Derivatives of benzo(f)of khinoksalinona, methods for their preparation and drug

 

(57) Abstract:

Describes new derivatives of benzo(f)of khinoksalinona formula

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where the values of R1, R4- R10specified in paragraph 1 of the claims. The compounds have the means to AMPA-receptors and therefore can be used in the treatment of diseases of the Central nervous system. Describes how they are getting on the basis of the above compounds and drug. 6 S. p. f-crystals.

The invention relates to a derivative of benzo(f)of khinoksalinona, their preparation and application in medicine.

It is known that derivatives of cinoxacin have affinity to Quisqualat-receptors and binding receptor suitable as pharmaceuticals for the treatment of diseases of the Central nervous system.

Proposed according to the invention, the compounds correspond to the formula 1:

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where R1and R4are identical or different and denote hydrogen; substituted with R2(C1-C12)alkyl; substituted with R2(C2-C12)alkenyl; substituted with R2(C2-C12)quinil; substituted with R2(C3-C72; or -(CH2)n-heteroaryl, in which heteroaryl or alkyl residue substituted with R2;

R1and R4at the same time do not represent hydrogen;

R5, R6, R7, R8, R9and R10are the same or different and represent hydrogen, nitro group, NA16R17, NHCOR11, SO0-3R12, (C3-C7)cycloalkane group, COR13, cyano-group, CF3, OCH2CF3, (C1-C6)alkyl or (C1-C4)alkoxyl; and

R2represents-CN, -tetrazole, -C(NOH)NH2, -CO-R3or-PO-XY and R2is present in the amount of 1-2 in the same or different residues; and

"n" represents 0, 1, 2, 3, 4 or 5;

R3denotes hydroxyl, (C1-C6)alkoxy or NR14R15;

X and Y are identical or different and denote hydroxyl, (C1-C6)alkoxyl, -O-(CH2)p-O (C1-C4)-alkyl or NR14R15; and p represents 1, 2 or 3; and

R11means (C1-C6)alkyl or phenyl which may be substituted with halogen;

R12denotes hydrogen, (C1-C4)alkyl, NH2N(C1-C4)- alkyl)2, -NH(C1-C41-C6)alkoxy, (C1-C6)alkyl or NR14R15;

R14and R15, R16and R17are 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 form a 5-7-membered saturated, a heterocycle, which can contain another N-, S - or O-atom and may be substituted; or form an unsaturated 5-membered heterocycle, which may contain 1-3 N-atoms and may be substituted; as well as their isomers, or salts, and if R5- R10denote hydrogen, R1or R4not indicate metaphosphate acid or ethane-1-phosphonic acid.

Compounds of General formula (1) also cover the possible tautomeric forms and include the 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.

Deputy R2is the number 1 or 2 in the form of identical or different residues in any put to the A.

The term "alkyl" is meant a linear or branched alkyl residue, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. -butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, preferably (C1-C6)alkyl residues.

The term "alkenyl" covers, in particular, (C1-C6)alkeneamine residues, which can be linear or branched, such as, for example, propen-2-yl, butene-2-yl, 3-methyl-propen-2-yl, propen-1-yl, butene-1-yl, vinyl.

As etkinlik residues, in particular, suitable ethinyl, propyne-1-yl, propyne-2-yl, butyl-1-yl with 2-4 carbon atoms.

Under (C3-C7)cycloalkyl understand cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, in particular (C3-C5)cycloalkyl.

As the aryl residue should be called, for example, phenyl, naphthyl, biphenyl and indell, in particular, (CH2)nis phenyl with n = 0, 1, or 2.

As the heteroaryl residue suitable 5 - or 6-membered heteroaromatic compounds with 1 to 3 nitrogen atoms, such as, for example, pyrazole, imidazole, pyrazin, pyridine, pyrimidine, pyridazine, triazine.

Under the halogen should be understood fluorine, chlorine, Bohm nitrogen form a saturated a heterocycle, it represents, for example, piperidine, pyrrolidine, morpholine, thiomorpholine, hexahydroazepin or piperazine. As substituents of the heterocycle should be called (C1-C4)alkyl groups as N-methylpiperazine, 2,6-dimethyl-morpholine, or aryl group, as phenylpiperazin. Substituents may be 1-3.

If R14, R15and R16, R17together with the nitrogen atom form a saturated a heterocycle, it should be called, for example, imidazole, pyrazole, pyrrole and triazole, which can be one or twice substituted by cyano group, a C1-C4the alkyl, phenyl or CO2(C1-C6)alkyl.

Preferred compounds with R2in the value-COR3or-POXY and R1/R4in the meaning of alkyl.

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 such grounds as N-methylglucamine, dimethylglycine, ethylparaben, lysine, 1,6-hexadien, ethanolamine, glucosamine, sarcosine, serinol, Tris-hydroxyethylaminomethyl, aminopropanol, the basis of sowaka, 1 aminobutane-2,3,4-triol.

If contains the main function is UB>, phosphoric acid, citric acid, tartaric acid and others.

The compounds of formula (1), and their physiologically acceptable salts on the basis of their affinity for AMPA - or Kainat-receptors used as 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 because they AMPA receptors displace radioactively labeled specific agonist (R,S)- amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA), they are especially suitable for treatment of such diseases that are affected by the receptors of excitatory amino acids, particularly AMPA-receptor, as and for the treatment of neurological and psychiatric diseases. Neurologic diseases which can be treated functionally and oseltamivir, are, for example, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's Hungtinton, side amiotroficheskii post-ischemic cell death, cell death after brain injury, stroke, hypoxia, anoxia and hypoglycemia and for the treatment of senile dementia, mnogoaspektnoe dementia, and epilepsy and plastic muscles. To psychiatric diseases include state of fear, schizophrenia, migraine, pain status, and treatment of sleep disorders or prohibitive symptoms after abuse of drugs, as in the case of the prohibition of alcohol, cocaine, benzodiazepine or opiate.

To apply the proposed according to the invention compounds as medicines, they are cured to form a pharmaceutical preparation, which along with the biologically active substance contains suitable for intestinal or parenteral administration, pharmaceutical, organic or inorganic inert carriers, such as water, gelatin, gum Arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. Pharmaceutical preparations can be in solid form, for example in the form of tablets, pills, suppositories, capsules with the medicine, or in liquid form, for example in the form of solutions, suspensions or emulsions. If necessary they moreover contain vspomogate the th 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 carriers can be used as surface-active auxiliary substances, such as salts of bile acids or vegetable or animal phospholipids, but also mixtures thereof, as well as liposomes or their components.

For oral administration especially suitable tablets, coated tablets or capsules with the medication that contain talc and/or hydrocarbon carriers or binders, such as lactose, corn or potato starch. Application can be made in liquid form, such as juice, to which, if necessary, added a sweet substance.

The dosage of the biologically active substances may vary depending on 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 the form once the input dose or divided into 2 or more daily doses.

Getting offered with the (1) receive the, that

a) compound of formula II or III:

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where R1- R10have the above meaning,

ciclitira with oxalic acid or a reactive derivative of oxalic acid; or

b) the compound of formula (IV) or (V):

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where R1- R10have the above meaning,

enter into interaction with oxalic acid or a reactive derivative of oxalic acid and cyclist after recovery nitro group; or

C) the compound of formula VI

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where R5- R10have the above meaning,

enter into interaction in the presence of a base with R1= Z or R4= Z, where Z represents the group that you want; and if desired, 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 an amino group exchanged for halogen or cyano group; or give the nitro-group or halogen; or a nitrile transferred to tetrazol or amidoxime or nucleophile replace; or share isomers; or get salt.

The cyclization of compounds of formulas (II) and (III) with oxalic sour. the AK should be considered 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 of a partial ester of oxalic acid, or reactive imidazole derivative of oxalic acid in polar solvents, such as cyclic or acyclic ethers, and halogenated hydrocarbons, such as tetrahydrofuran, diethyl ether or methylene chloride, in the presence of a base, such as organic amines, such as triethylamine, pyridine, base Hunga or diethylaminopropyl. The last cyclization can be carried out in a basic or acidic, preferably, however, in an acidic medium, and the solvent can be added alcohol.

Suitable bases for the two-stage method are also hydrides of alkali metals, such as NaH that use inert solvents such as hydrocarbons and ethers, as dimethoxyethane, THF, and others.

Option b) after acylation with oxalic acid or a reactive derivative of oxalic acid in the usual way to restore the nitro-group, catalytically or by restoring using iron powder in execlist, as explained above.

The introduction of substituents R1and R4carried out according to the way in) conventional methods of alkylation by the fact that hinoksidin enter into interaction with R1-Z or R4-Z, where Z denotes, for example, tosylate, mesilate, triplet, nonflat or halogen, in the presence of bases, at room temperature or at elevated temperature, in an aprotic solvents. The anion can also be obtained before add R1-Z or R4-Z. as a reason suitable, for example, compounds of alkali metals such as potassium carbonate, sodium hydroxide, alcoholate of alkali metals and, in particular, the hydrides of metals, such as sodium hydride. Depending on the circumstances, compounds of alkali metals can also enter into cooperation in the conditions of the transfer phase. If you get a mixture of compounds with substituents R1accordingly, R4then they are divided in the usual way. Usable solvents are aprotic polar solvents, such as dimethylformamide, N-organic, however, it is also cyclic ethers like dioxane or tetrahydrofuran.

If the version of the method) conduct interaction with 2 moles of R1-Z area is STI subsequent saponification of the ester group can be done in basic or preferably under acidic conditions, what hydrolyzing at a temperature from high to boiling point of the reaction mixture in the presence of acids as highly concentrated aqueous hydrochloric acid, in solvents, 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 or by treating with trimethylsilylethynyl and by subsequent treatment with water.

The etherification to complex ether carboxylic acids or phosphonic acids conduct itself in a known manner using the appropriate alcohol in the acid or in the presence of an activated derivative of the acid. As an activated derivative of the acid used, for example, acid chloride, imidazole or acid anhydride. In the case of phosphonic acids esterification to esters can be achieved by introducing into interaction with complex areafile, if necessary, with the addition of catalysts, such as p-toluensulfonate.

The amidation is carried out with the use of free acids or their reactive derivatives, such as, for example, chlorine is sponding amines or 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, under hydrogen pressure. As catalysts suitable metals, such as Raney Nickel, or catalysts based on noble metals, such as palladium or platinum, in the presence of barium sulfate or media. Instead of hydrogen can be used in a known manner also the ammonium formate. You can also apply a reducing agent, as the chloride of tin(II) or chloride titanium(III), as well as complex metal hydrides, if necessary in the presence of salts of heavy metals. Preferred may be the introduction before the reduction of the ester group. The nitro group can also be selectively restore the usual way with the help of Na2S or dithionite sodium.

If it is desirable alkylation of amino group, you can alkilirovanii conventional methods, for example using alkylhalogenide, or variant Mitsonubo by entering into 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 you have the e (see, for example, Verardo, etc., Synthesis, 1993, 121; Synthesis, 1991, 447; Kawaguchi, Synthesis 1985, 701; Micovic, etc., Synthesis, 1991, 1043).

The acylation of the amino group to carry out the usual way, for example, using galodamadruga acid or anhydride of the acid, if necessary, in the presence of a base, as dimethylaminopyridine, in solvents, such as methylene chloride, tetrahydrofuran, or pyridine, or by the reaction of Schotten-Baumann.

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

The introduction of the Halogens chlorine, bromine or iodine through the amino group can be accomplished, for example, by Sandmeyer the fact that the intermediate formed with NITRILES diazonium salts enter into interaction with the chloride of copper(I) or copper bromide(I) in the presence of the corresponding acid as hydrochloric acid or Hydrobromic acid, or enter into interaction with potassium iodide.

When using complex organic ester of nitrous acid, the halogen can be entered, for example, by adding methylaniline or tetrabromomethane, of Balt-Samanna when using diatonicinterval.

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. You can also enter the nitro group, for example, using nitrouse acid in water or in concentrated sulfuric acid as solvent, at a temperature of 0o-30oC.

The introduction of halogen carried out by known methods of halogenation, as, for example, by electrophilic aromatic substitution. For example, you can idiopath method with iodine and iodine acid Wirth and others [Liebigs Ann. Chem. 634, 84 (1960)] or by using N-iodosuccinimide in solvents, such as tetrahydrofuran, dimethylformamide or triftoratsetata.

The introduction of tetrazole carried out by introducing into the interaction of the corresponding nitrile with an azide, for example, 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, when the nitrile using hydroxylaminopurine, for example, in mixtures of alcohol and water as a solvent.

Nucleophilic substitution is carried out according to known literature methods in the presence of a base and is favored at the expense of activating the acceptor group, such as nitro-, cyano group, trifluoromethyl, preferably in the o-position. As a suitable nucleophiles, for example, primary and secondary amines, N-containing unsaturated and saturated heterocycles, cyanides, 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 hydroxides of alkaline or alkaline-earth metals or carbonates of alkaline 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, and, if necessary, you can work without the other solvent or under pressure. For example, an activated derivative of sulfonic acids as the acid chloride is(C1-C4alkyl) or H2N-CH2CONH2or H2N-CH2-R2) or nucleophilic C-derivatives (such as CF3anion or CH2-CHNH2-anion).

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

Obtaining salts carried out in the usual way by the fact that the solution of the compounds of formula (I) is mixed with an equivalent amount or an excess of the compounds of alkali or alkaline earth metal, which, if necessary, dissolved, and the precipitate was separated or solution treated in the usual way.

If the starting compounds is not described, these are known or are obtained by analogy with the known compounds, such as, for example, according to WIPO 93/08171 or according to methods described here.

The following examples should clarify the receipt of the offer according to the invention compounds.

Example 1: (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[1] cinoxacin-1-yl)metanfetamina acid

Synthesis of 2,4-dinitro-1-fluoro-naphthalene is carried out, as described in the literature: J. Chem. Soc. 1962, 2616.

Synthesis of 2,4-dinitro-1-chloro-naphtho ester of toluenesulfonic acid is carried out, as described in the literature: Berichte, 1908, 41, 3932.

a) 2,4-Dinitro-naphthas-1-alawy ester of triftoratsetata

2 g of 2,4-dinitro-naphthas-1-ol (Martius) in 30 ml of dichloromethane is mixed with 1,72 ml = 1.2 equivalent of anhydride of triftoratsetata and 1.43 ml of triethylamine and stirred at room temperature until the disappearance of the educt. Diluted with dichloromethane, neutralized, washed with brine and the solvent is removed. The crude product is recrystallized from hot ethanol. Get 89% of the product.

Similarly from nonatherosclerotic in toluene receive 2,4-dinitro-naphthas-1-alawy ester of nonoptimality.

b) Diethyl ether (2,4-dinitro-1-naphthylamine)-metaphosphates acid

4 g of 2,4-dinitro-1-chloronaphthalene (15,84 mmol) was dissolved in 6.5 g of diethyl ether aminomethylphosphonic acid and 4 g difenilmetana and stirred for 72 hours at room temperature. The mixture is diluted with methylene chloride, washed with 1 H solution NOH and twice with brine, dried and evaporated on a rotary evaporator. The crude product chromatographic on silica gel using 3.5 l of cyclohexane to ethyl acetate in the ratio of 1:1 as the eluting means. On 1.15 (6H, t), 4 (4H, D. K.), 4.25 (2H, m,), 7.8, 7.98, 8.9, 9.05 ( according 1H), 8.6 (2H, d).

In the same way get:

diethyl ether 1-phenyl-1-(2,4-dinitro-1-naphthylamine)metaphosphates acid;

diethyl ether 1-(2,4-dinitro-1-naphthylamine)ethane-1-phosphonic acid;

diethyl ether 1-(2,4-dinitro-1-naphthylamine)propane-1-phosphonic acid;

diethyl ether 1-(2,4-dinitro-1-naphthylamine)butane-1-phosphonic acid;

diethyl ether 1-(2,4-dinitro-1-naphthylamine)hexane-1-phosphonic acid.

C) Diethyl ether (2-amino-4-nitro-1-naphthylamine)- metaphosphates acid

1,352 g diethyl ether (2,4-dinitro-1-naphthylamine)metaphosphates acid are dissolved in 32 ml of ethanol and 23 ml of water, the resulting solution was added to 4.4 ml of 25% ammonium hydroxide solution, of 1.61 g of ammonium chloride and of 2.81 g of 35% aqueous sodium sulfide and the solution is heated for several hours at 90oC. the Ethanol-water mixture concentrated on a rotary evaporator, treated the residue with water, extracted with ethyl acetate, washed with brine, dried and concentrated on a rotary evaporator. The crude product chromatographic on silica gel using 2 l of cyclohexane to ethyl acetate in the ratio of 1:1 and 1 liter of ethyl acetate as the eluting means. Receive from the:

diethyl ether 1-(2-amino-4-nitro-1-naphthylamine)ethane-1 - phosphonic acid;

diethyl ether 1-(2-amino-4-nitro-1-naphthylamine)butane-1 - phosphonic acid;

diethyl ether 1-(2-amino-4-nitro-1-naphthylamine)hexane-1 - phosphonic acid;

diethyl ether 1-phenyl-1- (2-amino-4-nitro-1-naphthylamine)metaphosphates acid;

diethyl ether 1-(2-amino-4-nitro-1-naphthylamine)propane-1 - phosphonic acid (yield 79%).

g) in Diethyl ether (6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo [1]cinoxacin-1-yl)metaphosphates acid

100 mg diethyl ether (2-amino-4-nitro-1-naphthylamine)- metaphosphates acid dissolved in a few milliliters of tetrahydrofuran and at a temperature bath with ice is treated with 95 µl of distilled heterocalixarenes and 118 μl of triethylamine. The solution is stirred first at room temperature and then at 55oC. Interaction brought to a complete transformation when the temperature of the oil bath. The reaction mixture was concentrated, treated with ethyl acetate and washed with brine, dried and concentrated on a rotary evaporator. The crude product chromatographic on silica gel using ethanol as the eluting means. Get as polar fraction 7(1H).

Similarly get:

diethyl ether 1-(6-nitro-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-1-yl)ethane-1-phosphonic acid so pl. > 300oC (decomposition);

diethyl ether 1-(6-nitro-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-1-yl)propane-1-phosphonic acid so pl. > 300oC (decomposition);

diethyl ether 1-(6-nitro-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-1-yl)butane-1-phosphonic acid;

diethyl ether 1-(6-nitro-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)hexane-1-phosphonic acid;

diethyl ether 1-phenyl-1-(6-nitro-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-1-yl)metaphosphates acid.

d) (6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo [f] cinoxacin-1-yl)metanfetamina acid

32 mg of diethyl ether (6-nitro-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)metaphosphates acids contribute in 2 ml of acetonitrile under nitrogen atmosphere and at room temperature. Was added dropwise 80 μl of trimethylsilylpropyne. The solution is stirred for 20 hours at room temperature and concentrate. The residue is suspended in water and washed with water. After drying the crude product is obtained 21 mg of phosphonic acid.

NMR-spectrum (Machaut:

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl) ethane-1-phosphonic acid so pl. > 300oC;

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)propane-1-phosphonic acid so pl. > 300oC;

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)butane-1-phosphonic acid;

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)hexane-1-phosphonic acid;

1-phenyl-1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)metaphosphate acid.

Example 2. Diethyl ether 1-(2,4-dinitro-1-naphthyl-N - amoxicill amino)-propane-1-phosphonic acid

To 100 mg (0.24 mmol) of diethyl ether 1-(2,4-dinitro-1 - naphthylamine)propane-1-phosphonic acid in 1.5 ml of tetrahydrofuran gradually add in the whole of 1.2 mmol of triethylamine and 1.2 mmol of heterocalixarenes and stirred for 20 hours at an oil bath temperature of 80oC. the Solvent is removed, the crude product is partitioned between water and a large amount of ethyl acetate, the organic phase is washed with brine, dried and concentrated on a rotary evaporator. The resulting mixture chromatographic on silica gel using ethyl acetate as the eluting means. Get as polar is the Jethro-1 - naphthyl-N-amoxicill amino-metaphosphates acid.

Example 3. (6,10-Dinitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)-metanfetamina acid

a) Diethyl ether (6,10-dinitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)-metaphosphates acid

90 mg of diethyl ether (6-nitro-2,3-dioxo - 1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)-metaphosphates acid dissolved in 1 ml of methylene chloride and together with 30 mg of tetrafluoroborate sodium stirred at the temperature of the ice bath and later at room temperature. Using sodium hydrogen carbonate solution set pH 8, the organic phase is washed with brine, dried and concentrated on a rotary evaporator. The resulting mixture chromatographic on silica gel. Obtain 24 mg of product.

Similarly receive diethyl ether 1-(6,10-dinitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)ethane-1-phosphonic acid.

b) Similar to that described in example 1D) methodology ester omelet. Get (6,10-dinitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)-metaphosphate acid and similarly 1-(6,10-dinitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)ethane-1-phosphonic acid.

Example 4. (6-Nitro-7-sulfamoyl-2,3-dioxo - 1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)-mutant is R> a) 2-Nitro-5-sulphonamido-naphthas-1-ol and 2,4-dinitro-5-sulphonamido-naphthas-1-ol

1 g of 5-sulfonamides-1-ol nitrous using a mixture of nitric acid and water while cooling in an ice bath. The mixture is neutralized with solid sodium bicarbonate, extracted with a large amount of methylene chloride, washed with brine, dried and concentrated on a rotary evaporator. The resulting mixture chromatographic on silica gel. Get a mixture of 2-nitro-5-sulphonamido-naphthas-1-ol and 2,4-dinitro-5-sulphonamido-naphthas-1-ol.

NMR-spectrum (DMSO, M. D.): 7.8 (4H, m), 8.2 (2H, m), 8.4 (1H, d); respectively, 7.05 (2H, s), 7.6 (1H, DD), 8.3 (1H, d); 8.5 (1H, d), 8.8 (1H, s) for dinitrophenol.

b) Similarly described in the literature methods get esters toluenesulfonic acid. Get:

2,4-dinitro-5-sulphonamido-naphthas-1-alawy ester of toluenesulfonic acid and

2-nitro-5-sulphonamido-naphthas-1-alawy ester of toluenesulfonic acid.

in the same way described in example 1B) methodology esters enter into interaction with diethyl ether aminoalkylphosphonic acids. Thus get:

diethyl ether 1-phenyl-1-(2,4-dinitro-5-sulfamoyl)-1 - naphthylamine)metaphosphates acid;

diethyl ether 1-methyl-1-(2,4-dinitro-5-sulfa is apostoloi acid;

diethyl ether 1-(2,4-dinitro-5-sulfamoyl)-1-naphtylamine - propane-1-phosphonic acid; thus:

diethyl ether 1-phenyl-1-(2-nitro-5-sulfamoyl)-1-naphthylamine) metaphosphates acid;

diethyl ether 1-methyl-1-(2-nitro-5-sulfamoyl)-1-naphthylamine) ethane-1-phosphonic acid;

diethyl ether (2-nitro-5-sulfamoyl)-1-naphthylamine) metaphosphates acid;

diethyl ether 1-(2-nitro-5-sulfamoyl)-1-naphthylamine) propane-1-phosphonic acid.

g) in the same manner as described in example 1B), get:

diethyl ether 1-phenyl-1-(2-amino-4-nitro-5-sulfamoyl)-1 - naphthylamine)metaphosphates acid,

diethyl ether 1-methyl-1-(2-amino-4-nitro-5-sulfamoyl)-1 - naphthylamine)ethane-1-phosphonic acid,

diethyl ether (2-amino-4-nitro-5-sulfamoyl)-1 - naphthylamine)metaphosphates acid,

diethyl ether 1-(2-amino-4-nitro-5-sulfamoyl)-1 - naphthylamine)propane-1-phosphonic acid; thus:

diethyl ether 1-phenyl-1-(2-amino-5-sulfamoyl)-1 - naphthylamine)metaphosphates acid,

diethyl ether 1-methyl-1-(2-amino-5-sulfamoyl)-1 - naphthylamine)ethane-1-phosphonic acid,

diethyl ether (2-amino-5-sulfamoyl)-1 - naphthylamine)metaphosphates acid,

diethyl-the activity with reactive derivatives of oxalic acid, as, for example, described in example 1G), or according to known methods, get:

diethyl ether 1-(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-1-yl)ethane-1-phosphonic acid,

diethyl ether 1-(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-1-yl)propane-1-phosphonic acid,

diethyl ether 1-phenyl(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-1-yl)metaphosphates acid,

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

and also:

diethyl ether 1-(7-sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)ethane-1-phosphonic acid,

diethyl ether 1-(7-sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)propane-1-phosphonic acid,

diethyl ether 1-phenyl-1-(7-sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-1-yl)metaphosphates acid,

diethyl ether (7-sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-1-yl)metaphosphates acid.

(e) By a similar procedure as described in example 1D), amyraut esters. Get:

1-(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)Ethan-1-fovuyu acid,

1-phenyl-1-(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)metaphosphate acid,

(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)metaphosphate acid; as well as:

1-(7-sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)ethane-1-phosphonic acid,

1-(7-sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)propane-1-phosphonic acid,

1-phenyl-1-(7-sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)metaphosphate acid,

(7 sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)metaphosphate acid.

Example 5.

(6-Nitro-9-sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)metaphosphate acid is obtained in a similar way after defending sulfonic acids of sales flavins acid (5,7-dinitro-8-hydroxy-naphthalene-2-sulfonic acids).

Example 6.

1-(6-Nitro-9-sulfamoyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)ethane-1-phosphonic acid is obtained analogously to example 5 from sales flavins acid (5,7-dinitro-8-hydroxy-naphthalene-2-sulfonic acids).

Example 7. (6-Amino-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-1-yl)metanfetamina cikatovo ether (6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl) metaphosphates acid dissolved in 10 ml of DMF and add 10 mg of catalyst based on platinum oxide, pre-saturated with hydrogen. Hydronaut three hours at normal pressure and room temperature using hydrogen. The catalyst is sucked off through celite, the mother liquor is diluted with water and the formed precipitate is sucked off. Get 44% of theory diethyl ether (6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-1-yl) metaphosphates acid. As described in example 1D) or under standard conditions, omelet with HCl to (6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl) metaphosphates acid (respectively, to its hydrochloride).

Similarly receive (6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-4-yl) metaphosphate acid.

b) applying a catalyst of palladium/barium sulfate similarly get:

1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-1-yl) acetonitrile from 1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl) acetonitrile and

1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin - 4-yl)acetonitrile from 1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin - 4-yl)acetonitrile.

Example 8.

Diethyl ether (6-cyano-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin - 1-yl)metapontino acid by diazotization and reaction Sandmeyer with copper cyanide(I). After saponification of ester by known methods get (6-cyano-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin - 1-yl)metaphosphate acid.

Similarly receive (6-cyano-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin - 1-yl)metaphosphate acid from diethyl ether (6-cyano-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin - 4-yl)metaphosphates acid.

Example 9. Diethyl ether (6-nitro-7-sulphonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)metaphosphates acid and diethyl ether (6-nitro-7-sulphonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)metaphosphates acid

150 mg of 6-nitro-7-sulphonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] finokalia, which is synthesized by known methods, is dissolved in 1 ml of dimethyl sulfoxide and added 10 equivalents of diethyl ether triftormetilfullerenov acid, which is obtained by standard methods from the available alcohol and diethyl ether 1-hydroxymethylphosphonate acid. After heating the mixture at 160oC a few hours later process. Dilute solution of sodium bicarbonate, extracted with methylene chloride, dried and concentrated. The crude product chromatographic n is added to the basis for linking triftoratsetata.

Get a new connection:

diethyl ether (6-nitro-7-sulphonamido-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)metaphosphates acid, and diethyl ether (6-nitro-7-sulphonamido-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-4-yl)metaphosphates acid.

In the same way get:

diethyl ether (6-nitro-8-sulfonamide-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-1-yl)metaphosphates acid and

diethyl ether (6-nitro-8-sulfonamide-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-1-yl)metaphosphates acid;

diethyl ether (6-nitro-8,10-disulfonated-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)metaphosphates acid and diethyl ether (6-nitro-8,10-disulfonated-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-4-yl)metaphosphates acid;

diethyl ether (6-nitro-7-sulfonylmethane-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-1-yl)metaphosphates acid and

diethyl ether (6-nitro-7-sulfonylmethane-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-4-yl)metaphosphates acid;

diethyl ether (6-nitro-7-cyano-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)metaphosphates acid and diethyl ether (6-nitro-7-cyano-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] henok xalin-1-yl)metaphosphates acid and

diethyl ether (6-nitro-8-cyano-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-4-yl)metaphosphates acid;

diethyl ether (6-nitro-7-bromo-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl)metaphosphates acid and

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

diethyl ether (6-nitro-7-trifluoromethyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-1-yl)metaphosphates acid and

diethyl ether (6-nitro-7-trifluoromethyl-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-4-yl)metaphosphates acid.

Example 10. (6-Nitro-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-4-yl)metanfetamina acid.

A mixture of 1-nitro-2-fluoro-naphthalene is carried out, as described in the literature. Synthesis of 1-nitro-2-chloro-naphthalene is carried out, as described in the literature. 1-Nitro-2-hydroxy-naphthalene can be obtained by doing so or by oxidation of nitroso-2-hydroxy-naphthalene.

a) 1-Nitro-naphthas-2-alawy ester of toluenesulfonic acid

5 g of 1-nitro-naphthas-1-ol are dissolved in 30 ml of triethylamine from 5.54 g (= 1.1 equivalent) of the acid chloride toluenesulfonic acid at 60oC and stirred at this temperature until the disappearance of the educt. The mixture tons of hot ethyl acetate. Gain of 9.1 g of the product. NMR-spectrum (DMSO): 2.44 (3H, s), 7.5 (3H, d), 7.8 (5H, m), 8.17 (1H, m), 8.34 (1H, d).

Known way get:

1-nitro-naphthas-2-alawy ester of nonoptimality;

1-nitro-naphthas-2-alawy ester of triftoratsetata;

1-nitro-naphthas-2-alawy ester of methansulfonate.

b) Diethyl ether (1-nitro-naphthylamine)metalfestival acid

450 mg of 1-nitro-naphthas-2-olowahu of ester of toluenesulfonic acid are dissolved in 436 mg of diethyl ether aminomethylphosphonic acid and 0.6 g difenilmetana and stirred for 72 hours at 40o-60oC. the Mixture is diluted with methylene chloride, washed with 1 N NaOH solution and twice with brine, dried and concentrated on a rotary evaporator. The crude product chromatographic on silica gel using mixtures of hexane with ethyl acetate in the ratio of 1:1 as the eluting means. Get along with 60% of the educt, 31% of the product as a viscous dark oil.

In the same way get:

diethyl ether 1-phenyl-1-(1-nitro-naphthyl-amino)metalfestival acid,

diethyl ether 1-(1-nitro-2-naphthylamine)ethane-1-phosphonic acid,

diethyl ether 1-(1-nitro-2-naphthylamine)propane-1-phosphonic acid,

dieti the but)metaphosphates acid

170 mg of diethyl ether (1-nitro-2-naphthylamine)metaphosphates acid in 2 ml of glacial acetic acid restores using 10 equivalents of iron powder. After 2 hours the mixture becomes viscous and finally hardens. Dilute with ethyl acetate, remove the iron and chromatographic using ethyl acetate. Receive product with a yield of 60%.

In the same way get:

diethyl ether 1-phenyl-(1-amino-2-naphthylamine)metaphosphates acid,

diethyl ether 1-(1-amino-2-naphthylamine)ethane-1-phosphonic acid,

diethyl ether 1-(1-amino-2-naphthylamine)propane-1-phosphonic acid,

diethyl ether 1-(1-amino-2-naphthylamine)butane-1-phosphonic acid.

g) As described in example 1, cyclist amine derivative of oxalic acid with the receipt:

diethyl ether 1-phenyl-1-(2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-4-yl)metaphosphates acid,

diethyl ether 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)ethane-1-phosphonic acid,

diethyl ether 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)metaphosphates acid,

diethyl ether 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)propane-1-phosphonic acid,

diethyl avonaco leads to

diethyl ether 1-(6-nitro-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-4-yl)ethane-1-phosphonic acid,

diethyl ether 1-(6-nitro-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-4-yl)metaphosphates acid; so pl. 243oC,

diethyl ether 1-(6-nitro-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-4-yl)propane-1-phosphonic acid,

diethyl ether 1-(6-nitro-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-4-yl)butane-1-phosphonic acid,

diethyl ether, 1-phenyl-1-(6-nitro-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-4-yl)metaphosphates acid.

e) Saponification to phosphonic acids carried out analogously to example 1D). Get:

1-(6-nitro-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-4-yl)ethane-1-phosphonic acid so pl. > 300oC (decomposition).

NMR-spectrum (DMSO): 1.7 (3H, d), 5.85 (1H), 7.8 (2H, m), 8.5, 8.8, 9.4 (1H);

1-(6-nitro-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-4-yl)metaphosphate acid; NMR spectrum (DMSO): 4.7 (2H, d), 7.8 (2H, m), 8.5, 8.7, 8.8 (1H);

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] quinoline-4-yl)propane-1-phosphonic acid so pl. > 300oC (decomposition);

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)butane-1-phosphonic acid;

1-phenyl-1-(6-nitro-2,sulfonamide-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)metaphosphate acid is obtained by the above method from 4-amino-3-hydroxy-naphthalene-1 - sulfonic acids. Similarly synthesize 1-(6-sulfonamide-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)ethane-1-phosphonic acid.

Example 12.

1-(8-Sulfonamide-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)metaphosphate acid is obtained by the above method from the salt of 6-hydroxy-naphthalene-2-sulfonic acids. Similarly receive 1-(8-sulfonamide-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)ethane-1-phosphonic acid.

Example 13.

In the same way and with the usual amino acids methods in the application of the sales of amino acids and their derivatives, such as complex tert.-butyl esters, get the following compounds

(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)metacarbonate acid,

(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)metacarbonate acid,

(7 sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)metacarbonate acid,

(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)metacarbonate acid,

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl)ethane-1-carboxylic acid,

1-(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin - acid.

Example 14. 1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)acetonitrile

a) 1-Nitro-naphthylamine-acetonitrile

To 21,58 g (80,7 mmol) of 1-nitro-naphthas-1-olowahu complex ester methanesulfonate add 32,1 g obtained by known methods 1-amino-acetonitrile. Stirred for 8 hours at 60oC, then diluted with dichloromethane, and the mixture is passed through filled with silica gel column. The chromatography was carried out using toluene gives along with 7 g of 1-nitro-naphthas-2-ol 13% of theory (1-nitro-2-naphthylamine)acetonitrile.

In the same way get:

(1-nitro-2-naphthylamine)methyl-acetonitrile,

(1-nitro-2-naphthylamine)-1,1-dimethyl-acetonitrile.

b) (1-Amino-2-naphthyl)aminoacetonitrile

0.45 g of 1-nitro-2-naphthylamine-acetonitrile in 65 ml of dioxane hydronaut at room temperature in the presence of Pd/barium sulfate as catalyst. After removal of the catalyst receive 100% of raw product - (1-amino-2-naphthyl)aminoacetonitrile.

Similarly get:

(1-amino-2-naphthylamine)methyl-acetonitrile,

(1-amino-2-naphthylamine)-1,1-dimethyl-acetonitrile.

C) 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-4-yl) acetonitrile

0,41 g of the crude (1-amino-2-NN-4-yl)acetonitrile. So pl. > 350oC. NMR spectrum (DMSO): 5.4 (2H), 7.55 (2H), 7.75, 8.03, 8.63 (1H, d), 12.24 (1H, s).

Similarly get:

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-4-yl) methylacetamide,

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)- dimethyl-acetonitrile,

g) 1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)acetonitrile

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)acetonitrile enter into interaction with 65% nitric acid for 3 hours at room temperature. Precipitated from the water, yellow crystals are washed and get 51% of the product so pl. > 300oC (slow decomposition).

Similarly get:

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)methyl-acetonitrile,

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)dimethyl-acetonitrile.

Example 15. 1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)metatarsal and 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)metatarsal

301 mg of 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-4-yl)acetonitrile in 12 ml of N-methylpyrrolidone for 2.5 hours at 150oC mixed with 3 equivalents of sodium azide and 1.5 equivalents of triethylamine acetonitrile and dried. Get 83% 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl) metatarsal with so pl. 320oC.

1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl) metatarsal get analogously to example 14g) of 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-4-yl) melanterite, so pl. > 300oC.

Example 16. Amidoxime 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-4-yl) metacarbonate acid

100 g of 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-4-yl) acetonitrile with 2 equivalents of hydroxylaminopurine and sodium bicarbonate in 0.2 ml of water and a small amount of ethanol is refluxed for 4 hours. After dilution with water, the product precipitates and is sucked off. The output is 62%. NMR-spectrum (DMSO): 4.9 (2H, s), 5.55 (2H, s), 7.55 (3H, m), 7.75, 7.95, 8.6 (1H), 9.2 (OH), 12.2 (1H, broadened).

Example 17. 1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-1-yl) acetonitrile and 1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-1-yl) ndimethylacetamide

In the same manner as in example 14a), from the corresponding esters of methansulfonate get:

2-nitro-1-naphthylamine-acetonitrile,

(2-nitro-1-naphthylamine)-methyl-acetonitrile,

(2-nitro-1-naphthylamine)-1,1-dim is/BR>(2-amino-1-naphthyl)aminoacetonitrile,

(2-amino-1-naphthylamine)-1,1-dimethyl-acetonitrile,

receive the following connections:

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl) acetonitrile, NMR-spectrum (DMSO): 5,2 (2H,), 7.45, 7.53, 7.68, 7.83, 8.03, 8.14 ( according 1H), 12.2 (1H, s);

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl) methylacetamide,

1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl) dimethylacetamide.

1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-1-yl) ndimethylacetamide:

1-(2,3-Dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl) acetonitrile enter into interaction with 65% nitric acid at room temperature for 3 hours. Precipitated from the water, yellow crystals are washed and get about 100% of the crude product with so pl. > 300oC (slow decomposition). We are talking about 1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-1-yl) ndimethylacetamide.

1-(6-Nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl) acetonitrile obtained when applying nitrone-tetrafluoroborate; it melts at > 300oC.

Similarly get:

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl) methylacetamide,

1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahed is drobenko[f] cinoxacin-1-yl) metatarsal (so pl. 305o-315oC with decomposition) and 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-1-yl) metatarsal (so approximately 310 squareoC with decomposition) are obtained as described in example 15.

Example 19. Amidoxime 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-1-yl) metacarbonate acid

100 mg of 1-(2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-1-yl) acetonitrile with 2 equivalents of hydroxylaminopurine and sodium bicarbonate in 0.2 ml of water with a small amount of ethanol is refluxed for 7 hours. The product precipitates upon dilution with water and it sucked. The output is 67%.

NMR-spectrum (DMSO): 4.9 (2H, s), 5.7 (2H, s), 7.5 (3H, m), 7.75, 7.95, 8.4 (1H), 9.12 (OH), 12.14 (1H, broadened).

Example 20. Diethyl ether [6-(piperidine-1-yl)- (2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-1-yl] metaphosphates acid

To 37 mg diethyl ether (6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl) metaphosphates acid in 2 ml of tetrahydrofuran, to which was added 13 mg of sodium borohydride, with stirring and at the temperature of the ice bath is added a mixture of 100 μl of aqueous glutaraldehyde (approximately 25%), 300 ál of diluted sulfuric acid and 1 ml of a mixture of tetrahydro the Mixture is neutralized and extracted with ethyl acetate. Obtained after chromatography with a small amount of silica gel 16 mg of product.

After saponification of ester receive [6-(piperidine-1-yl)- 2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]cinoxacin-4-yl]- metaphosphate acid.

Similarly synthesize:

diethyl ether [6-(piperidine-1-yl)- 2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl] - metaphosphates acid [6-(piperidine-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-1-yl]-metaphosphate acid.

Example 21. [6-(Morpholine-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl]-metanfetamina acid.

Diethyl ether [6-(morpholine-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl]-metaphosphates acid is obtained from diethyl ether (6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4 - yl)metaphosphates acid as described in example 20 method by interacting with the dialdehyde 3-oxa-glutaric acid. The usual way to receive [6-(morpholine-1-yl)-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f] cinoxacin-4-yl)metaphosphate acid.

Similarly get:

diethyl ether [6-(morpholine-1-yl)-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-4-yl]-metaphosphates acid [6-(mo the Olin-1-yl)-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl]-acanthostega acid, 1-[6-(morpholine-1-yl)-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl] -acanthostega acid.

Example 22.

Diethyl ether 1-[6-(imidazolyl)-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl] -acanthostega acid, respectively, 1-[6-(imidazolyl)-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl]-acanthostega acid, obtained by nucleophilic aromatic substitution of the halide derivatives with imidazole as a nucleophile.

In the same way get:

diethyl ether [6-(imidazolyl)-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl]-metaphosphates acid,

[6-(imidazolyl)-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-1-yl] -metaphosphate acid,

diethyl ether [6-(imidazolyl)-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-4-yl]-metaphosphates acid,

[6-(imidazolyl)-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f] cinoxacin-4-yl] -metaphosphate acid.

Compounds according to the invention suitable for the production of medicines due to its affinity for AMPA-receptor.

The applicant has indicated the proposed activity of the compounds in the form of values of IC 50.

The concentration at which 50% Oxalis-4-yl]-ethane-1-phosphonic acid is IC50= 2 µmol,

for (6-nitro-2,3-dioxo-1,2,3,4 - tetrahydrobenzo[f]cinoxacin-4-yl]-metatarsal is IC50= 1.4 Microm.

Medicines along with the connection according to the invention as active principle contain pharmaceutically suitable excipients and carriers. Daily dose medications is usually 0.5 to 1,000 mg

In the manufacture of a medicinal product in the form of tablets the active ingredient is mixed with, for example, lactose and starch. Moisten the mixture with an aqueous solution of policiesprocedures. The wet mixture is sieved, dried, and sift again. Add microcrystalline cellulose and a small amount of hydrogenated vegetable oil. The components are thoroughly mixed and pressed into tablets.

In the manufacture of a medicinal product in the form of capsules the active ingredient is mixed with, for example, lauryl sulfate, starch, lactose, silicon dioxide and magnesium stearate. The mixture then fill in the appropriate gelatin capsules, each of which typically contains 20 mg of the active ingredient.

1. Derivatives of benzo(f)of khinoksalinona formula I

2or (CH2)nthe phenyl substituted in the alkyl residue, R2, R5, R6, R7, R8, R9and R10are identical or different and denote hydrogen, halogen, a nitro-group, NR16R17SO2R12, cyano, CF3and R2denotes CN, tetrazolyl, -C(=NOH)NH2, COR3or ROCH, n denotes an integer from 1 to 5, R3denotes hydroxyl, (C1- C6) alkoxyl, amino, X and Y are the same and denote hydroxyl or (C1- C6) alkoxy, R12- NH2or (C1- C4)alkyl, R16and R17denote hydrogen or R16and R17together with the nitrogen atom form piperidino, morpholino or imidazolidinyl group or their salts, and in the case when R5- R10denote hydrogen, R1or R4doesn't mean metaphosphate or ethane-1-phosphonic acid.

2. Derivatives of benzo(f)of khinoksalinona under item 1, representing: (6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo(f)cinoxacin-1-yl)metaphosphate acid, (6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzo(f)cinoxacin-1-yl)metaphosphate acid, (6-nitro-7-sulphonamido-2,3-dioxo-1,2,3,4-tetrahydrobenzo(f)hinonfatal acid, (6-nitro-8-sulfonamide-2,3-dioxo-1,2,3,4-tetrahydrobenzo(f)cinoxacin-4-yl)metaphosphate acid, (6-nitro-8,10-disulfonated-2,3-dioxo-1,2,3,4-tetrahydrobenzo(f)cinoxacin-1-yl)metaphosphate acid, (6-nitro-8,10-disulfonated-2,3-dioxo-1,2,3,4-tetrahydrobenzo(f)cinoxacin-4-yl)metaphosphate acid, (6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo(f)cinoxacin-1-yl)metacarbonate acid, (6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzo(f)cinoxacin-1-yl)metacarbonate acid, (6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo(f)cinoxacin-4-yl)metacarbonate acid, 1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo(f)cinoxacin-1-yl)ethane-1-carboxylic acid, 1-(6-nitro-7-sulfamoyl-2,3-dioxo-1,2,3,4-tetrahydrobenzo(f)cinoxacin-1-yl)ethane-1-carboxylic acid, 1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo(f)cinoxacin-4-yl)ethane-1-carboxylic acid (6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo(f)cinoxacin-4-yl)metaphosphate acid.

3. A drug that has affinity for AMPA receptors containing the active principle and a pharmaceutically suitable excipients and carriers, characterized in that the active agent it includes the compound of formula I on PP.1, 2.

4. The method of obtaining compounds of formulas is a great value,

cyclist with oxalic acid or a reactive derivative of oxalic acid, and if desired, then amyraut ester group, or an acid group atrificial to ester or lidiruyut, or restore the nitro-group to the amino group, or alkylate or acelerou the amino group, or exchange of the amino group by halogen or cyano, or give the nitro-group or halogen, or nitrile transferred to tetrazol or amidoxime or nucleophile replace, or share isomers, or get salt.

5. The method of obtaining compounds of formula I on p. 1, characterized in that the compound of formula IV or V

< / BR>
where R1- R10has the above value,

enter into interaction with oxalic acid or a reactive derivative of oxalic acid and cyclist after recovery, nitro, and optionally then amyraut ester group; or an acid group atrificial to ester or lidiruyut, or restore the nitro-group to the amino group, or alkylate or acelerou the amino group, or exchange of the amino group by halogen or cyano, or give the nitro-group or halogen, or nitrile transferred to tetrazol or amidoxime or nucleophile compound of formula VI

< / BR>
where R5- R10have the above meaning,

in the presence of a base enter into interaction with R1- z or R4- z, where z denotes the group that you want, and if desired, then amyraut ester group, or an acid group atrificial to ester or lidiruyut, or restore the nitro-group to the amino group, or alkylate or acelerou the amino group, or exchange of the amino group by halogen or cyano, or give the nitro-group or halogen, or nitrile transferred to tetrazol or amidoxime or nucleophile replace, or share isomers, or get salt.

 

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< / BR>
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