Derived the condensed pyrazine

 

(57) Abstract:

The invention relates to a derivative of pyrazine, which has antagonistic activity relative to the glutamate receptor, represented by the formula:

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in which Z represents C or N, provided that two Z are nitrogen atoms; R1is:

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which is or , R6represents H or alkyl, and R7and R8are each H, alkyl, nitro or phenyl, or alternatively, R7and R8taken together, represent butadiene or 1,4-butylene; R2and R3are each H, F, cyano, acyl, nitro, alkyl, morpholino or one of the above definitions for R1; R4and R5are each H, hydroxyl, alkyl, cycloalkyl, heterocycle, phenyl, or Y-substituted alkyl; Y represents a hydroxyl, acyloxy, F - substituted methyl, cycloalkyl, tetrahydrofuranyl, carboxyl, alkoxycarbonyl or ; R9and R10each represents H or alkyl, or alternatively, R9and R10taken together, represent a 5 - or 6 - element cyclic group which may contain oxygen atoms. 1 C.p. f-crystals.

The invention Amnesty relatively receptors, glutamate, in particular antagonistic activity relative to the receptors of the NMDA glycocol and antagonistic activity relative to AMPA receptors.

Some amino acids such as L-glutamic acid and L-aspartic acid, is well known as the main "transmitters" of nerve impulses. It is also known that the accumulation of such "excitatory amino acids leads to a stable overstimulate nerve cells, which in turn leads to neural exhaustion, and mental and motor dysfunction, which can be seen in trochaic Huntington's, Parkinson's disease, epilepsy, senile dementia or after cerebral ischemia, oxygen starvation or hypoglycemia.

Thus, at present, considered any medications that may modulate the pathological actions of these excitatory acids as effective when used to treat neural exhaustion and mental illness.

Excitatory amino acids show their effects through specific receptors, which are available in post or presinapticheskih areas. These receptors are classified into the following five groups based on electroheater AMPA (2-amino-3-/3-hydroxy-5-methyl-4-isoxazol/propionic acid).

3) Receptor kainate.

4) Receptor metabotropic glutamate.

5) the AR Receptor-4 (2 - amino-4-postbalance acid)

L-glutamic acid and L-aspartic acid activate the above-mentioned receptors, causing them to transmit impulses. If we assume the effect of excessive NMDA, AMPA or kainate on nerve cells, it leads to nervous disease. It is known that 2-amino-5-bostonballerina acid and 2-amino-7-postgateway acid, which are selective antagonists of the NMDA receptor, are very effective tools in the treatment of nervous diseases caused by NMDA, as well as epilepsy or cerebral ischemia in animal models (JPET, so 250, 100 C., 1989; JPET, I. 240, C. 737, 1987; Science, I. 226, 850 C. 1984).

It was found that the NMDA receptor is an allosteric functioning under the action of the receptor glycocol (EJP, T. 126, S. 303, 1986), and ON-966, which is an antagonist of the receptor glycocol is effective in animal models of cerebral ischemia (1989, Congress of American Society of Neuroscientists).

It is also known that NBQX (6-nitro-7-sulfamoylbenzoic [f] cinoxacin), a selective antagonist of AMPA-receptor, is an effective agent in an animal model of ishemia Goa for receptor kainate, metabotropic glutamate and AR-4.

The purpose of the invention is to provide a connection dimethyloxetane or diketopiperazine, which has antagonistic activity relative to the glutamate receptor, in particular NMDA receptor-glycocol, and/or antagonistic activity relative to AMPA-receptor. Several derivatives of dimethyloxetane, which has antagonistic activity relative to NMDA glycocol and/or AMPA already known (JP-A-63-83074, JP-A-63-258466, JP-A-1-153680, JP-A-2-221263 and JP-A-2-221264; the term "JP-A" means "untested published patent application of Japan"). However, the connection of the invention is a new compound which has structural characteristics, namely that it has imidazolinone or triazolium group on the ring dimethyloxetane or diketopiperazine.

Thus, the invention relates to a derivative of pyrazine represented by the formula:

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in which a represents a benzene ring of the formula or the pyridine ring of the formula

R1is:

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X represents a nitrogen atom or a carbon atom substituted R8, R7and R8which may be identical or different, qgradient (-CH=CH-CH=CH-or 1,4-butylene (-CH2-CH2-CH2-CH2-); R2and R3that may be the same and represent hydrogen or different, and each represents hydrogen, fluorine, cyano, lower acyl, nitro, unsubstituted or substituted by fluorine, lower alkyl, morpholino or one of the above definitions for R1same with R1; R4and R5which may be identical or different, each represents hydrogen, hydroxyl, C1-10linear or branched alkyl, C5-8cycloalkyl, which may be substituted amino, nitrogen-containing 5 - or 6-membered heterocyclic group which may be substituted by lower alkyl and which can be connected by a bridge of 1 to 3 methylene groups, phenyl or Y-substituted C1-6linear or branched alkyl; Y represents a hydroxyl, lower acyloxy, methyl, substituted by fluorine, C5-8cycloalkyl, tetrahydrofuryl, carboxyl, lower alkoxycarbonyl or (where R9and R10which may be identical or different, each represents hydrogen or lower alkyl, or alternatively, R9and R10together represent a 5 - or 6-membered cyclic group that may contain oxygen), or its salts.

"5 - or 6-element cyclic group which may contain oxygen" represented by R9and R10together, denotes morpholino among other things.

The term "lower alkyl group" in the above definition means a linear or branched C1-6hydrocarbon group. Examples of such groups are methyl, ethyl, butyl, isopropyl, etc. "Lower allowa group" means an formid, acetyl, propionyl, butanoyl etc.

While the above compound of formula (I) can exist in the form of stereoisomers or tautomers, depending on the substituents, such isomers in an isolated form, as well as mixtures thereof are contained in the area covered by the invention.

The salts of the above compounds (I) include salts with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid etc., salts with organic acids such as fumaric acid, tartaric acid, alkane (mono)sulfonic acids, aryl(mono), etc. and salts with organic bases, such as diethylamine etc.

The compound of the invention can be obtained in accordance with the following reaction scheme:

< / BR>
in which Y denotes a halogen atom; the ring A, X, R4, R2, R3, R7, R5and R6have already been defined above.

To implement the above reaction, the halide (II) and either the compound of imidazole, or a connection triazole (III) interact in stoichiometric quantities. This reaction is in General carried out in a solvent such as dimethylformamide, dimethyl sulphates, acetonitrile, acetone, tetrahydrofuran, etc., when heated. This reaction can be accelerated by adding a base such as the hydroxide of sodium, potassium hydroxide, etc.

The compound of the invention can also be obtained in accordance with the following reaction scheme:

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This reaction is carried out through the interaction of the diamino compounds (IV) with ravnomernym or excessive amounts of oxalic acid or its reactive derivative (V) at room temperature or when heated. Reactive derivatives of oxalic acid, for example, may be a corresponding salt, complexity is whether alcohol solvent. In a preferred embodiment, add the acid, such as hydrochloric acid, etc. to speed up the reaction.

To obtain the compound (I') you can use the following alternative procedure:

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in which R8represents a lower alkyl group; the other symbols have been defined previously.

This reaction, including recovery cyclization of compounds of lower alkoxyamino (VI) can be carried out using procedures catalytic reduction using a Nickel of Ranea, etc. as a catalyst.

Another procedure for obtaining compounds of the invention includes the introduction of a new group of the substituent in the ring And compounds obtained by using any of the above procedures or by changing the substituents. The compound of the invention in which R1is the nitrogroup, for example, can be obtained by nitration of the corresponding compounds in which R1is hydrogen. The nitration reaction can be performed using a procedure that includes the interaction of compounds containing the nitro group, with nitric acid or its salt under acidic conditions in the presence of sulfuric acid or acetic dioxide is containing a series of heating the above-mentioned connection tetrafluoroborate nitronium in an organic solvent, such as sulfolan.

The compound of the invention has a relatively strong affinity of NMDA receptor-glycocol and/or AMPA receptor. Effects on the NMDA receptor ([3H]-MK-801 binding inhibitory activity) was observed at a concentration of 1 . Linking AMPA-receptor inhibitory activity, for example, the compounds of example 8 was 96% at a concentration of 1 m, and its Ki-value was 21 nm. The compounds of examples 9 and 15 inhibited audiogone convulsions at a concentration of 3 mg/kg when injected 15 min prior to stimulation by sound.

In addition, when the compound of the invention, for example compound from example 15, was used in 60, 70 and 85 min after 5 min of ischemia, it provided 60% protecting neuronal activity with assessment of lesions 1,2.

Experimental techniques

The activity of compounds of the invention relative to the NMDA receptor-glycocol ([3H] -MK-801 binding inhibitory activity) and [3H]-AMPA binding inhibitory activity, activity for inhibiting audiogenic cramps and activity for the protection of neurons compounds were determined using the following methods.

Effects on NMDA receptor-glycocol (analysis of binding of [3H]-MK-801 inhibitory actiregularis by analyzing binding, using [3H]-MK-801 as a ligand.

Determination of the binding of [3H]-AMPA - activity:

The mixture (0.5 ml) of about 45 nm [3H]-AMPA (2-amino-3-/3-hydroxy-5-methyl-4-isoxazol/propionic acid), about 300 mg of the sample membranes of cerebral cells of the rat and the test compound were given the opportunity to interact on a mixture of ice water for 45 minutes Number of [3H]-AMPA associated with the receptors hashalovoy acid, was determined using one of the methods of filtration. From the total number of associated material part, replaced by 1 m jihlavou acid, considered as specific binding. The test compound was analyzed by determining the percent inhibition of specific binding.

Determination of inhibitory activity for audiogenic convulsions in mice DBA/2

Ten male rats aged 21-28 days were placed in a soundproof box and in this box was placed stimulator of sound frequency of 12 KHz and 120 dB at 1 min or until, while mice do not develop tonic convulsions (seizures).

The test compound suspended in 0.5% solution of methylcellulose or dissolved in physiological saline races the CSOs compounds investigated after the onset of convulsions, it was determined the minimum effective dose (MED).

Action for the protection of neurons in hippocampi

Protective action when the necrosis of nerve cells caused by cerebral ischemia, were tested using the model of the gerbil ischemia, based on the occlusion of bilateral common carotid arteries.

Procedure

Bilateral common carotid artery gerbils corked for 5 minutes under anesthesia with halothane gas, while the animal was kept warm to avoid hypothermia, and then the animal was allowed to recover from anesthesia. After 4 days, the brain was separated and prepared parts for histological study of the degree of neural lesions in CA1 of the hippocampus.

Method of application

Test connection or suspended in 0.5% solution of methylcellulose or dissolved in a physiological salt solution, was applied by intraperitoneal way. Used two modes of doses. In the implementation mode 1 used 30 mg/kg/dose for 45 and 15 min before ischemia and after 5 min and 1, 2, 3, 6 and 24 hours after receipt of recanalization. In the implementation mode 2 used 30 mg/kg/dose after 60, 70 and 85 min after receiving recanalization.

M the degree of damage to nerve cells in region CA1 of the hippocampus was assessed on a 4-point scale: damage (score 0), mild necrosis (score 1), moderate necrosis (score 2) and necrosis (score 3).

The compound of the invention and its salts salladay antagonistic activity relative to glutamate receptors, in particular antagonistic activity against one of the receptors of the NMDA glycocol and/or AMPA-, or against both, inhibitory activity against the neurotoxic action of excitatory amino acids, and have protivogololednoy activity. Therefore they can be used especially to prevent nervous exhaustion and mental and motor dysfunction with trochaic Huntington's, Parkinson's disease, epilepsy, senile dementia or after cerebral ischemia, oxygen deficiency, hypoglycemia, or seizures.

The compound represented by formula (I) or its salt is in General applied systematically or local manner, for example tematicheskie or parenteral. The dosage may vary depending on age, body weight, clinical conditions, a therapeutic response, method of application, time of treatment, etc. When stomachache 50 - 200 mg, which is administered as a single dose or as multiple doses. Parenteral application of the use of intravenous method 1 500 mg of the compound as a single dose or as multiple doses, or by intravenous infusion over 1 to 24 hours of Course, as mentioned above, the dosage should be changed depending on various conditions, with sufficient efficiency can be obtained when using doses smaller than those indicated above.

Examples. The invention is described in more detail with reference to examples, but they should not be construed as limiting thereof. Examples of different methods of obtaining the main source of materials for use in these examples are given below as examples for reference.

Among the symbols used in the representation of the physico-chemical data, NMR indicates a range of nuclear magnetic resonance, MS denotes the mass spectrum.

Reference example 1

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In 80 ml of N, N-dimethylformamide was dissolved 4,00 g 2-amino-6-chloro-3-nitropyridine and 15,69 g of imidazole and the solution was stirred overnight at 120oC. After spontaneous cooling to room temperature, was added 100 ml of water and obtained in resultaten, to get 3,76 g 2-amino-6-imidazolyl-3-nitropyridine.

Physico-chemical properties:

NMR /DMCO d6TMC/ /tetramethylsilane was translated/; 7,16 /doublet, 1H/, 7,16 /Quartet, 1H/, 9,95 /triplet, 1H/, 8,18 /broad, 2H/, 8,56 /doublet, 1H/, to 8.57 /doublet, 1H/.

MS /E1/: 205 /M+/.

Reference example 2

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In a mixture of 5.6 g of 2-amoxacillin-5-peritrabecular and 170 ml of DMF was added 0.3 g of 10% Pd-C, and the hydrogenation reaction was carried out at room temperature and atmospheric pressure. The reaction mixture was then filtered and concentrated under reduced pressure. The resulting residue was subjected to recrystallization from ethanol to obtain 3,68 (85% 7-fluoro-1-oxygenation-2,3-/1H, 4H)- dione.

Physico-chemical properties:

NMR /DMCO-d6; TMC/: 6,93 7,31 /multiplet, 3H/, 11,83 /singlet, 1H/, 12,1 /singlet, 1H/.

MS /FAB/: 197 /M+1/. The temperature of the melting point: 138-140oC /Razlog./ /E+/.

Elemental analysis (for C8H5N2O3F): Calculated: C, 48,99, H, 2.57 m, N, Of 14.28% Found: C, 48, 79, H, 2,68, N, 14,16%

Reference example 3

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In 20 ml of sulfuric acid was dissolved to 1.34 g of 7-fluoro-1-oxygenation-2,3-/1H, 4H/-Dion, then added 0,76 g of potassium nitrate under ice cooling. The mixture was cooled the Alla was isolated by filtration, washed with water and subjected to recrystallization from ethanol-water to obtain 0,82 g (50%) of 7-fluoro-1-hydroxy-6-nitrophenoxy-2,3-/1H, 4H/-Dion.

Physico-chemical properties:

NMR /DMCO-d6; TMC/: 7,50 /doublet, 1H/, to $ 7.91 /doublet, 1H/, 12,20 /1H/, 12,32 /1H/.

MS /E1/: 241 /M+/. The temperature of the melting point: 202oC /decomposition/ /EtOH-H2O/.

Elemental analysis (for C3H4N3O5F): Calculated: C, 39,85, H, 1,67, N, 17,43% Found: C, 40,24, H, 1,80, N, 17,18%

Reference example 4

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In 10 ml of DMF was dissolved in 1.00 g of 4-fluoro-2-nitro-5-triftoratsetilatsetonom and of 2.56 g of imidazole and the solution was stirred at a temperature of 150oC for 3 hours the Reaction mixture was then diluted with 30 ml water and the resulting crystals were isolated by filtration and subjected to purification using chromatographic column (chloroform-methanol 20:1) to obtain 0,53 g (52%) 4-/1-imidazolyl/-2-nitro-5 - triptorelin.

Physico-chemical properties:

NMR /DMCO-d6; TMC/: 7,05 /singlet, 1H/, 7.31 /singlet, 1H/, to 7.61 /singlet, 1H/, 7,75/singlet, 1H/, 7,95 /singlet, 2H/, 8,04 /singlet, 1H/.

MS /E1/: 272 /M+/.

Reference example 5

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In 20 ml of DMF was dissolved 0,70 g of 4-amino-2-fluoro-5-nitroacetophenone and 1.20 g promo mixture was diluted with 60 ml of water. The resulting crystals were collected by filtration and subjected to processing on a chromatographic column (chloroform-methanol 3:1) to obtain 0.28 g (32%) of 4-amino-2-/1-imidazolyl-5-nitroacetophenone.

Physico-chemical properties:

NMR /DMCO d6; TMC/: 2,18 /single, 3H/, 6,98/singlet, 1H/, 7,08 /singlet. 1H/, 7,37 /triplet, 1H/, 7,84 /singlet, 1H/, 8,03 /broad, 2H/, charged 8.52 /singlet, 1H/.

MS /E1/: 246 /M+/.

Reference example 6

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In 5 ml of DMF was dissolved 1 g of 4-amino-2-fluoro-5-nitrobenzonitrile and 1.1 g of imidazole and the mixture was stirred at 100oC for 1 h, the Reaction mixture was then diluted with water and the resulting crystals were isolated by filtration, to obtain 1.2 g of 4-amino-2-/1-imidazolyl/-5 - nitrobenzonitrile.

Physico-chemical properties:

NMR /DMCO d6; TMC/: 7,11 /singlet, 1H/, 7,18 /singlet. 1H/, to 7.61 /singlet, 1H/, 8,10 /singlet. 1H/, 8,21 /singlet, 2H/, 8,64 /singlet, 1H/.

MS /E1/: 229 /M+/.

Reference example 7

230 mg of sodium hydride were washed with hexane and suspended in 10 ml of DMF (dimethylformamide). After cooling, ice was added to 1.30 g of 4-(1H-imidazol-1-yl)-2-nitro-5-triptorelin and after 5 min was added 0,84 ml diethyloxalate.

Physico-chemical properties:

MS (m/z) 372 (M),

NMR (CDC13: d TMC (tetramethylsilane): USD 1.43 (3H, t), 4,50 (2H, HF), 7,14 (1H, s), 7.24(1H, s), the 7.65 (1H, s): a 8.34 (1H, s), 9,43 (1H, s), 11,96 (1H, s).

Reference example 8

The procedure of reference example 7 was repeated, except that instead of 4-(1H-imidazol-1-yl)-2-nitro-5-triptorelin was used 4

(1H-4-Mei-1-yl)-2-triptorelin. The result was obtained N-ethoxalyl-4-(1H - 4-Mei-1-yl)-2-nitro-5-cryptomelane.

Physico-chemical properties:

MS (m/z) 386 (M).

NMR (CDC13: d TMC): to 1.48 (3H, t), 2,31 (3H, s), 4,50 (2H, HF), at 6.84 (1H, s), 7,53 (1H, s), 8,30 (1H, s), 9.41 (1H, s) 11,94 (1H, s)

Example 1

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In a mixed solution of 40 ml of methanol and 2 ml acetic acid is suspended 3,68 g 2-amino-6-imidazolyl-3-nitropyridine. Then 0.20 g of 10% palladium on carbon was added to the mixture and the hydrogenation was carried out at atmospheric pressure. The reaction mixture was filtered, and the filtrate to the oxalic acid, then the mixture was delegirovali during the night. After spontaneous cooling to room temperature, the resulting crystals were isolated by filtration and subjected to recrystallization from N, N-dimethylformamide, to obtain 2.30 g of the monohydrate hydrochloride 6-imidazolidine [2,3-b] pyrazin-2,3-dione.

Physico-chemical properties:

NMR /DMCO-d6; TMC/: 7,80 /singlet, 2H/, 7,88/Quartet, 1H/, 8,24 /triplet, 1H/, 9,75 /triplet, 1H/, 12,43 /singlet, 1H/, 12,67 /singlet, 1H/.

MS /FAB/: 230 /M++1/. The melting point > 300oC (DMF)

Elemental analysis (for C10H7N5O2HClH2O0,1 Me2NCHO):

Calculated: C, 42,52, H, 3,71, N, RUB 24.55, C1, 12,18. Found: C, 42, H, 3,52, N, To 24.84, C1, 12,02.

Example 2

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In 10 ml of sulfolane was dissolved 1.01 g of the monohydrate hydrochloride 6-imidazolidine [2,3-b] pyrazin-2,3-dione, then added 1.35 g of tetrafluoroborate nitronium and the mixture was stirred at a temperature of 120oC for 4 h Then the reaction mixture was allowed to cool to room temperature, it was diluted with 10 ml of water and neutralized 1 N solution of hydrate of sodium oxide. The resulting crystals were isolated by filtration and washed with a small amount of water. Obtained the hydrochloric acid and then 5 ml of ethanol. The crystals were recovered by filtration and dried under reduced pressure to obtain 0,63 g of the hydrochloride of 6-imidazolyl-7-nitropyrene [2,3-b] pyrazin - 2,3-dione.

Physico-chemical properties:

NMR /DMCO-d6; TMC/: 7,87 /multiplet, 1H/, 8,67 /multiplet, 1H/, 8,46 /singlet, 1H/, at 9.53 /multiplet, 1H/, 12,74 /singlet 1H/, 13,16 /broad, 1H/.

MS /FAB/: 275 (M++1/. The melting point > 300oC /EtOH-H2O/.

Elemental analysis (for C10H6N6O4HClO,2H2O): Calculated: C, 38,22, H, 2,37, N, 26,74% C1, 11,28. Found: C, 38,33, H, 2,34, N, 26,63, C1, 11,40.

Example 3

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In DMF was stirred 1 g of 6-fluoro-7-nitrogenation-2,3-/1H, 4H/-Dion and 1.8 g of 2-methylimidazole when heated to 130oC for 8 h, the Reaction mixture was then concentrated and diluted with water to precipitate crystals. These crystals were subjected to recrystallization from DMF-water to obtain 540 mg of 6-/2-methylimidazole/-7-nitrogenation-2,3-/1H, 4H/-Dion.

Physico-chemical properties:

NMR /DMCO-d6: TMC/: 2,09 /singlet, 3H/, 6,93/1H/, 7,12 /singlet, 1H/, 7,19 /1H/, 7,95 /singlet, 1H/, 12,42/2N/.

MS /FAB/: 288 /M++1/. The melting point > 300oC /DMF-H2O/.

Element,59.

Example 4

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Repeating the same procedure as in example 3 except that 2-ethylimidazole used instead of 2-methylimidazole. As a result received 450 ml 6-/2-ethylimidazole/-7-nitrogenation-2,3-/1H, 4H/-Dion.

Physico-chemical properties:

NMR /DMCO-d6; TMC/: 1.10 /triplet, 3H/, 2,38 /double doublet, 2H/, 6,92 /doublet, 1H/, 7,09 /singlet, 1H/, 7,15 /doublet, 1H/, 7,92 /singlet, 1H/.

MS /FAB/: 302 /M++ 1/. The melting-point: 249-250oC /DMF H2O/.

Elemental analysis (for C13H11N5O4H2O): Calculated: C, 48,91, H, 4,10, N, 21,94: Found: C, 48,61, H, 4,00, N, 21,74%

Example 5

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Repeating the same procedure as in example 3 except that 4-Mei is used instead of 2-methylimidazole. The result obtained 6-/4-methyl-1-imidazolyl/-7-nitrogenation-2,3-/1H, 4H)-dione or 6-/5-methyl-1-imidazolyl/-7-nitrogenation-2,3-/1H, 4H)-dione in the form of one material relative to the spectrum of nuclear magnetic resonance /NMR/.

Physico-chemical properties:

NMR /DMCO-d6: TMC/: 2,16 /singlet, 3H/,? 7.04 baby mortality /triplet, 1H/, 7,08 /singlet, 1H/, 7,12 /doublet, 1H/, a 7.85 /singlet, 1H/, KZT 12.39 /2N/.

MS /FAB/: 288 /M++1/. The melting point > 300oC /DMF HH, 3,30, N, 23,87%

Example 6

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Repeating the same procedure as in example 3, except that used 4,5,6,7-tetrahydroimidazo instead of 2-methylimidazole. As a result received 450 mg of 6-nitro-7-/4,5,6,7-tetrahydro-1-benzimidazolyl/cinoxacin-2,3-/1H, 4H/-Dion.

Physico-chemical properties:

NMR /DMCO d6; TMC/: 1,70 /4H/, 2,18 /2N/, 2,50 /2N/, 12,35 /2N/.

MS /FAB/: 328 /M++ 1/. The melting point > 300oC.

Elemental analysis (for C15H13N5O41,5 H2O): Calculated: C, 50,85, H, 4,55, N, 19,77% Found: C, 50,58, H, 4,54, N, 19,57.

Example 7

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The solution dry DMCO containing 1.2 g of 6-fluoro-7-nitrogenation-2,3-/1H, 4H/ Dion, 740 mg of powdered potassium hydroxide and 1.3 g of benzimidazole, was stirred while heating to 130oC for 5.5 h, the Reaction mixture was then poured into a mixture of ice water was added hydrochloric acid and the mixture was filtered at a pH of about 9 to separate insoluble materials. The filtrate is then brought to a pH of about 7 using hydrochloric acid, and the crystals were again separated. These crystals were collected by filtration, to obtain 210 mg 6-/benzimidazole-1-yl/-7-nitrogenation-2,3-/1H, 4H/-Dion.

Physis /FAB/: 324 /M++ 1/. Temperature of melting point > 300oC /KOHaq-HClaq/.

Elemental analysis (for C15H9N5O4H2O): Calculated: C, 52,79, H, 3,25, N, To 20.52% Found: C, 52,20, H, 3,37, N, 20,12%

Example 8

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In 5 ml of DMF was dissolved 0.5 g of 7-fluoro-1-hydroxy-6-nitrophenoxy-2,3-/1H, 4H/-Dion and 0.7 g of imidazole and the mixture was stirred while heating to 120oC for 1.5 h, After cooling to room temperature the reaction mixture was diluted with water and the pH was provided at the level of 6 by adding 1 N hydrochloric acid. The resulting crystals were isolated by filtration, washed with water and ethanol to obtain 0.33 g of solid material. This solid was subjected to recrystallization from DMF and the resulting crystals were washed with ethanol to obtain 0.12 g (20% ) of 1-hydroxy-7-imidazolyl-6-nitrophenoxy-2,3-/1H, 4H/- Dion.

Physico-chemical properties:

NMR /DMCO-d6; TMC/: 3,5 /1H/, 7,10 /singlet, 1H/, 7,42 /singlet, 1H/, 7,45 /singlet, 1H/, to $ 7.91 /singlet, 1H/, 7,97 /singlet, 1H/, 12,5 /1H/.

MS /FAB/: 290 /M++ 1/. The melting point 235oC /Razlog./ /DMF/.

Elemental analysis (for C11H7N5O50,5 DMF,5 H2O): Calculated: C, 44,85, H, Of 3.46, N, 23,01. N the 10 ml of ethanol was added 0.05 g of 10% palladium on carbon and the hydrogenation was carried out at room temperature and atmospheric pressure for 30 minutes The reaction mixture is then filtered, and the filtrate was concentrated. To the residue was added 0.17 g of oxalic acid and 15 ml of 4N hydrochloric acid and the mixture was subjected to reflux distilled within 5 hours After self cooling, the resulting crystals were isolated by filtration and washed with a small amount of water. Then the crystals were dried under reduced pressure to obtain 0.14 g of the hydrate of the hydrochloride of 6-/1-imidazolyl/-7-cryptometrics-2,3-/1H, 4H/-Dion.

Physico-chemical properties:

NMR /DMCO d6; TMC/: 7,49 /singlet, 1H/, 7,69 /singlet, 1H/, 7,86 /singlet, 1H/, 8,00 /singlet, 1H/, 9,43 /singlet, 1H/, 12,4 /singlet, 1H/, 12,60 /singlet, 1H/.

MS /FAB/: 297 /M++ 1/. The melting point > 300oC.

Elemental analysis (for C12H7N4O3F3H2O): Calculated: C, 41,10, H, 2,87, N, 15,98, F, 16,25, Cl, 10,11. Found: C, 41,14, H, 2,95, N, 15,96, F, 16,22, Cl, 10,28%

Example 10

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In 30 ml of ethanol was dissolved 0.27 g of 4-amino-2-/1-imidazolyl/-5-nitroacetophenone, then added 0.27 g of Nickel the struggle of renée and the hydrogenation was carried out at room temperature and atmospheric pressure for 30 minutes, the Reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. if within 5 hours The reaction mixture was allowed to cool and the resulting crystals were removed by filtration. The crystals were washed with a small amount of hydrochloric acid and dried under reduced pressure to obtain 0.08 g (23%) 1.5 hydrate of the hydrochloride of 6-acetyl-7-/1-imidazolyl/cinoxacin-2,3-/1H, 4H/-Dion.

Physico-chemical properties:

NMR (DMCO-d6; TMC): 2,45 /singlet, 3H/, 7,34 /singlet, 1H/ 7,84-7,92 /multiplet, 3H/, 9,39 /triplet, 1H/, 12,34 /singlet, 1H/, 12,56 /singlet, 1H/.

MS /FAB/: 271 /M++ 1/. The temperature of the melting point: 285oC /Razlog./

Elemental analysis (for C13H10N4O3HCl 1,70 H2): Calculated: C, 46, 29, H, 4,30, N, 16,52, Cl, 10,69.

Example 11

< / BR>
In 20 ml of 1N hydrochloric acid was added 1.6 g of 4-amino-2-/1-imidazolyl/-5-nitrobenzonitrile, then added 0.2 g of 10% palladium on carbon and the hydrogenation was carried out under these conditions. The reaction mixture was filtered and concentrated under reduced pressure. To the residue was added 20 ml of 4N hydrochloric acid and 0.9 g of oxalic acid and the mixture was delegirovali 4 h Then the reaction mixture was allowed to cool to room temperature and the resulting crystals from the g of the hydrochloride of 6-/1-imidazolyl/-7-cyanogenesis-2,3-dione.

Physico-chemical properties:

NMR /DMCO d6; TMC/: 7,52 /singlet, 1H/, 7,73 /single, 1H/, of 7.90 /singlet, 1H/, 8,14 /singlet, 1H/, 9,54 /singlet, 1H/, 12,48 /singlet, 1H/, 12,69 /singlet, 1H/.

MS /FAB/: 254 /M++ 1/. The melting point > 300oC /4N HCl/.

Elemental analysis (for C12H7N5O21HCl): Calculated: C, 49,76, H, 2,78, N, 24,18, Cl, 12,24% Found: C, 49,40, H, 2,85, N, 23,95, Cl, 12,32.

Example 12

< / BR>
In a mixture of 10 ml ethanol and 1 ml of concentrated hydrochloric acid was dissolved to 0.60 g of 4-[1-/4-methylimidazole]-2-nitro-5-triptorelin, which was synthesized from 4-fluoro-2-nitro-5-triftoratsetilatsetonom and 4-methylimidazole using the procedure described in example 4 links. To this solution was added 0.06 g of 10% palladium on carbon and the hydrogenation was carried out at room temperature and atmospheric pressure for 3 h Then the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added 0.20 g of oxalic acid and 12 ml of 4N hydrochloric acid, and the mixture was subjected to reflux distilled 6 hours After spontaneous cooling, the resulting crystals were isolated by filtration, washed with a small amount CHLOROTHALONIL/]-7-cryptometrics-2,3-/1H, 4H/-Dion.

Physico-chemical properties:

NMR /DMCO-d6; from TMS/: 2,37 /singlet, 3H/, 7,51 /singlet, 1H/, 1.74 /singlet, 2H/, 9,42 /singlet, 1H/, 12,49 /singlet, 1H/.

MS /FAB/: 311 /M++ 1/. The melting point > 300oC.

Elemental analysis (for C13H9N4O2F32,1 H2O): Calculated: C, 40,61, H, 3,72, N, Of 14.57, F, 14,82, Cl, Which 9.22% Found: C, 40,60, H, 3,42, N, 14,51, F, accounted for 14.45, Cl, 9,60%

Example 13

< / BR>
In 5 ml of sulfolane was dissolved 0.5 g of 6-fluoro-7-nitrogenation-2,3-/1H, 4H/-Dion and 0.65 g of triazole sodium and the mixture is stirred at a temperature of 180oC 2 h Then the reaction mixture was diluted with ice-water and neutralized with hydrochloric acid. The resulting crystals were removed by filtration, washed with water and then with alcohol to obtain 470 mg of 6-nitro-7-/1,2,4-triazole-1-yl/cinoxacin-2,3-/1H, 4H/-Dion.

Physico-chemical properties:

NMR /DMCO-d6; TMC/: 7,30 /singlet, 1H/, 7,88 /singlet, 1H/ 8,24 /singlet, 1H/, 9,02 /singlet, 1H/, 12,40/2N/.

MS /FAB/: 275 /M++ 1/. The temperature of the melting point: > 300oC.

Elemental analysis (for C10H6N6O40.5 H2O): Calculated: C, 42,41, H, 2,49, N, 29,68% Found: C, 42,85, H, 2,50, N, 29,74%

Example 14

< / BR>
And the solution was subjected to reflux distilled during the night. After cooling to room temperature, the resulting crystals were isolated by filtration and was dissolved in sulfuric acid. The solution was poured into a mixture of ice-water, when it again appeared crystals. These crystals were isolated by filtration and dried to obtain 0.65 g of 6-imidazolidinedione-2,3-/1H, 4H/-Dion polysulfate monohydrate.

Physico-chemical properties:

NMR /DMCO-d6; TMC/: 7,22 of 7.36 /2N/, 7,42 /doublet, 1H/, 7,52 /singlet, 1H/, of 7.90 /singlet, 1H/, 8.90 /singlet, 1H/.

MS /E1/: 228 /M+/. The melting point 300oC > /H2SO4H2O/.

Elemental analysis (for C11H6N4O21/2H2SOH2O): Calculated: C, 44, 75, H, 3,76, N, 18,98, S, 5,43% Found: C, 44,85, H Of 3.77, N, 19,07, S, 5,38.

Example 15

< / BR>
In 5 ml of sulfuric acid was dissolved 0.5 g of the hydrochloride of 6-imidazolidinedione-2,3-/1H, 4H/-dione, and then was added 0.21 g of potassium nitrate, and the resulting mixture was heated to 70oC for 5 min After spontaneous cooling to room temperature the reaction mixture was poured into a mixture of ice-water and the pH was provided at the level of 4-5 aqueous solution of hydrate of sodium oxide, when it again fell crystals. These crystals were separated by filtration, and then, for example,/P> Physico-chemical properties:

NMR /DMCO-d6; TMC/: 7,28 /singlet, 1H/, 7,50 /singlet, 1H/, 7,82 /singlet, 1H/, 8,02 /singlet, 1H/, 8,68 /singlet/.

MS /E1/: 272 /M++ 1/. The melting point > 300oC /-DMF H2O/.

Elemental analysis (for C11H7N5O4): Calculated: C, 48,36, H, 2,58, N, 25,63% Found: C, 48,36, N, 2,68, N, 25,66.

Example 16-1

< / BR>
A mixture of 4.2 g of 4-/1-imidazolyl/-2-p-Propylenediamine, 0.8 g of 10% palladium on carbon and 60 ml of 1N hydrochloric acid was subjected to the hydrogenation reaction. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added 20 ml of 4N hydrochloric acid and 3 g of oxalic acid and the mixture was delegirovali 5 hours After spontaneous cooling to room temperature, the resulting crystals were removed by filtration and subjected to recrystallization at 4 hydrochloric acid to obtain 3 g of the hydrochloride of 7-/1-imidazolyl/-1-p-propylenoxide-2,3-/1H, 4H/-Dion, I. pl. > 300oC.

Elementary analysis (for C14H14N4O2HCl0,8H2O). Calculated: 52,36, N To 5.21, N 17,45, Cl 11,04). Found: 52,71, N 5,71, N 17,55, Cl 11,23, MC 271 (M++1) NMR: 0,96; is Edery (examples 16-2 16-12).

16-2: the Hydrate of the hydrochloride of 1-oxyethyl-7-/1-imidazolyl/ cinoxacin-2,3-/1H, 4H/-Dion, I. pl. > 300o.

Elemental analysis (for C14H14NO2NO2HCl0,8H2O). Calculated: 47,79, N 4,63, N 17,15, Cl 10,85. Found: Of 47.55, N 4,69, N 17,15, Cl of 11.15% 273 MS (M++1), NMR: 3,70; 4,31; 7,38; 7,59; 8,35; 9,86; 12,33.

16-3: 2.5 hydrate hydrochloride 7-/1-imidazolyl/-1-/N-morpholino/utilisation-2,3-/1H, 4H/-Dion, I. pl. 240-241oC,

Elemental analysis (for C14H14N4O2HCl0,8H2O). Calculated: 44,45 H 5,71 N 15,25, Cl 15,44. Found: 55,67 5,09 14,98, 15,11. MS 342 (M++1), NMR: 3,48; 3,92; 4,67; 7,43; 7,67; 7,91; 8,06; 8,45; 9,97; 12,37;

16-4: Hydrate hydrochloride 7-/1-imidazolyl/-1-/tetrahydrofuranyl/-methylpenicillin-2,3-/1H, 4H/-Dion, I. pl. 300oC.

Elemental analysis (for C14H14N4O2HClO.8Y2O): Calculated: 52,39; N 5,22; N 15,27, C l9,67; Found: 52,07; N 5,33; N,15,23; C,l9,85. MS 313 (M++1), NMR: 1,86; 3,66; 4,33; 7,43; 7,61; 7,93; 8,32; 9,84; 12,45.

16-5: 1,5-hydrate of the hydrochloride of 1-decyl-7-/1-imidazolyl/ cinoxacin-2,3-/1H, 4H/-Dion, I. pl. 183-186oC.

Elemental analysis (C14H14N4O2HCl0,8H2O). Calculated: 58,39; N 7,47; N 12,97; C 18,21; Found: 58,71; N 7,00; N 13,08; Cl 8,29. MC 369 (M++1), NMR: 0,84; 1,23; 1,64; 4,19; 7,41; 7,61; 7,76; 7,93; 8,31; 9,81; 12,37.

Elemental analysis (C15H17N5O2). Calculated: 45,12; N. Of 5.55; N Comprised 17.54; Cl 17,76; Found: 45,30, N 5,35; N 17,63; Cl 17,60. MC 300 (M++1). NMR: 2,90; 3,45; 4,64; 7,46; 7,65; 7,94; 8,05; 8,48; 10,03; 10,85; 12,43.

16-7: dihydrate cordigera 1-/2-aminocyclohexanol/-7-/1-imidazolyl/ cinoxacin-2,3-/1H, 4H/-Dion, I. pl. 284oC.

Elemental analysis (C17H19N5O22HCl2H2O); Calculated: 47.01; N, 5.80; N, 16.12; Cl 16.33; Found: C, 47.05; H, 5.59; N, 15.77; Cl 14.52. MC 326 (M++1). NMR: 1.3-2.5 (8H); 4.28 (1H); 4.72 (1H); 7.39 (g, 1H); 7.58 (g, 1H); 7.93 (1H); 8.14 (1 H), 8.56 (1H), 10.15 (1H); 12.30 (s, 1H)

16-8: the trihydrate of cordigera 7-/1-imidazolyl/-1-/2,2, 6,6-tetramethylpiperidine-4-yl/cinoxacin-2,3-/1H, 4H/-Dion, I. pl. > 300oC.

Elemental analysis (C20H25N5O22HCl3H2O). Calculated: C, 48.59; H, 6.73; N, 14.16; Cl 14.34; Found: 48.29; 7.01; 14.20; 14.18 MS 368(M++1), NMR 1.53-1.58 (M); 1.85 (2H):2.94 (2H); 4.65 (1H); 7.42 (1H); 7.58 (1H); 7.90 (1H); 8.29 (1H); 9.5:(1H):9.84(1H):12.35(1H)

16.9: hydrochloride 7-/1-imidazolyl/-1-methylpenicillin-2,3-/1H, 4H/-Dion, I. pl. > 3000oC.

Elemental analysis (C12H10N4O2HCl). Calculated: 51.72 N 3.98 N 20.10 Cl 12/72. Found: at 51.47 4.03 20.03 12.87 MS 243 (M++1), NMR: 3.58 (S, 3H); 7.34 (g, 1H); 7.59 (g, 1H); 7.76 (c, 1H); 7.98 (c, 1H); 8.29 (c, 1H); 9.64 (c, 1H); 12.26 (c, 1H).

16-10: hydrate hydrochloride 7SUB>H18N4O2HClO.7H2). Calculated: 56.81; M 5.72; N, 15.59; Cl 9.86; Found: C, 56.71; H, 5.54; N, 15.60; Cl 10.01, MC 311 (M++1). NMR: 1.77(m, 8H); 2.49 (m, 2H); 4.50 (m, 1H); 7.39 (g, 1H); 7.56 (gg, 1H); 7.90 (g, 1H); 7.92 (c, 1H); 8.28 (c, 1H); 9.81 (c, 1H); 12.31 (c, 1H).

16-11: 1.5 hydrate of the hydrochloride of 7-/1-imidazolyl/-1-cyclohexylmethoxy-2,3-/1H, 4H/-Dion, I. pl. > 300oC.

Elemental analysis (C18H20N4O2HCl1,5H2O). MS 325, NMR: 1.06-1.14 (m, 5H); 1.59-1.86, 4.10 (g, 2H); 7.39 (g, 1H); 7.57 (g, 1H); 7.75 (g, 1H); 7.92 (c, 1H); 12.34 (c, 1H).

16-12: 1,5-hydrate hydrochloride 7-/1-imidazolyl/- 1-isopenicillin-2,3-/1H-4H/-Dion.

Example 17

< / BR>
In a solution of 1 g of the hydrochloride of 7-/1-imidazolyl/-1-p-propylenoxide-2,3-/1H, 4H/-dione in 8 ml of sulfuric acid was added 0.4 g of potassium nitrate, and the mixture was stirred over night. The reaction mixture was poured into a mixture of ice-water and the pH was regulated at level 7. The resulting crystals were subjected to recrystallization from 1N hydrochloric acid, to obtain 0.9 hydrochloride 7-/1-imidazolyl/-6-nitro-1-p-propylenoxide-2,3-/1H, 4H/-Dion, I. pl. > 300oC, Elemental analysis (C14H13N5O4HCl): C 47,81, H 4,01, N Of 19.91, Cl 10,08. Found: 47,54, H 4,15 N 19,78, There Is A 10.03 Cl. MS 316 (M+1), NMR: 0.93, 1.67, 4.07, 7.92; 8.00; 8.06; 8.30; 9.57; 12.80.

oC.

Elemental analysis (C13H11N5O5.H2O): 46,57, H 3,91, N 20,89. Found: 45,74, H 3,53, N Vs. 20.62. MC 318 (M++1), NMR: 3.72; 4.39; 4.89; 7.15; 7.91; 8.02; 8.17; 8.41; 11.45.

17-3: Hydrate-7-/-imidazolyl/-1-/N - morpholino/ethyl-6-nitro-cinoxacin-2,3-/1H, 4H/-Dion, I. pl. 193-198oC.

Elemental analysis (C17H18N6O5H2O): 50,49, H 4,99, N 0,78. Found: 50,94, H 4,79, N 20,96. MS 387 (M++1). NMR: 2.44-2.50; 3.46; 4.28; 7.10; 7.45; 7.67; 7.94; 12.39.

17-4: Dehydrate 7-/1-imidazolyl/-1-/N-morpholino/ethyl-5-nitrophenoxy-2,3-/1H, 4H/-Dion, I. pl. 247-249oC.

Elemental analysis (C17H18N6O52H2O): 48,34, H A 5.25, N 19,20. Found: 48,25, H Of 5.05, N 19,81. MC 387 (M++1). NMR: 2.50(6N); 3.47(4H); 4.42(2H); 7.17(1H); 7.94(2H); 8.18(1H); 8.44(1H); 11.42(2N).

17-5: Dehydrate 7-/1-imidazolyl/-6-nitro-1-/3-hinokitiol/-cinoxacin-2,3-/1H, 4H/-Dion, I. pl. > 300oC.

Elemental analysis (C18H18N6O42H2O). MC (M++1) 383. NMR: 1.35; 1.60; 1.90; 1.95; 2.80; 3.00; 4.0; 4.65; 7.10(1H); 7.35(1H); 7.46(1H); 7.94(2H)

17-6: Hydrochloride of 1-decyl-7-/1-imidazolyl/-6-nitrophenoxy-2,3-/1H, 4H/Dion, I. pl. 188-192oC.

Elemental analysis (C21H27N4O4HCl). MC 414(M++1). NMR: 0.85(T, 3H)); 1.23; 1.61(16�6- nitrogenation-2,3-/1H, 4H/-Dion, I. pl. 284-287oC.

Elemental analysis (C15H16N4O42HCl) MC 345 (M++1) NMR: 2.88 (s, 3H), 3.40(2H); 4.54(2H); 7.74(1H); 7.98(1H); 8.05(1H); 8.11(1H); 9.28(1H); 12.56(1H);

17-8: 1 isopropyl alcohol hydrochloride of 1-/2-aminocyclohexanol/7-/1-imidazolyl/-6-nitrophenoxy-2,3-/1H, 4H/-Dion, I. pl. 252oC.

Elemental analysis (C17H18N6O4HCl (isopro). MS 371 (M++1). NMR: 1.02(6N); 1.33-2.34; 3.77(1H); 4.19; 4.64; 4.84; 7.89; 7,92; 8.09-8.63; 9.82; 10.18; 12.59.

17-9: 7-/1-imidazolyl/-6-nitro-1-/2,2,6,6-tetramethylpiperidine-4-yl/cinoxacin-2,3-/1H, 4H)-dione, T. pl. > 300oC.

Elemental analysis (C20H24N6O42HCl1,5H2O). Calculated: C, 46.88, H 5.70, N 16.40, Cl 13.84. Found: 46.70, H 5.76, N 16.19, Cl 13.73 NMR: 1.4-1.9(14N); 2.94(2H); 7.84(1H); 8.30(1H); 9.56(1H); 12.70(1H); p.

17-10: Hydrate sulfate 7-/1-imidazolyl/-6-nitro-1-cyclohexylaniline-2,3-/1H, 4H/-Dion, I. pl. > 300oC

Elemental analysis (C17H17N5O4H2SO40. 7H2O). Calculated: C 43.81, H 4.41, N 15.03, S 6,88. Found: C, 43.89, H 4.44, N 15.27, S 6.55 MS 356 (M++1). NMR: 1.49-2.49; 4.50; 7.39; 7.56; 7.90; 7.92; 8.28; 9.81; 12.31;

17-11: the Dihydrate of sodium 7-/1-imidazolyl/6-nitro-1-methylpenicillin-2,3-/1H, 4H/-Dion, I. pl. > 300oC.

Elemental analysis (C12H18

Elemental analysis (C18H11N5O20,8 H2O): Calculated: 62.90, H 3.69, N 20.37. Found: At 63.01, H 3.48, N 20.22. MS 330(M++1). NMR: 6.33; 7.06; 7.4-7.65; 7.89; 12.45.

The following compounds were synthesized using a similar procedure.

Hydrate 6-cyano-7-/1-imidazolyl/-1-/2-carboxyethyl/-cinoxacin-2,3-/1H, 4H/-Dion, I. pl. > 300oC.

Elemental analysis (C15H11N5O4H2O. Calculated: 52.48, H 3.82, N 20.40. Found: 52.80, H 4.12, N 19.84. MS 326 (M++1). NMR: 2.61; 4.34; 7.17-8.10.

The dihydrate hydrochloride of 6-cyano-7-/1-imidazolyl/-1-/2,2,2-triptorelin/-cinoxacin-2,3-/1H, 4H/-Dion, I. pl. 208-212oC8, F 13.98, Cl 8.70. Found: 41.88, H 4.69, N 16.38, F 12.42, Cl 9.13. MS 336(M++1). NMR: 5.14; 7.91; 7.99; 8.19; 8.23; 9.63; 12.87.

Example 19

< / BR>
A mixture of 2.5 g of cordigera 3,5-di-/1-imidazolyl/-2-nitroaniline, 300 mg of 10% palladium on carbon and 25 ml of 1N hydrochloric acid was subjected to the hydrogenation reaction. Then the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added 15 ml of 4N hydrochloric acid and 900 mg of oxalic acid and the mixture was subjected to delegirovano under stirring for 10 hours Then the reaction mixture was concentrated under reduced pressure, was dissolved in water and neutralized by the hydroxide of sodium. The resulting crystals were washed with ethanol-water to obtain 870 mg of 5,7-di- /1-imidazolyl/cinoxacin-2,3-/1H, 4H/-Dion.

Example 20

< / BR>
In 3 ml of concentrated sulfuric acid was dissolved 290 mg hydrate 5,7-di-/1-imidazolyl/cinoxacin-2,3-/1H, 4H/-Dion, then added 220 mg of potassium nitrate under ice cooling. After cooling to room temperature the reaction mixture is then stirred at a temperature of 80oC for 30 minutes After cooling to room temperature the reaction mixture was poured into a mixture of ice-water and the pH REIA and washed with water, to obtain 124 mg of 5,7-di-/1-imidazolyl/ -6-nitrophenoxy-2,3-/1H, 4H/-Dion.

Example 21

< / BR>
In a mixture of 2 ml of methanol and 1 ml of 1N hydrochloric acid was dissolved 0.16 g 4-/1-imidazolyl/-3-methyl-6-nitroaniline and the solution was subjected to a hydrogenation reaction in the presence of 16 mg of 10% Pd-C at room temperature and atmospheric pressure for 3 hours, the Reaction mixture was filtered, and the filtrate was concentrated. To the residue was added 46 mg of oxalic acid and 9 ml of 4N hydrochloric acid, and the mixture was subjected to delegirovano during the night. After self cooling the reaction mixture to room temperature, the resulting crystals were removed by means of filtration and subjected recrystallization of a mixture of water-DMF) to obtain 25 mg of the hydrochloride of 6-/1-imidazolyl/-7-methylpenicillin-2,3-/1H, 4H/-Dion.

Example 22-1. In 40 ml of 4N hydrochloric acid was added 2 g 5-/1-imidazolyl/-3-/N-morpholino/-2-nitrobenzylamine and the mixture was heated 1 h, and the reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in 20 ml of 1N hydrochloric acid was then added 1 g of 10% palladium on carbon and carried out the hydrogenation. The reaction Ti and the mixture was dissolved in 12 ml of 4N hydrochloric acid. The reaction mixture was subjected to reflux distilled for 5 h, after which the mixture was allowed to cool to room temperature and the resulting crystals were isolated by means of filtration, to obtain 1.7 g, 1.5 hydrate of the hydrochloride of 7-/1-imidazolyl/-5-/N-morpholino/cinoxacin-2,3-/1H, 4H/-Dion.

Example 22-2

In a mixture of 15 ml of acetic anhydride and 3 ml of acetic acid and 2 ml of sulfuric acid was dissolved 1.5 g of 7-/1-imidazolyl/-5-/N-morpholino/cinoxacin-2,3-/1H, 4H/-Dion, then added 0.33 ml fuming nitric acid at a temperature not exceeding 10oC. the Mixture was stirred at room temperature for 1 h, after which it was concentrated. The concentrate was diluted with ice-water and the pH was adjusted to 7 using alkaline solution. The mixture was then purified using a resin HP-20, to obtain 600 mg of hydrate 6-/1-imidazolyl/-8-/N-morpholino/5-nitrophenoxy-2,3-/1H, 4H/-Dion.

Example for reference 9. In a mixture of 6.2 g of 2-amoxicilline-4-peritrabecular and 124 ml of DMF solution was added 5,64 g of ammonium chloride in 40 ml of water. Then in small portions was added 5.7 g of zinc dust. The reaction mixture was stirred circuit monitoring via (5% methanol-chloroform) and when the source material has disappeared, the mixture was filter and the resulting crystals of the inorganic salt was separated by filtration. The organic layer was added methanol and the resulting crystals were isolated by filtration, to obtain 2,73 g of 6-fluoro-1-hydroxy-cinoxacin-2,3-/1H, 4H/-Dion.

Example for reference 10. In 22 ml of sulfuric acid was dissolved 1.6 g of 6-fluoro-1-hydroxy-cinoxacin-2,3-/1H, 4H/-Dion, then added 0.9 g KNO3. The mixture was interacted at room temperature for 3 h, after which it was poured into a mixture of ice-water. The resulting crystals were isolated by filtration, to obtain 310 mg of 6-fluoro-1-hydroxy-7-nitrogenation-2,3-/1H, 4H/-Dion.

Example 23. A mixture of 1 g of cordigera 4,5-di/1-imidazolyl/-2-nitroaniline, 5 ml acetic acid, 5 ml of methanol and 0.1 g of 10% palladium on carbon was subjected to the hydrogenation reaction. The reaction mixture was filtered, and the filtrate was washed with hydrochloric acid and concentrated under reduced pressure. The concentrate was dissolved in 350 ml of oxalic acid 6 ml of 4N hydrochloric acid and the solution was subjected to dry distillation during the night. The resulting crystals were isolated by filtration and subjected to recrystallization from a 4N solution of hydrochloric acid, to obtain 170 mg of the dihydrate of cordigera 6,7-di/1-imidazolyl-2,3-/1H, 4H/-Dion.

Example 24. A mixture of 1.3 g histopathology acid was subjected to the hydrogenation reaction. The reaction mixture was filtered and washed with hydrochloric acid ethanol. The filtrate was concentrated under reduced pressure, the concentrate was dissolved in 1 g of oxalic acid in 20 ml of 4N hydrochloric acid and the mixture was subjected to delegirovano within 3 hours the resulting crystals were removed by filtration and subjected to recrystallization from 1N hydrochloric acid, to obtain 900 mg of the hydrate of the hydrochloride of 6-fluoro-7-/1-imidazolyl/cinoxacin-2,3-/1H, 4H/-Dion.

Example 25. A mixture of 370 mg of 6-fluoro-1-hydroxy-7-nitrogenation-2,3-/1H, 4H/-Dion, 320 mg of imidazole and 37 ml of DMF was stirred at a temperature of 100oC for 4 h the Reaction mixture was concentrated, and then diluted with water. The aqueous layer was neutralized with hydrochloric acid and the resulting crystals were isolated by filtration and washed with water to obtain 214 mg 1/2 hydrate of 1-hydroxy-6-/1-imidazolyl/-7-nitrogenation-2,3-/1H, 4H/-Dion.

Example 26. In 10 ml of 1N hydrochloric acid was dissolved 0.5 g 4-/1-imidazolyl/-2-nitro-5-trifluoromethyl-N-propylaniline, then added 50 ml of 10% palladium on carbon and carried out the hydrogenation reaction. The reaction mixture was filtered and the filtrate was washed veritosalgado acid, and then the solution was delegirovali. The resulting crystals were separated by filtration, and wrap the solution was neutralized 1N solution in water of hydrate of sodium oxide. The resulting crystals were isolated by filtration, to obtain 110 mg of hydrate 6-/1-imidazolyl/-1-propyl-7-cryptometrics-2,3-/1H, 4H/-Dion.

Example 27. Repeating the same procedure as in example 3, except that used 4-phenylimidazol instead of 2-methyl-imidazole. The result obtained 270 mg hydrate 6-nitro-7-/4-phenylimidazol-1-yl/cinoxacin-2,3-/1H, 4H/-Dion.

Example 28. Repeating the procedure of example 3, except that 4-nitroimidazol used instead of 2-methylimidazole. As a result received 100 mg of 6-nitro-7-/4-nitroimidazol-1-yl/cinoxacin-2,3-/1H, 4H/-Dion.

Example 29

< / BR>
A mixed solution of 7-fluoro-1-hydroxy-6-nitro-2,3-(1H, 4H)-khinoksalinona (1.0 g, 41 mol), 2-methylimidazole (1,7 g) and DMF (5 ml) was stirred at 120oC for 2 h the Reaction solution was concentrated, and was added water. The obtained crystals were filtered and recrystallized from 1N hydrochloric acid to obtain 1-hydroxy-7-(1H-2-Mei-1-yl)-6-nitro-2,3-(1H, 4H)-chynoxalinilmethylen (- d6; from TMS): the 2.46 (3H, s), to 7.77 (1H, s), 7,81(1H, s), 8,01 (1H, s), 8.26 (1H, s), 12,36 (1H, s), 12,81(1H, s), about 15.2 (1H, scrap.S.).

Example 30

< / BR>
The same procedure as in example 29 was carried out, except that instead of 2-methylimidazole was used 2-ethylimidazole. The result was obtained 1-hydroxy-7-(1H-2-ethylimidazole-1-yl)-6-nitro-2,3-(1H, 4H)-chynoxalinilmethylen.

Physico-chemical properties:

MS (m/z): 318 (M+1). So pl. 235oC (decomposition). NMR (DMCO-d6; from TMS): to 1.19 (3H, t) 2,84 (2H, HF), 7,81 (1H, s), 7,83(1H, s) 8.03 (1H, s), of 8.28 (1H, s), about 12.4 (1H, s), 12,86 (1H, s), about 15,3 (1H, scrap.S.).

Example 31

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The same procedure as in example 29 was repeated, except that instead of 2-methylimidazole was used 2-propylimidazol. The result was obtained 1-hydroxy-7-(1H-2-propylimidazol-1-yl)-6-nitro-2,3-(1H, 4H)-chynoxalinilmethylen, physico-chemical properties:

MS (m/z): 332 (M+1). So pl. 235oC (decomposition). NMR (DMCO - d6): from TMS): or 0.83 (3H, t), of 1.62 (2H, m), was 2.76 (2H, m), 7,80 (1H, s), to 7.84(1H, s), 8.03 (1H, s), of 8.28 (1H, s), 12,37 (1H, s), 12,86 (1H, s).

Example 32

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The procedure of example 29 was repeated, except that instead of 2-methylimidazole was used 4-Mei. The result was poluchila:

MS (m/z): 304 (M+1). So pl. > 300oC. NMR DMCO d6; from TMS): is 2.37(3H, s), 76 (1H, s), 7,89(1H, s), of 8.25 (1H, s), 9,40 (1H, s); KZT 12.39 (1H, s), is 12.85(1H, s)

Example 33

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To a solution of 1.2 g of N-ethoxalyl-4-(1H-imidazol-1-yl)-2-nitro-5-triptoreline in 18 ml DMCO was added 0.12 g of 5% iridium-carbon with subsequent hydrogenation reaction at normal temperatures and pressure. The reaction mixture was then filtered, and the filtrate was concentrated. The obtained crystals were recrystallized from 1N-hydrochloric acid to obtain 820 mg (69%) of 7-(1H-imidazol-1-yl)-1-hydroxy-6-trifluoromethyl-2,3-(1H, 4H)-chynoxalinilmethylen.

Physico-chemical properties:

MS (m/z): 313 (M+1). So pl. 256-262oC (decomposition). NMR (DMCO - d6from TMS): 7,86(1H, s), to $ 7.91 (1H, s), to 7.99 (1H, s), of 8.04 (1H, s), of 9.56 ( 1H, s), about to 12.2 (1H, scrap. C.), 12,84 (1H, s).

Example 34

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The procedure of example 33 was repeated, except that there was used N-ethoxalyl-4-(1H-4-Mei-1-yl)-2-nitro-5-cryptomelane. The result was obtained 7-(1H-4-Mei-1-yl)-1-hydroxy-6-trifluoromethyl-2,3-(1H, 4H)-chynoxalinilmethylen.

Physical properties:

MS (M/z): 327 M + 1). So pl. 280-285oC (decomposition). NMR (DMCO - d6; from TMS): is 2.37 (3H, s), 7,74 (1UP>C.

In each ampoule:

The compound from example 32 50 mg (0.5%)

Citric acid 210 mg (2.1 per cent)

D-mannitol 100 mg (1.0%) of 10 ml

In 800 ml of water were successively dissolved 5 g of the compound of example 32, 21 g of citric acid and 10 g of D-mannitol, followed by the addition of water to 1000 ml. The solution was aseptically filtered the filtrate, 10 ml were filled vials amber color, after which the filtrate in the vials were dried at a temperature below 0oC obtaining injectable, which is moistened again before using.

Example 36. Dried by freezing exposure

Each bubble:

The compound from example 15 or 9 of 50 mg (0.5%)

Citric acid 210 mg (2.1 per cent)

D-mannitol 100 mg (1.0%) of 10 ml

In 800 ml of water successively dissolved 5 g of the compound from example 15 or 9, 21 g of citric acid and 10 g of D-mannitol, then add sufficient water to make 1000 ml. This solution was filtered under sterile conditions and the filtrate was filled with 10 ml portions bubbles amber color and was dried by freezing to get injectisome spooling, which is ready for use.

1. Derived the condensed pyrazine General the s

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R1-

< / BR>
where X is nitrogen or carbon, substituted R8;

R6hydrogen or lower alkyl group;

R7and R8the same or different and each is hydrogen, lower alkyl, nitro or phenyl, and if one of them has a value other than hydrogen, the other is hydrogen, or R7and R8taken together, butadienyl (-CH=CH-CH=CH-or 1,4-butylene(-CH2-CH2-CH2-CH2-);

R2and R3that may be as identical and denote hydrogen or different and each is hydrogen, fluorine, cyano, lower acyl, nitro, unsubstituted or fluoro-substituted lower alkyl, morpholino or one of the mentioned values of R1;

R4and R5the same or different and each is hydrogen, hydroxyl, C1WITH10linear or branched alkyl, C5WITH8-cycloalkyl, which may be substituted amino, nitrogen-containing 5 - or 6-membered heterocyclic group which may be substituted by lower alkyl and may be connected to bridge communication using a 1-3 methylene groups, phenyl or Y-substituted C1C6-linear or branched alkyl;

Y is hydroxyl(lower)alloctype, fluoro-substituted methyl,5UP>0the same or different and each is hydrogen or lower alkyl, or alternatively, R9and R10together represent a 5 - or 6-membered cyclic group that may contain oxygen,

moreover, if one of R4and R5has a value other than hydrogen, and the other denotes hydrogen,

or its salt.

2. Connection on p. 1, wherein R4Y-substituted straight line WITH the1WITH6-alkyl, Y carboxyl.

Priority signs:

06.11.90 with A benzene ring,

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when R4and R5the hydrogen.

11.01.91 when A pyridine cycle formula

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R7and R8taken together, butadienyl.

29.03.91 when R2or R3hydrogen, CF3, CN, lower acyl or nitro, R4or R5hydrogen or hydroxyl, R6is hydrogen or a lower alkyl group,

27.06.91 when X is nitrogen or carbon, substituted R8.

 

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