal)amino-metaphosphates acid in 50 ml of ethanol is mixed with 2.5 g of Raney Nickel and hydronaut at normal pressure of hydrogen at room temperature for 2 hours. After extraction of the catalyst, the filtrate is concentrated. Obtain 660 mg of diethyl ether N-(2-amino-5-forfinal)aminomethylphosphonic acid.

Similarly get:

diethyl ester of N-(2-amino-4-forfinal)aminomethylphosphonic acid; diethyl ester of 1-[(2-amino-4-trifluoromethyl-phenyl) amino]-4-methoxypropiophenone acid;

diethyl ether 1-[N-(2-amino-4-forfinal)amino]acanthostega acid;

diethyl ether 1-[N-(2-amino-5-forfinal)amino]acanthostega acid;

1-(2-amino-5-triptoreline)amino-2-methoxy-ethane;

N-1-(methanesulfonyl)-N-2-(2-amino-4-triptoreline) Ethylenediamine;

N-1-(berenil)Ethylenediamine;

N-1-(nicotineamide)-N-2-(2-amino-4-triptoreline)Ethylenediamine;

N-1-(phenylcarbonylamino)-N-2-(2-amino-4-triptoreline) Ethylenediamine.

Receiving target compounds

Example 5: Diethyl ether (7-fluoro-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl)-metaphosphates acid

660 mg of Diethyl ether N-(2-amino-5 - forfinal)-aminomethylphosphonic acid in 70 ml of absolute tetrahydrofuran is mixed with 509 mg of triethylamine. To this solution is slowly added dropwise a solution of 685 mg of the acid chloride ethyl ester of oxalic acid in 30 ml of tetrahydrofuran. The mixture is stirred for 4 hours at room temperature. After sucking osadivshih salts, the filtrate is concentrated and then in a mixture of 23 ml of ethanol and 23 ml of 1N. hydrochloric acid is boiled for 2 hours at a bath temperature of 110oC. Concentrated to dryness and the residue chromatographic through silica gel using a mixture of methylene chloride with ethanol in a ratio of 10:1. Receive 561 mg diethyl ether (7-fluoro-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl) metaphosphates acid.

Similarly receive: diethyl ether (6-fluoro-1,2,3,4 - tetrahydro-2,3-dioxo-cinoxacin-1-yl) metaphosphates acid;

diethyl ether 1-[(7-feito-2,3 - dioxo-cinoxacin-1-yl]acanthostega acid.

In principle, similarly get:

6-trifluoromethyl-1-(1-metoxi-yl-2-)-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin; so pl. = 244,4oC,

6-trifluoromethyl-1-(1-N-benzoylamine-et-Il-2)-1,2,3,4-tetrahydro - 2,3-dioxo-cinoxacin; so pl. = 275oC,

6-trifluoromethyl-1-(1-N-methanesulfonylaminoethyl-Il-2)-1,2,3,4-tetrahydro - 2,3-dioxo-cinoxacin; so pl. = 287,5oC,

diethyl ether 1-(6-trifluoromethyl-1,2,3,4-tetrahydro-2, 3-dioxo-cinoxacin-1-yl)-3-methoxy-papapostolou acid;

6-trifluoromethyl-1-(1-N-phenylcarbonylamino-Il-2)-1,2,3,4-tetrahydro - 2,3-dioxo-cinoxacin; so pl. > 250oC,

6-trifluoromethyl-1-(1-N-nicotinamine-2)-1,2,3,4 - tetrahydro-2,3-dioxo-cinoxacin; so pl. 269,8oC,

6-trifluoromethyl-1-(1-N-4-chloro-benzoylamino-Il-2)-1,2,3,4 - tetrahydro-2,3-dioxo-cinoxacin, so pl. > 300oC.

Example 6

1 g of 6-Trifluoromethyl-1-(1-metoxi-Il-2)-1,2,3,4-tetrahydro-2,3 - dioxo-finokalia in 20 ml of absolute acetonitrile is mixed with 3.15 ml of trimethylsilane and 1.4 g of sodium iodide and heated for 1 hour at a bath temperature of 80oC. After the addition of 25 ml of water, extracted with ethyl acetate. The organic phase is separated, concentrated and chromatographic through silica gel using a mixture of toluene with ice oxynorm obtain 330 mg of 6-trifluoromethyl-1-(1-hydroxy-ETH-Il-2)-1,2, 3,4-tetrahydro-2,3-dioxo-khinoksalinona.

Example 7

615 mg Diethyl ether (7-fluoro-1,2,3,4-tetrahydro-2,3-dioxo - cinoxacin-1-yl)metaphosphates acid in 60 ml of methylene chloride is mixed with 743 mg detroitmetroairport. The mixture is stirred for 2 hours at room temperature. Mixed with 50 ml of water and after separation the organic phase is shaken out three times with methylene chloride. The combined organic phase is dried, filtered and concentrated. The remainder chromatographic through silica gel using a mixture of methylene chloride with ethanol in a ratio of 10:1. Get 350 mg diethyl ether (6-nitro-7-fluoro-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl)metaphosphates acid, so pl. of 147.7oC.

In principle, similarly get:

diethyl ether (6-fluoro-7-nitro-1,2,3,4-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl)metaphosphates acid; so pl., 218,9oC;

diethyl ether 1-[(6-fluoro-7-nitro-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl)]acanthostega acid;

diethyl ether 1-[(7-fluoro-6-nitro-1,2,3,4-tetrahydro-2, 3-dioxo-cinoxacin-1-yl)]acanthostega acid;

diethyl ether 1-[(6-trifluoromethyl-7-nitro-1,2,3,4 - tetrahydro-2,3-dioxo-cinoxacin-1-yl)]acanthostega acid;

diethyl ester of N-[(6-t-7-nitro-1,2,3,4-tetrahydro-2, 3 dioxo-cinoxacin-1-yl)]acetonitrile.

Example 8

140 mg of Diethyl ether (6-nitro-7-fluoro - 1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin-1-yl) metaphosphates acid together with 129 mg of the research is heated 1.5 hours at a bath temperature of 120oC. After concentration in vacuo the residue chromatographic through silica gel using a mixture of toluene with glacial acetic acid and water at a ratio of 10:10:1. After concentration of appropriate fractions receive 300 mg of diethyl ether (7 morpholino-6-nitro-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl) metaphosphates acid.

Similarly get:

diethyl ether [6-(N-imidazolyl)-7-nitro-1,2,3,4-tetrahydro - 2,3-dioxo-cinoxacin-1-yl]metaphosphates acid;

diethyl ether 1-[6-(N-imidazolyl)-7-nitro-1,2,3,4 - tetrahydro-2,3-dioxo-cinoxacin-1-yl]acanthostega acid;

diethyl ether 1-[7-(N-imidazolyl)-6-nitro-1,2,3,4-tetrahydro - 2,3-dioxo-cinoxacin-1-yl]acanthostega acid;

diethyl ether (6 morpholino-7-nitro-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl)-metaphosphates acid;

diethyl ether 1-[(6-morpholino-7-nitro-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl)]acanthostega acid;

diethyl ether 1-[7-morpholino-6-nitro-1 is-6-nitro-1,2,3,4-tetrahydro - 2,3-dioxo-cinoxacin-1-yl)]metaphosphates acid;

diethyl ether 1-[(7-N-methylpiperazine-6-nitro-1,2, 3,4-tetrahydro-2,3-dioxo-cinoxacin-1-yl)]metaphosphates acid; so pl. 300oC,

diethyl ether 1-[7-(4-Mei-1-yl)-6-nitro-1,2,3,4 - tetrahydro-2,3-dioxo-cinoxacin-1-yl]metaphosphates acid;

diethyl ether 1-[7-(2-Mei-1-yl)-6-nitro-1,2,3,4 - tetrahydro-2,3-dioxo-cinoxacin-1-yl]metaphosphates acid;

diethyl ether 1-[7-(2,4-dimethylimidazole-1-yl)-6-nitro-1,2, 3,4-tetrahydro-2,3-dioxo-cinoxacin-1-yl]metaphosphates acid;

diethyl ether (7 dimorpholino-6-nitro-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl)metaphosphates acid;

diethyl ether (7-N,N-dipropylamino-6-nitro-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl)metaphosphates acid;

diethyl ether (7-N,N-dipropylamino-6-nitro-1,2,3,4 - tetrahydro-2,3-dioxo-cinoxacin-1-yl) acanthostega acid;

diethyl ether (7-N-methyl-N-propylamino-6-nitro-1,2,3,4-tetrahydro - 2,3-dioxo-cinoxacin-1-yl)metaphosphates acid;

diethyl ester of N-[7-(1,2,4-triazole-1-yl)-6-nitro-1,2,3,4 - tetrahydro-2,3-dioxo-cinoxacin-1-yl]metaphosphates acid.

Example 9

375 mg diethyl ether (7-fluoro-6-nitro-1,2,3,4 - tetrahydro-2,3-dioxo-cinoxacin-1-yl)metaphosphates acid added is hydrofuran. Then heated for 4.5 hours at a temperature of 70oC. the Mixture is concentrated, treated the residue with 50 ml of water, acidified with 1N. hydrochloric acid and extracted three times with ethyl acetate. The organic phase is dried, filtered and concentrated. The remainder chromatographic through silica gel with a mixture of toluene with glacial acetic acid and water at a ratio of 10: 10: 1. After concentration and dilution with ethanol obtain 19 mg of diethyl ether (6-nitro-7-triptoreline-1,2,3,4-tetrahydro - 2,3-dioxo-cinoxacin-1-yl)metaphosphates acid.

1H-NMR (DMSO):

1,2(t, 7.5 Hz, 6H), 4,05(p, 7.5 Hz, 4H), and 4.8(d, 10 Hz, 2H), 4,85(q, 7.5 Hz, 2H), and 7.3(s, 1H), and 7.7(s, 1H).

Example 10

259 g of diethyl ether (6-nitro-7-morpholino-1,2,3,4-tetrahydro - 2,3-dioxo-cinoxacin-1-yl)metaphosphates acid in 10 ml of absolute acetonitrile is mixed with 628 mg of trimethylsilane and stirred for 1 hour at room temperature. Add water and concentrate. The remainder chromatographic through silanizing silica gel with methanol. Receive 60 mg of (6-nitro-7-morpholino-1,2,3,4 - tetrahydro-2,3-dioxo-cinoxacin-1-yl)metaphosphates acid.

Similarly get:

1-(6-trifluoromethyl-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin - 1-yl)-3-methoxypropan-post.sq. 240oC,

1-[(6-morpholino-7-nitro-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin-1 - yl)] acanthostega acid;

1-[(7-morpholino-6-nitro-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin-1 - yl)] acanthostega acid;

1-[7-(2-methoxyethylamine-6-nitro-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl)]metaphosphate acid; so pl. > 300oC,

1-[(7-N-methylpiperazine-6-nitro-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl)]metaphosphate acid; so pl. > 250oC;

(7 dimorpholino-7-nitro-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin - 1-yl)metaphosphate acid; so pl. > 300oC,

[(6-trifluoromethyl-7-morpholino-cinoxacin-2,3-Dion)-1 - yl]metaphosphate acid; so pl. > 300oC;

1H-NMR spectrum in DMSO, , M. D. (ppm):7.9 in (S., 1H); 7,4 (S., 1H); 4,6 (D., J= 11 Hz, 2H); 3,7 (t, J= 5 Hz, 2H); 2,9 (t, 7 = 5 Hz, 2H).

Similarly get:

[(6-trifluoromethyl-7-[piperidine-1-yl] cinoxacin-2,3-Dion)-1 - yl] metaphosphate acid; so pl. > 300oC;

[(6-trifluoromethyl-7-[2,6-dimethyl-(morpholine-1-yl)] cinoxacin-2,3 - Dion)-1-yl]-metaphosphate acid; so pl. > 300oC,

[(6-trifluoromethyl-7-(hexahydroazepin-1-yl)cinoxacin-2,3-Dion)- 1-yl]-metaphosphate acid; so pl. > 300oC,

[(6-trifluoromethyl-7-[(4-phenylpiperazin-1-yl)cinoxacin-2,3-Dion)- l] -acanthostega acid, so pl. > 300oC,

Example 11

250 mg Diethyl ether [(6-N-imidazolyl)-7 - nitro-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin-1 - yl]metaphosphates acid is heated in 3 ml of concentrated hydrochloric acid for 2.5 hours at a bath temperature of 110oC. After concentration, the residue is treated with water and usageprice the product is sucked off. Receive 100 mg of [6-(N-imidazolyl)-7-nitro - 1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin-1-yl]metaphosphates acid, so pl. > 300oC.

Similarly get:

(6-nitro-7-fluoro-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin-1-yl)- metaphosphate acid; so pl. 193 - 195oC.

(7-nitro-6-fluoro-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin-1-yl) metaphosphate acid;

1-[6-(N-imidazolyl)-7-nitro-1,2,3,4-tetrahydro-2,3-dioxo - cinoxacin-1-yl]-acanthostega acid;

1-[7-(N-imidazolyl)-6-nitro-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin - 1-yl]acanthostega acid;

1-[(6-fluoro-7-nitro-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin-1-yl)] acanthostega acid;

1-[(7-fluoro-6-nitro-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin-1 - yl)] -acanthostega acid;

1-[7-(2-Mei-1-yl)-6-nitro-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl]metaphosphate acid;

1-[7-(4-Mei-1-yl)-6-the ro-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl]metaphosphate acid; so pl. > 300oC;

(7-N, N-dipropylamino-6-nitro-1,2,3,4-tetrahydro-2,3-dioxo - cinoxacin-1-yl)metaphosphate acid;

(7-N, N-dipropylamino-6-nitro-1,2,3,4-tetrahydro-2,3-dioxo - cinoxacin-1-yl)-acanthostega acid;

(7-N-methyl-N-propylamino-6-nitro-1,2,3,4-tetrahydro-2,3-dioxo - cinoxacin-1-yl)metaphosphate acid;

1-[(6-trifluoromethyl-7-imidazolyl-cinoxacin-2,3-Dion)-1-yl] acanthostega acid;

1-[(6-trifluoromethyl-7-(4-Mei-1-yl-cinoxacin-2,3-Dion)- 1-yl] -metaphosphate acid;

N-(6-trifluoromethyl-7-amino-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin - 1-yl)-metaphosphate acid;

1-(6-trifluoromethyl-7-amino-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin - 1-yl)acanthostega acid;

1-[(6-trifluoromethyl-7-(piperidine-1-yl)cinoxacin-2,3-Dion)-1 - yl]acanthostega acid;

1-[(6-trifluoromethyl-7-[piperidine-1-yl]cinoxacin-2,3-Dion)-1 - yl]-acetic acid;

N-[6-trifluoromethyl-7-amino-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin - 1-yl]-acetic acid;

1-[6-trifluoromethyl-7-propylamino-1,2,3,4-tetrahydro-2,3-dioxo - cinoxacin-1-yl]ethane-1-phosphonic acid;

1-[6-trifluoromethyl-7-hexylamino-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl]ethane-1-phosphonic acid;

N-[(6-trifluoromethyl-7-[hexylamino-1]cinoxacin-2,3-Dion)-1-yl]- methane is[(6-trifluoromethyl-7-(hexyl-2-amino)-cinoxacin-2,3-Dion)-1 - yl] -metaphosphate acid;

N-[7-(1,2,4-triazole-1-yl)-6-nitro-1,2,3,4-tetrahydro-2,3-sinacilin - 1-yl]metaphosphate acid.

Example 12: Diethyl ether N-(6-trifluoromethyl-7-morpholino - cinoxacin-2,3-Dion-1-yl)metaphosphates acid

A.

of 3.3 g (30 mmol) Aminomethylphosphonic acid in 120 ml of water and 120 ml of ethanol unite with 3,37 g (of 31.8 mmol) of sodium carbonate and mixed with 7.8 g (97%, 30 mmol) 3 - trifluoromethyl-4,6-dichloromethyl-4,6-dichloronitrobenzene and stirred for 4 hours under reflux at a bath temperature of 120oC. After removal of the ethanol on a rotary evaporator and extracted with three times 100 ml of ethyl acetate. The organic phase is washed with a small amount of water. It contains original material, and its cast. The combined aqueous phase is acidified to pH 1 with 4n. hydrochloric acid and extracted with three times 100 ml of ethyl acetate. The organic phase is washed with water, dried, filtered and concentrated. Get 6.85 g (68 % of theory) of N-(2-nitro-4-trifluoromethyl-6-chlorophenyl) aminomethylphosphonic acid so pl. 207,3oC.

Similarly get:

1-[(2-nitro-4-trifluoromethyl-5-chlorophenyl)amino]acanthostega acid.

B. C.

6.85 g of 20.5 mmol) of N-(2-nitro-4-trifluoromethyl-5-is C. Is evaporated on a rotary evaporator to dryness and the residue with 100 ml teeterboro ether orthomorphisms acid and 779 mg (41 mmol) of p-toluenesulfonic acid is heated to 3.8 hours at a bath temperature of 150oC. After concentration on a rotary evaporator to dryness, the residue treated with 100 ml of water, mixed with NaCl and extracted three times 100 ml of ethyl acetate. United an ethyl acetate phase is washed with diluted aqueous sodium chloride, dried, filtered and concentrated. The yield of diethyl ether N-(2-nitro-4-trifluoromethyl - 5-morpholino-phenyl)aminomethylphosphonic acid is 10.6 g (> 100% of theory; contains another morphologicaland).

D.

10.6 g (20 mmol) of Diethyl ether N-(2-nitro-4 - trifluoromethyl-5-morpholino-phenyl)aminomethylphosphonic acid in 250 ml of ethanol hydronaut in the presence of 4.5 g of palladium - on-coal (10%) at normal pressure of hydrogen at room temperature for 3.5 hours. After extraction of the catalyst through silica gel and concentrate the filtrate gain of 9.2 g (>100% of theory; contains another morphologicaland) diethyl ether N-(2-amino-4-trifluoromethyl-5-morpholino-phenyl) aminomethylphosphonic acid.

Similarly, according to B. C. D. p is diethyl ester of N-(2-amino-4-trifluoromethyl-5-/2,6-dimethyl - morpholino/-phenyl) aminomethylphosphonic acid;

diethyl ester of N-(2-amino-4-trifluoromethyl-5-hexahydroazepin - phenyl)-aminomethylphosphonic acid;

diethyl ester of N-(2-amino-4-trifluoromethyl-5-phenylpiperazin - phenyl)-aminomethylphosphonic acid;

diethyl ether 1-[(2-amino-4-trifluoromethyl-5-morpholinoethyl)amino] acanthostega acid;

diethyl ester of N-[(2-amino-4-trifluoromethyl-5-Gex-1-yl-AMINOPHENYL) amino]metaforas acid;

diethyl ester of N-[(2-amino-4-trifluoromethyl-5-Penta-1-yl - AMINOPHENYL)-amino]metaphosphoric acid;

diethyl ester of N-[(2-amino-4-trifluoromethyl-5-Gex-2-yl-AMINOPHENYL)- amino]metaphosphates acid.

E.

1.26 g (2.7 mmol) of Diethyl ether N-(2-amino-4-trifluoromethyl-5-morpholino-phenyl) aminomethylphosphonic acid in 60 ml of absolute tetrahydrofuran combine together with 0,79 ml (5.7 mmol) of triethylamine. The mixture is mixed dropwise with a solution of 0.63 ml (5.7 mmol) of the acid chloride complex ethyl ester of oxalic acid in 20 ml of tetrahydrofuran. Then stirred at room temperature for 3 hours. The mixture is sucked off and the filtrate concentrated. The residue after kontsentrirovanija filtrate is treated with 20 ml ethanol and 20 ml of 1N. hydrochloric acid and stirred for 2 hours at a bath temperature of 110ooC.

Similarly get:

diethyl ether [(6-trifluoromethyl-7-[piperidine-1-yl]cinoxacin - 2,3-Dion)-1-yl]metaphosphates acid; so pl. 221,8oC,

diethyl ether [(6-trifluoromethyl-7-[2,6-dimethyl-(morpholine-1 - yl)]-cinoxacin-2,3-Dion)-1-yl]metaphosphates acid;

diethyl ether [(6-trifluoromethyl-7-(hexahydroazepin-1-yl) cinoxacin-2,3-Dion)-1-yl]metaphosphates acid;

diethyl ether [(6-trifluoromethyl-7-phenyl-piperazine-1-yl) cinoxacin]-2,3-Dion-1-yl]metaphosphates acid; so pl.>300oC,

diethyl ether 1-[(6-trifluoromethyl-7-[morpholine-1-yl]cinoxacin - 2,3-Dion)-1-ID]acanthostega acid; so pl. 213,1oC,

diethyl ester of N-[(6-trifluoromethyl-7-(hexyl-1 - amino]cinoxacin-2,3-Dion)-1-yl]metaphosphates acid;

diethyl ester of N-[(6-trifluoromethyl-7-[pentyl-1-amino] cinoxacin-2,3-Dion)-1-yl]metaphosphates acid;

diethyl ester of N-[(6-trifluoromethyl-7-[Gex-2-yl-amino] cinoxacin-2,3-Dion)-1-yl]metaphosphates acid.

Example 13: Diethyl L) 1-[(2-nitro-4-trifluoromethyl-5-chlorophenyl) amino]acanthostega acid (according to example 8, A.) together with 1.70 g of imidazole is stirred for 4 hours at a bath temperature of 160oC. is Treated with water in an amount of 100 ml and stirred three times with ion exchanger 1R 120 (strongly acidic form, amberlite, 20 - 50 mesh.) and sucked off. After that concentrate on a rotary evaporator to dryness and the residue together with 24 ml teeterboro ether orthomorphisms acid and 156 mg (0.82 mmol) of p-toluenesulfonic acid is heated for 10 hours at a bath temperature of 150oC. After concentration to dryness on a rotary evaporator chromatographic through silica gel using a mixture of methylene chloride with ethanol in a ratio of 10: 1. Obtain 222 mg (17% of theory) of diethyl ether 1-[(2-nitro-4-trifluoromethyl-5-imidazolyl-phenyl)amino] ethane - phosphonic acid.

Similarly get:

diethyl ether 1-[(2-nitro-4-trifluoromethyl-5-(4-methyl-imidazol-1 - yl)-phenyl)-amino]metaphosphates acid.

B.

572 mg (1.4 mmol) of Diethyl ether 1-[(2-nitro-4 - trifluoromethyl-5-imidazolyl-phenyl)amino] acanthostega acid in 60 ml of ethanol hydronaut in the presence of 300 mg of palladium - on-coal (10%) at normal pressure of hydrogen for 1.5 hours at room temperature. After extraction of the catalyst through silica gel and concentration f is about acid.

Similarly get:

diethyl ether 1-[(2-amino-4-trifluoromethyl-5-(4-Mei-1 - yl)-phenyl)amino]metaphosphates acid.

C.

531 mg (1.4 mmol) of Diethyl ether 1-[(2-amino-4 - three-vermeil-5-imidazolyl-phenyl)amino]acanthostega acid in 35 ml of absolute tetrahydrofuran combined with 0.4 ml (2.9 mmol) of triethylamine. The mixture dropwise mixed with a solution of 0.32 ml (2.9 mmol) chlorohydrination ester of oxalic acid in 10 ml of tetrahydrofuran. Then stirred for 3 hours at room temperature. The mixture is sucked off and the filtrate concentrated. The residue after concentration of the filtrate is treated with 15 ml of ethanol and 15 ml of 1N. hydrochloric acid and stirred for 2 hours at a bath temperature of 110oC. After removal of the ethanol in vacuo, the residue diluted with water to 30 ml and shaken out three times with ethyl acetate using each time in 25 ml of ethyl acetate. United an ethyl acetate phase is washed once with water in an amount of 30 ml, dried, filtered and concentrated. Receive diethyl ether 1-[(6-trifluoromethyl-7 - imidazolyl-cinoxacin-2,3-Dion)-1-yl]ethane-phosphonic acid.

Similarly get:

diethyl ether 1-[(6-trifluoromethyl-7-(4-Mei-1-yl - cinoxacin-2 is l]

A.

6 g (28.7 mmol) 4-Fluoro-3-nitrobenzotrifluoride in 120 ml of water is mixed 4.08 g (28.7 mmol) of 3-aminopropionitrile (in the form of fumarata) and 0.36 g (60 mmol) of sodium carbonate and heated 3 hours at a bath temperature of 110oC. the Separated solid is sucked off. Get a 5.1 g (68.5% of theory) of 2-N-[(2-nitro-4-trifluoromethyl-phenyl)amino]-propionitrile.

B.

2 g (7.7 mmol) of 2-N-[(2-trifluoromethyl - phenyl)amino]propionitrile in 200 ml of ethanol hydronaut in the presence of 500 mg of palladium-on-active coal (10%) at room temperature for one hour under normal pressure of hydrogen. After filtration of the catalyst and concentration of the filtrate receive 1.5 g (88.4% of theory) of 2-N- [(2-amino-4-triptoreline)amino]propionitrile.

C.

1.5 g (6.5 mmol) of 2-N-[(2-amino-4-trifluoromethyl-phenyl)amino] propionitrile combined with 0.8 ml (7,3 mmol) of triethylamine in 90 ml of tetrahydrofuran and, at 0oC dropwise mixed with a solution of 0.75 ml (7,3 mmol) of the acid chloride ethyl ester of oxalic acid in 20 ml of tetrahydrofuran. After stirring for 2 hours at room temperature is sucked off from the salts and the filtrate concentrated. The residue in 100 ml of 1N. hydrochloric acid with 100 ml of ethanol for 2 Cai, the organic phase is concentrated and the residue is stirred with ethyl acetate. Obtain 510 mg (44,8% of theory) of 3-(6-trifluoromethyl-cinoxacin-2,3-Dion-1-yl)propionitrile, so pl. 246,6oC.

Similarly get:

2-[(6-trifluoromethyl-cinoxacin-2,3-Dion-1-yl)acetonitrile]; so pl. 300oC,

2-[(6-trifluoromethyl-cinoxacin-2,3-Dion-1-yl)ethyl]the acid.

Example 15: 2-[(6-Trifluoromethyl-cinoxacin-2,3-Dion-1-yl) ethyl]tetrazol

345 mg (1.2 mmol) of 3-[(6-Trifluoromethyl-cinoxacin-2,3 - Dion-1-yl)propionitrile] together with 407 mg (6.3 mmol) of sodium azide and 333 mg (6.3 mmol) of ammonium chloride in 13 ml of dimethylformamide is heated 3 hours at a bath temperature of 120oC. After the addition again 203 mg (3.2 mmol) of sodium azide and 160 mg (3.1 mmol) of ammonium chloride, again heated at a bath temperature of 120oC for 5 hours. After dilution with water and establishing pH 2, extracted with ethyl acetate. When shaken with a saturated solution of sodium chloride from the organic phase precipitates the target connection. By concentrating the organic phase and stirring in ethyl acetate receive the further fraction. In General receive 150 mg (37.8% of theory) of 2-[(6-trifluoromethyl-cinoxacin-2,3-Dion-1-yl-ethyl]- tetrazole with so pl. 279,8oC.

Analogic tormentil-cinoxacin-2,3-Dion-1 - yl)ethyl]chloride

1.3 g (4.7 mmol) of 2-(6-trifluoromethyl-cinoxacin - 2,3-Dion-1-yl)-ethanol in 20 ml of thionyl chloride is stirred for 4 hours at room temperature. After concentration and subsequent distillation with toluene gain of 1.34 g (97% of theory) of 2-[(6-trifluoromethyl-cinoxacin-2,3-Dion-1-yl)ethyl]chloride, so pl. 221,3oC.

Example 17: N-[(6-Trifluoromethyl-cinoxacin-2,3-Dion-1 - yl)ethyl]imidazol

392 mg (1 mmol) 2-[(6-Trifluoromethyl-cinoxacin-2,3-Dion-1 - yl)ethyl]-chloride together with 150 mg (2.2 mmol) of imidazole in the course of 3 hours, heated at a bath temperature of 150oC. When the distribution in a mixture of 10 ml of ethyl acetate and 10 ml of water, the organic phase is concentrated and the residue chromatographic through silica gel using a mixture of methanol with butanol, water, and ammonia in the ratio of 75: 25:17:3 as eluting funds. Obtain 54 mg (17% of theory) of 2-[(6-trifluoromethyl-cinoxacin-2,3-Dion-1-yl) ethyl]imidazole with so pl. > 250oC.

Similarly get:

2-[(6-Trifluoromethyl-cinoxacin-2,3-Dion-1-yl)ethyl]morpholine (resin)

Example 18: 6-Trifluoromethyl-7-nitro-1-(1-methoxy-ethyl - 2)-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin

100 mg of 6-Trifluoromethyl-1-(1-methoxy-)t-2-yl)-1,2,3,4-tetrahydro - 2,3-dioxo-finokalia suspended in 1 ml of conc the new nitric acid in the ratio of 1:1 and stirred for 1 hour at 4oC. After that, everything goes into solution. Then the solution is poured on ice and the precipitation is sucked off. Get 59 mg (50% of theory) of 6-trifluoromethyl-7-nitro-1-(1-methoxy - ETH-2-yl)-1,2,3,4-tetrahydro-2,3-dioxo-finokalia, so pl. > 300oC.

Example 19: 6-Trifluoromethyl-7-iodine-1-(1-methoxy-ethyl-2)-1,2, 3,4-tetrahydro-2,3-dioxo-cinoxacin

288 mg of 6-Trifluoromethyl-1-(1-methoxy-ethyl-2-)-1,2,3,4 - tetrahydro-2,3-dioxo-finokalia in 5 ml of glacial acetic acid is mixed with 0.05 ml of water, 0,012 ml of concentrated sulfuric acid, to 34.4 mg of innovati acid and to 88.4 mg of iodine and heated for 4 hours at 80oC. After concentration, the residue is treated with water, alkalinized and extracted with methylene chloride. The organic phase is dried, filtered and concentrated and the residue chromatographic through silica gel using a mixture of toluene with glacial acetic acid and water at a ratio of 10:10:1 as the eluting means. Get 40 g of 6-trifluoromethyl-7-iodine-1-(1 - methoxy-ETH-2-yl-1,2,3,4-tetrahydro-2,3-dioxo-finokalia. The remainder represents the original substance, which again can be used in the reaction, so pl. 265,9oC.

Example 20: Diethyl ether N-[(6-Cyano-cinoxacin-2,3-Dion)- 1-yl]-acanthostega acid

A

2,77 g (15,2 mesilat 16 hours at 30oC. the Reaction mixture was then chromatographic through silica gel using a mixture of methylene chloride with ethanol in a ratio of 95:5 as the eluting means. Get 3,86 g (80% of theory) of diethyl ether 1-[N-(2-nitro-4-cyanophenyl)amino]acanthostega acid.

Century

3.1 g of Diethyl ether N-(2-nitro-4-cyanophenyl)aminoethylphosphonic acid are dissolved in 55 ml of tetrahydrofuran, 3 ml of triethylamine and at 0oC dropwise mixed with a solution of 2.35 ml of acid chloride ethyl ester of oxalic acid in 16 ml of tetrahydrofuran. After stirring for 3 days at room temperature, diluted with 300 ml ethyl acetate and washed successively with water and concentrated solution of sodium chloride. The organic phase is dried, filtered and concentrated. Get 5,43 g of crude amide incomplete complex ethyl ester of N- (diethylphosphino-ethyl-1)-N-(2-nitro-4-cyanophenyl) of oxalic acid, which is injected into the interaction without further purification.

C.

1,25 g of Amide incomplete complex ethyl ester N-(di etilfosfonova-et-1-yl)-N-(2-nitro-4-cyanophenyl)of oxalic acid in 60 ml of glacial acetic acid is mixed with 12.9 g (230 mmol) of iron powder and heated for 60 minutes at 90oC the shape, dissolve in ethyl acetate and washed repeatedly with water. The organic phase is dried, filtered and concentrated. The remainder chromatographic through silica gel using a mixture of toluene with ethanol in a ratio of 8:2 as the eluting means. Get 1,43 g (32,9% of theory) of diethyl ether N-[(6-cyano-cinoxacin-2,3-Dion)-1 - yl] acanthostega acid.

Example 21: N-[(6-Cyano-cinoxacin-2,3-dio)-1-yl]acanthostega acid

600 mg of Diethyl ether N-[6-cyano-cinoxacin-2,3-Dion)-1 - yl]acanthostega acid was dissolved in 20 ml of methylene chloride and slowly added dropwise mixed with 2 ml (13,4 mmol) trimethylsilylmethyl. After stirring for 4 hours at room temperature forms a brown solution. It is shaken out with water and sucked off the resultant precipitation. United crystallinity will recrystallized from ethanol-water. Receive 300 mg (83% of theory) of N-[(6-cyano-cinoxacin-2, 3-dione)-1-yl]acanthostega acid so pl. = 280oC.

Example 22: Diethyl ether-N-[6-trifluoromethyl-7-amino-1,2,3, 4-tetrahydro-2,3-dioxo-cinoxacin-1-yl]metaphosphates acid

600 mg of Diethyl ether N-[6-trifluoromethyl-7-nitro-1,2,3,4 - tetrahydro-2,3-dioxo-cinoxacin-1-yl] metaphosphates acid R is ri room temperature. After extraction of the catalyst, the catalyst is again boiled with ethanol: the combined filtrate and concentrate obtain 590 mg of diethyl ether N-(6-trifluoromethyl-7-amino-1,2, 3,4-tetrahydro-2,3-dioxo-cinoxacin-1-yl)acanthostega acid.

Similarly get:

diethyl ester of N-(6-trifluoromethyl-7-amino-1,2,3,4-tetrahydro - 2,3-dioxo-cinoxacin-1-yl) metaphosphates acid;

ethyl ester of N-(6-trifluoromethyl-7-amino-1,2,3,4-tetrahydro - 2,3-dioxo-cinoxacin-1-yl)acetic acid;

6-trifluoromethyl-7-amino-1-(1-methoxy-ethyl-2)-1,2,3,4-tetrahydro - 2,3-dioxo-cinoxacin, so pl. 221,3oC.

Example 23: Ethyl ester of N-[6-trifluoromethyl-7-nitro-1,2,3,4 - tetrahydro-2,3-dioxo-cinoxacin-1-yl]acetic acid

A.

(1.1 mmol) 2-Cryptometrics-2,3-Dion-1-yl)acetonitrile in 10 ml of concentrated hydrochloric acid is refluxed for 4 hours. Usageprice the product is sucked off. Obtain 188 mg of 2-[(6-trifluoromethyl-cinoxacin-2,3-Dion)-1-yl]acetic acid.

Century

150 mg (0.52 mmol) of 2-[(6-trifluoromethyl-cinoxacin - 2,3-Dion)-1-yl]acetic acid in 7 ml ethanol solution of hydrogen chloride is refluxed for 2 hours. Then koncentriruiutsia 2 hours at room temperature. Then shaken with water, the organic phase is dried, filtered and concentrated. Get the ethyl ester of N-(6-trifluoromethyl-7-nitro - 1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin-1-yl)-acetic acid.

Example 24: 6-Trifluoromethyl-7-iodine-1-(1-methoxy-ethyl-2)-1, 2,3,4-tetrahydro-2,3-dioxo-cinoxacin

90 mg of 6-trifluoromethyl-7-amino-1-(1-methoxy-ethyl-2)-1,2,3,4 - tetrahydro-2,3-dioxo-finokalia process in 8 ml ethanol solution of hydrogen chloride, concentrated and the hydrochloride is dissolved in 6 ml of dimethylformamide and 3 ml of methylaniline and at a bath temperature of 80oC is mixed with 0.08 ml of isoamylamine. After stirring for 3 hours at this temperature, the mixture was concentrated in vacuo. Obtain 105 mg of 6 - trifluoromethyl-7-iodine-1-(1-methoxy-ETH-2-yl)-1,2,3,4-tetrahydro-2,3 - dioxo-finokalia, so pl. 265oC.

Similarly get:

diethyl ester of N-(6-trifluoromethyl-7-iodine-1,2,3,4-tetrahydro-2, 3-dioxo-cinoxacin-1-yl)-metaphosphates acid;

ethyl ester of N-(6-trifluoromethyl-7-iodine-1,2,3,4-tetrahydro-2,3 - dioxo-cinoxacin-1-yl)-acetic acid.

Example 25: Diethyl ether 1-[(6-Trifluoromethyl-7-[piperidine-1-yl]- cinoxacin-2,3-Dion)-1-yl]acanthostega acid

At 0oC to a suspension of 100 mg of dietrologia of sodium in 3 ml of tetrahydrofuran was added dropwise a solution of 0.15 ml of 25% aqueous solution of glutaric dialdehyde acid and 0.45 ml of 3 M sulfuric acid in 3 ml of a mixture of tetrahydrofuran with methanol in the ratio 2:3. After the damping of the response, again administered 30 mg pieces of tablets sodium borohydride and then stirred for 1 hour at room temperature. Then establish a neutral reaction with sodium hydroxide solution and shaken with ethyl acetate. An ethyl acetate phase is dried, filtered and concentrated. After chromatography on silica gel using a mixture of toluene with glacial acetic acid and water at a ratio of 10:10:1 receive 60 mg of diethyl ether 1-[6 - trifluoromethyl-7-[piperidine-1-yl] cinoxacin-2,3-Dion)-1 - yl] acanthostega acid.

Similarly get:

ethyl ester of 1-[(6-trifluoromethyl-7-(piperidine-1-yl)cinoxacin-2,3 - Dion)-1-yl]acetic acid.

Example 26: Diethyl ether 1-[(6-trifluoromethyl-7-propylamino - cinoxacin-2,3-Dion)-1-yl]acanthostega acid

At 4oC, to a suspension of 80 mg of diethyl ether [(6 - trifluoromethyl-7-aminopenicillin-2,3-Dion)-1-yl] metaphosphates acid in 3 ml of tetrahydrofuran was added dropwise a solution of 0.02 ml of distilled propanol and 0.2 ml of 3 M sulfuric acid in 2 ml of tetrahydrofuran. To this stirred mixture is added 20 mg of pieces of tablets sodium borohydride. After the damping of the response, again add 10 mg of pieces of tablets sodium borohydride, post of sodium hydroxide solution and shaken with ethyl acetate. An ethyl acetate phase is dried, filtered and concentrated. After chromatography through silica gel using a mixture of toluene with glacial acetic acid and water at a ratio of 10: 10: 1, receive 40 mg of diethyl ether [(6 - trifluoromethyl-7-propylamino-cinoxacin-2,3-Dion)-1 - yl]acanthostega acid.

Example 27: Diethyl ether 1-[(6-trifluoromethyl-7-acetylamino - cinoxacin-2,3-Dion)-1-yl]-acanthostega acid

80 mg of Diethyl ether 1-[(6-trifluoromethyl-7-aminopenicillin - 2,3-Dion)-1-yl] acanthostega acid are dissolved in 8 ml acetic acid and mixed with 150 mg of acetanhydride and stirred for 3 hours at room temperature. After concentrating receive 50 mg of diethyl ether 1-[(6 - trifluoromethyl-7-acetylamino-cinoxacin-2,3-Dion)-1 - yl]acanthostega acid.

Example 28

N-[6-Trifluoromethyl-7-nitro-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin - 1-yl]acetic acid.

Get the above compound with a melting point of more than 300oC.

Example 29

Data characterizing the affinity of the compounds to AMPA receptors, are shown in table.

1. Derivatives of khinoksalinona formula I

< / BR>
where R1represents - (CH2)n-CR2H-(CH2)m-Z;

group, halogen, NR9R10, cyano or or14and R2denotes hydrogen, n and m each represents 0, 1, 2 or 3; z represents POXY, OR17, NR18R19, NHCOR20, NHSO2R21, CO2R23, halogen, cyano or tetrazol, R17represents C1-C4-alkyl, R14indicates, if necessary, 1 to 3 fold substituted with halogen (C1-C6)-alkyl, R20and R21denote (C1-C6)-alkyl, if necessary substituted with halogen phenyl or pyridyl, X and Y are the same and denote hydroxyl or (C1-C6) alkoxy, R9and R10are identical or different and denote hydrogen or (C1-C6) alkyl, which if necessary can be replaced by (C1-C4) alkoxyl or together with the nitrogen atom form a 6 - to 7-membered saturated, a heterocycle, which can contain another N -, S-or O-atom and can be substituted (C1-C4)alkyl or phenyl, or forms an unsaturated 5-membered heterocycle, which may contain 1-3 N atoms and can be substituted (C1-C4)alkyl; R18and R19together with the nitrogen atom form an unsaturated 5-membered heterocycle, which can contain the , R7and R8are not simultaneously hydrogen, b) if Z denotes the CO2R23, NR18R19or or17two different Deputy denote R5, R6, R7and R8and: 1) NR9R10doesn't mean the imidazole or triazole, 2) R6and R7independently of each other denotes NO2, halogen, CN or CF3and (C) if Z denotes OPXY, two different Deputy denote R5, R6, R7and R8while R7doesn't mean the imidazole, if R1is metaphosphates acid and R6means CF3or NO2.

2. Derivatives of khinoksalinona under item 1, representing diethyl ether (6-nitro-7-triptoreline-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin-1-yl)matapozuelos acid; (6-nitro-7-morpholine-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin-1-yl)metaphosphate acid; 1-/(7-morpholino-6-nitro-1,2,3,4-tetrahydro-2,3-dioxopiperidin-1-yl)/acanthostega acid; 1-/(7-(2-methoxyethylamine)-6-nitro-1,2,3,4-tetrahydro-2,3-dioxopiperidin-1-yl)/metaphosphate acid; /(6-trifluoromethyl-7-morpholino-cinoxacin-2,3-Dion)-1-Il/metaphosphate acid; /(6-trifluoromethyl-7-/piperidine-1-yl/cinoxacin-2,3-Dion)-1-yl/-mutant; (6-trifluoromethyl-7-(hexahydroazepin-1-yl)/(cinoxacin-2,3-Dion)-1-Il/metaphosphate acid; /(6-trifluoromethyl-7-/4-phenylpiperazin-1-yl/cinoxacin-2,3-Dion)-1-yl/-metaphosphate acid; 1-/(6-trifluoromethyl-7-/morpholine-1-yl/cinoxacin-2,3-Dion)-1-yl/-acanthostega acid; 1-/(6-trifluoromethyl-7-imidazolyl-cinoxacin-2,3-Dion)-1-Il/acanthostega acid; 1-/(6-trifluoromethyl-7-(4-Mei-1-yl)cinoxacin-2,3-Dion)-1-Il/metanfetamina acid; N-/6-trifluoromethyl-7-amino-1,2,3,4-tetrahydro-2,3-dioxopiperidin-1-yl/metanfetamina acid; 1-/7-(2-Mei-1-yl)-6-nitro-1,2,3,4-tetrahydro-2,3-dioxopiperidin-1-yl/metanfetamina acid; 1-[7-(4-Mei-1-yl)-6-nitro-1,2,3,4-tetrahydro-2,3-dioxopiperidin-1-yl] metanfetamina acid; 1-[7-(2,4-dimethylimidazole-1-yl)-6-nitro-1,2,3,4-tetrahydro-2,3-dioxo-cinoxacin-1-yl] metanfetamina acid.

3. Derivatives under item 1, in which Z stands for a group - POXY

4. The method of obtaining derivatives of khinoksalinona formula I, characterized in that the compound of formula II

< / BR>
where R1- R8are specified in paragraph 1 values, is subjected to cyclization with oxalic acid or a reactive derivative of oxalic acid.

5. The method of obtaining derivatives of khinoksalinona in paragraph 1 and one of the substituents R5', R6', R7'or R8'denote tsepliaeva group, and the others correspond to values of R5, R6, R7or R8specified in paragraph 1, is subjected to nucleophilic substitution, and, if necessary, then amyraut ester group; or a nitro group is reduced to amino group; or amino group alkylate; or amino group exchanged for halogen or introduce a nitro group, or halogen; or the alcohol is transferred to a halide; or the halogen nucleophile replace; or nitrile transferred to terazol; or share isomers; or get salt.

6. The pharmaceutical agent with affinity for AMPA receptors containing the biologically active substance and conventional auxiliary additives, characterized in that the biologically active substances it contains an effective amount of a derivative of khinoksalinona formula I under item 1 or its pharmaceutically acceptable salt.

Priority signs:

28.04.93 - all connections, except the Z - halogen, cyano, R20and R21- if necessary substituted with halogen phenyl, R9and R10together with the nitrogen atom form a 7-membered saturated, a heterocycle, or 5-membered heterocycle, substituted (C1-C

 

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< / BR>
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