1,2,3,4-tetrahydroquinoxaline derivatives and pharmaceutical composition

 

(57) Abstract:

Describes new derivatives of 1,2,3-tetrahydroquinoxaline formula I, where the values A, R, R1, R2X specified in paragraph (1 formulas, which have an antagonistic effect against glutamate receptor, a high degree of affinity for AMPA receptors, non-NMDA receptors, a strong inhibitory effect against neurotoxicity caused by kainic acid, inhibiting audiogenic attack action and a high degree of solubility. Also described pharmaceutical composition based on compounds of the formula I. 2 C. and 6 C.p. f-crystals, 7 PL.

The invention relates to khinoksalinona derivative or its salt, which has an antagonistic effect against glutamate receptor; a high degree of affinity for AMPA receptors, non-NMDA receptors; strong inhibitory effect against neurotoxicity caused by kainic acid; inhibiting audiogenic attack action; and a high degree of solubility. The present invention also relates to the agent, the inhibitory neurotoxicity caused by the action of kainic acid, and codesee the invention relates to pharmaceutical compositions, containing khinoksalinona derivative or its salt and a pharmaceutically acceptable carrier.

Background of the invention

It is known that amino acids such as L-glutamic acid and L-aspartic acid are neurotransmitters (neurotransmitters) of the Central nervous system. In other words, the extracellular accumulation of these excitatory amino acids and their continuous and excessive stimulating effect on the nervous tissue leads to such diseases as Huntington's chorea, Parkinson's disease, Alzheimer's disease, senile dementia, neurodegeneration, or lack of mental and motor functions, phenomena observed after cerebral ischemia, hypoxia or hypoglycemia.

In line with this it was concluded that the regulator abnormal activity of these excitatory amino acids can be used for therapeutic treatment of degeneration of the nervous tissue or mental illness.

Excitatory amino acids is mediated by glutamate receptors, which are specific postsynaptic or presynaptic receptors. Currently, on the basis of electrophysiological and Neuroptera;

2) non-NMDA receptor

a) AMPA-receptor (the receptor[2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid]),

b) receptor kainate

3) glutamate receptor metabolic steps.

The compound of the present invention is an antagonist of glutamate receptor and possesses inhibitory activity against neurotoxicity of kainic acid, and therefore it can be used as anti-ischemic or psychotropic drugs.

L-glutamic acid or L-aspartic acid activate the above glutamate receptors, and mediate the transmission of excitatory effects. Effects on neurons that have excessive amounts of NMDA, AMPA or kainic acid leads to their destruction. It was reported that 2-amino-5-vostanovlenija acid or 2-amino-7-phosphonopentanoate acid, which are selective antagonists of the NMDA receptor, are effective in experimental animal models with neuropathy, epilepsy or cerebral ischemia (J. Pharmacology and Experimental Therapeutics, 250,100 (1989); J. Pharmacology and Experimental Therapeutics, 240, 737 (1987); or Science, 226, 850 (1984)).

It was reported that NMDA receptor function is regulated allosteric picinbono receptor, possesses effective in experimental models in animals with cerebral ischemia (Annual meeting of Society for Neuroscience, 1989).

In addition, it was stated that NBQX (6-nitro-7-sulfamoylbenzoic [f] cinoxacin), which is a selective antagonist of AMPA-receptor, also has an effective action in experimental models in animals with cerebral ischemia (Science, 247,571 (1990)).

On the other hand, it was shown that all non-NMDA receptors, subjected to cloning), have affinity to kainic acid, and an assumption was made that among these receptors, the receptor with low affinity to kainic acid (AMPA/kainite-induced receptor), is responsible for the death of neurons during ischemia, for example, infarction of the brain (P. C. May & P. M. Robison, J. Neurochem., 60, 1171-1174 (1993)). This AMPA/kainite-induced receptor has high affinity for AMPA, however, the binding sites AMPA and kainic acid is still unknown. However, it was reported that AMPA and kainic acid exhibit different electrophysiological responses to AMPA/kainite-induced receptor. It was stated that in the test for neurotoxicity carried out using a culture system of nerve cells, the very kainic acid causes a significant loss of n is). In line with this, we can assume that the death of neurons caused by excessive excitatory action of glutamic acid in ischemic condition, be actively suppressed by compounds having inhibitory action against toxicity induced by kainic acid in the system of culture of nerve cells.

There are several works that describe diketone-kalinovye derivatives having antagonistic effect against NMDA - glycine receptor and/or AMPA-receptor (published unexamined Japanese patent application (Kokai) N 63-83074; published unexamined Japanese patent application (Kokai) N 63-258466; published unexamined Japanese patent application (Kokai) N 1-153680; published unexamined Japanese patent application (Kokai) N 2-48578; published unexamined Japanese patent application (Kokai) N 2-221263; published unexamined Japanese patent application (Kokai) - 2-221264; publication of international patent WO 92/07847; and publication of international patent WO 93/08173).

Description of the invention

As will be described in more detail below, the compound of the present invention has an antagonistic effect on itemuse NMDA receptor; intense inhibitory effect against neurotoxicity caused by the action of kainic acid; suppressor activity, overwhelming auditory reflex epileptic seizure; and a high degree of solubility.

In addition, the authors of the present invention conducted research related to dimethylarsinoyl derived. As a result of these studies it was found that the compound having a group: -A-COR2in the 1 - or 4-position diethyloxalate structure has highly effective pharmacological action (action, inhibiting neurotoxicity of kainic acid, an anticonvulsant effect, preventing auditory reflex epileptic seizures, or so forth), as well as a high degree of solubility, and therefore the specified connection has valuable properties, based on which we developed the present invention.

Thus, the present invention relates to 1,2, 3,4 - tetrahydroisoquinolinium derived or 1,2,3,4 - tetrahydropyrido[2,3-b]persikovomu derived the following formula (I):

< / BR>
where X is a nitrogen atom or a group of the formula CH;

R - imidazolidine group or di (NISS the group, mono - or di(lower alkyl) amino group, a lower alcoolica group, lower allylthiourea, lower alkylsulfonyl group, lower alkylsulfonyl group or carnemolla group;

(2) a lower alkyl group or lower CNS group which may be substituted by an atom (or atoms) of a halogen, a carboxyl group (or groups) or aryl group (or aryl groups);

(3) fenoxaprop, which may be substituted by lower alkoxycarbonyl group or a carboxyl group;

R2- hydroxyl group, lower CNS group, amino group or mono - or di(lower alkyl)amino group;

And the lowest Allenova group which may be substituted, or a group of formula: -O -; and

In the lowest Allenova group,

provided that excluded the case when R is imidazolidinyl group, R1represents a cyano, a represents an ethylene group, a R2is a hydroxyl group;

or tautomer of the above derivative, its salt, hydrate or MES. The present invention also relates to an antagonist of glutamate receptor, containing as an effective ingredient 1,2,3,4-tuttobene refers to the connection, which has an antagonistic effect against NMDA-glycine receptor and/or against AMPA-receptor, or activity, inhibiting Kainat-induced neurotoxicity, and which can be used as anti-ischemic or psychotropic drugs. In addition, the present invention relates to pharmaceutical compositions containing 1,2,3,4-Tetra-hydroxyoxindole derivative or its salt and a pharmaceutically acceptable carrier.

The following steps detail the connection represented by the above General formula (I).

In the above definition of the General formula (I), the term "lower", if not specified otherwise, refers to linear or branched carbon chain containing 1-6 carbon atoms.

Illustrative examples of lower alkyl groups are methyl; ethyl; propyl; isopropyl; butyl; isobutyl; sec-butyl; tert-butyl; pentyl(amyl); isopentyl; neopentyl; tert-pentyl; 1-methylbutyl; 2-methylbutyl; 1,2-dimethylpropyl; hexyl; isohexyl; 1-methylpentyl; 2-methylphenyl; 3-methylphenyl; 1,1-dimethylbutyl; 1,2-dimethylbutyl; 2,2-dimethylbutyl; 1,3-dimethylbutyl; 2,3-dimethylbutyl; 3,3-dimethylbutyl; 1-ethylbutyl; 2-ethylbutyl; 1,1,2-trimethylpropyl group, having 1-3 carbon atoms.

Used in the present description, the term "mono - or di(lower alkyl)amino group" means an amino group substituted by one or two lower alkyl groups, illustrated above. Illustrative examples of the mono(lower alkyl)amino are methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino-, second -, butylamino-, tert-butylamino, pentyl(amyl) amino-, isopentylamine, neopentylene - and tert-pentylamine; and examples of di(lower alkyl)amino group include dimethylamino, ethylmethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino and diisobutylamine. Of them, preferred are amino, methylamino, ethylamino-, dimethylamino -, and diethylaminopropyl.

Illustrative examples of the "lower alkanoyloxy groups are formyl, acetyl, propylaniline, isopropylaniline, Butyrina, isobutylene, valerina, isovaleryl, bialoleka, hexanoyl group, etc.

Used in the present description, the term "lower allylthiourea means of the above-described thiol group in which a hydrogen atom is substituted by a lower alkyl group. Illustrative examples is utilty-, tert-butylthio, pentyl(amyl)thio-, isopentyl, neopentyl-, tert-pentylthio-, 1-methylbutyl-thio-, 2-methylbutyl-, 1,2-dimethylpropyl-, hexylthio, isohexyl-, 1 methylphenylthio-, 2-methylphenylthio-, 3-methylphenylthio-; 1,1-dimethylbutyl-; 1,2-dimethylbutyl-; 2,2-dimethylbutyryl-; 1,3-dimethylbutyl-; 2,3 - dimetil-Tertio-; 3,3-dimethylbutyryl-; 1 ethylbutyryl-; 2 ethylbutyryl-, 1,1,2-trimethylpropyl-; 1,2,2-trimethylpropyl-; 1-ethyl-1-methylpropyl-; 1-ethyl-2-methylpropyloxy, etc. is Preferred allylthiourea having 1-3 carbon atoms.

Illustrative examples of the "lower alkylsulfonyl groups are methylsulfinyl, ethylsulfinyl, propylsulfonyl, isopropylaniline, butylsulfonyl-Naya, isobutylphenyl, second-butylsulfonyl, tert-butylsulfonyl, pentyl(amyl)sulfonylurea, isopentenyladenine, neopentylglycol, tert-pentylaniline; 1-methylbutylamine; 2-methylbutyronitrile; 1,2 - dimethylpropyleneurea; hexylaniline; itgenerally; 1-methylphenylsulfonyl; 2-methyl-pentylaniline; 3-methylphenylsulfonyl; 1,1-dimethylbutylamino; 1,2-dimethylbutylamine; 2,2 - Danilina; 1-ethylbutyraldehyde; 2-ethylbutyraldehyde; 1,1,2-trimethylphenylsulfonyl; 1,2,2-trimethylphenylsulfonyl; 1-ethyl-1-methylpropylsulfonic; 1-ethyl-2-methylpropylsulfonic group, etc. is Preferred alkylsulfonyl group having 1-3 carbon atoms.

Illustrative examples of the "lower alkylsulfonyl groups are methylsulfonyl; ethylsulfonyl; propylsulfonyl; isopropylaniline; butylsulfonyl; isobutyronitrile; second-butylsulfonyl; tert-butylsulfonyl; pentyl(amyl)sulfonylurea; isopentyl - sulfonylurea; neopentadactyla; tert-pentylaniline; 1-methylbutyronitrile; 2-methylbutyronitrile; 1,2-dimethylpropyleneurea; hexylaniline; itgenerally; 1-methylphenylsulfonyl; 2-methylphenylsulfonyl; 3-methylphenylsulfonyl; 1,1-dimethylbutylamino; 1,2-dimethylbutylamine; 2,2-dimethylbutylamino; 1,3-dimethylbutylamine; 2,3-dimethylbutylamine; 3,3-dimethylbutylamine; 1-ethylbutylamine; 2-ethylbutylamine; 1,1,2-trimethylphenylsulfonyl; 1,2,2-trimethylphenylsulfonyl; 1-ethyl-1-methylpropyl the PA, 1-3 atom operaia.

Examples of "lower CNS groups are methoxy, ethoxy-, propoxy-, isopropoxy, butoxy, isobutoxy-, second -, butoxy-, tert-butoxy-, pentyloxy (amyloxy), isopentylamine-, tert-pentyloxy, neopentylene-, 2-methylbutoxy-, 1,2-DIMETHYLPROPANE-, 1 ethylpropoxy, hexyloxy, etc. Of them preferred are methoxy, ethoxy-, propoxy - and isopropoxy.

Illustrated above lower alkyl group or lower CNS group can be substituted in any position by at least one Deputy, selected from a halogen atom, carboxyl group and aryl group.

Illustrative examples of substituted lower alkyl groups or lower CNS groups are trihalogen (lower alkyl), carboxy (lower alkyl), carboxy (lower alkoxy), aryl(lower alkoxy), etc. however, preferred are trihalomethyl, carboxymethoxy and benzyloxy. Aryl group, which is a surrogate, may itself be substituted by a halogen atom or a carboxyl group. As an example may serve carboxymethyloxime.

Used in the present description AI the term "aryl group" means, for example, carbocyclic aryl group. As examples of aryl groups can serve as phenyl, naftalina, antenna or phenanthroline group, etc.

Examples of "lower alkalinous groups in a or b are linear or branched alkylene group having from 1 to 6 carbon atoms. Illustrative examples of such groups are methylene, ethylene, trimethylene, methylmethyldopa, dimethylmethylene, 1-metilidinovy, 2-metilidinovy, tetramethylene, 1-methyltrienolone, 2-methyltrienolone, 3-methyltrienolone, 1-ethylethylene, 2-ethylethylene, 2,2-dimethylethylene, 1,1-dimethylethylene, ethylmethylamino, pentamethylene, 1-mediterraneita, 2-mediterraneita, 3-mediterraneita, 4-mediterraneita, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, 1,3-dimethyltrimethylene, 2,3-dimethyltrimethylene, 1,2-dimethyltrimethylene, 1,1,2-trimethylethylene, diethylethylene, hexamethylene, 1-methylpentylamino, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,3-dimethyltrimethylene, 1,4-dimethyltrimethylene group, etc.

Example of the substituent for the "lowest urography. As illustrative examples include phenyl, 4-nitroaniline, 3-nitroaniline, 2-nitroaniline group and so on, in this case, preferred is 4-nitroaniline group.

Of the groups represented by R, it is preferable imidazolidine group. The preferred group represented by R1can be defined as follows:

(1) a halogen atom, a nitro-group, cyano, mono - or di(lower alkyl)amino group, a lower alkylsulfonyl group, lower alkylsulfonyl group or carnemolla group;

(2) lower alkyl or lower CNS group which may be substituted by a carboxyl group or aryl group; and

(3) fenoxaprop, which may be substituted by lower alkoxycarbonyl group.

More preferred is a compound where R is a 1-imidazolidinyl group; X represents a group of the formula: CH, and R1represents a halogen atom, a nitro-group, triptorelin group, cyano, or benzyloxy. Particularly preferred compounds are:

2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl] acetic acid or its salt;

2-[>2-[6-benzyloxy-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4 - tetrahydroquinoxalin-1-yl-]acetic acid or its salt.

The compound (I) of the present invention is tautomer based diethyloxalate patterns. In addition, this compound can exist as optical isomers (optically active compounds, diastereoisomer, or etc.) depending on the group type. These isomers in pure form or mixtures of the isomers are also included in the scope of the present invention.

The compound (I) of the present invention forms a salt with acid or base. Examples of salts formed by the acid salts are joining acids, formed with inorganic acids, for example, mineral acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid or phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonate acid, econsultancy acid elegantissima bases such as sodium, potassium, magnesium, calcium or aluminum; organic bases such as methylamine, ethylamine or ethanolamine; and basic amino acids such as lysine, arginine, or ornithine; or ammonium salt. In addition, compound (I) of the present invention can form a hydrate, MES with alcohol, and has the ability to polymorphism.

Getter.

The compound of the present invention can be obtained by the method illustrated in reaction scheme presented in the end of the description,

where X, A, R1and R2are the same as defined above, Y represents a halogen atom; Y1represents an atom of halogen except fluorine atom; R1represents a hydrogen atom and the group defined above for R1; R3represents a lower alkyl group; Z1, Z2represent a hydrogen atom and a group of the formula: R3COCO-, provided that both Z1and Z2are not hydrogen atoms at the same time.

In the above formula, examples of the halogen atom are fluorine atoms, chlorine, bromine and iodine.

If the connection is hydroxyl group, represented RASS="ptx2">

Examples of connection with a protected carboxyl group and its equivalent are esters, amides and orthoepy; and derivatives described in "Protective Groups in Organic Synthesis, 2nd ed., edited by T. W. Greene &P. G. M. Wuts, John Willey & Sons, INC., Chapter 5 (1990)".

Method 1

The compound (I) or (IV) of the present invention can be obtained by reaction of a halogen compound (II) and imidazole (III) taken in appropriate for this reaction; however this reaction can be carried out in a solvent or in the absence of a solvent with stirring, and at a temperature of from -10 to 150oC, and preferably from 20 to 120oC.

This reaction is usually carried out by heating in a solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile, acetone or tetrahydrofuran (THF). To accelerate the reaction may be added a base such as sodium hydroxide or potassium hydroxide, or salt of copper.

The compound (I) of the present invention can also be obtained by reaction of the release of the compound (IV) or the reaction of removal of R2in accordance with the standard method.

The reaction of the release or removal of R2can be assisting, for example, can be carried out hydrolysis. As example can serve as acid hydrolysis carried out in the presence of hydrochloric acid or etc., and alkaline saponification carried out in the presence of a base such as sodium hydroxide.

Method 2

The compound (I), (IX) or (X) of the present invention can be obtained in the following way:

(1) Nitroaniline or nitroaniline compound (V) recover, resulting in a gain diamino compound (VI).

(2) Diamino compound (VI) is subjected to reaction with oksanatkalenko (VII), resulting in a gain amide compound (VIII) and its mixture.

(3) an Amide compound (VIII) and the mixture is subjected to reaction ring closure, resulting in a gain khinoksalinona connection or pyridopyrimidines compound (IX) or (X).

(4) Khinoksalinona connection or pyridopyrimidines compound (IX) is subjected to a known substitution reactions in aromatic nucleus, resulting in a gain substituted khinoksalinona connection or pyridopyrimidines the compound (X).

(5) the Reaction of the release or removal of R2carried out as described in Method 1.

Below OPI is in the stage of (1) can serve as catalytic reduction, implemented in a standard way using, for example, skeletal Nickel catalyst or Raney catalyst is palladium-on-coal, and recovery of the metal with the use of powdered iron or zinc dust.

An example of the amidation reaction in stage (2) is the reaction between Daminova compound (VI) and oksanatkalenko (VII) in the number corresponding to this reaction, which is carried out in a solvent such as chloroform or THF, at temperatures from -10 to 60oC, and preferably from 0oC to room temperature.

To accelerate the reaction it is preferable to add an alkali such as triethylamine.

The reaction ring closure in stage (3) is carried out, for example, by heating the amide compound (VIII) and mixtures thereof in the above solvent, or by heating in the presence of an acid catalyst such as hydrochloric acid. Examples of substitution reactions in aromatic nucleus, in stage (4), where R1in the compound (IX) is hydrogen, can serve as a method of exposure to nitric acid or its salt to khinoksalinona connection or pyridopyrimidines compound (IX) in sulfuric acid, in a mixture of acetic anhydride Eeekly between hinoksalinovym connection or perioperatively connection and tetrafluoroborate nitronium in an organic solvent, such as sulfolane or acetonitrile at a temperature of 0oC or when heated.

Method 3

The compound (I), (IX) or (X) of the present invention can be obtained in the following way:

(a) Nitroanilide connection restore as described in (2) Method 2, resulting in a gain aminoaniline compound (XII).

(b) Aminoaniline compound (XII) is subjected to reaction ring closure as described in (3) Method 2, resulting in a gain khinoksalinona compound (IX) or (X).

The subsequent process of obtaining the compound (I) of the present invention is carried out in accordance with the second method of obtaining.

The connection with the R1the nitrogroup, can be obtained, for example, by means of nitration, which is subjected to khinoksalinona compound (IX), where R1is a hydrogen atom, and which is carried out as described in (4) Method 2.

Method 4

The compound in which R1an amino group can be obtained by reduction reaction of compounds in which R1is the nitro-group, as described in (2) Method 2. Alternatively, this compound can be obtained by reaktsii in accordance with known methods.

Connection, where R1is mono - or di(lower alkyl)-amino group, can be obtained by reaction of compounds in which R1is an amino group, a halogen (lower alkyl)-containing compound, as described in Method 1. Alternatively, this compound can be obtained by reaction of the aldehyde compounds (such as formaldehyde) with aminoven compound in the solvent or in the absence of a solvent, preferably in the presence of acid, under similar conditions to the implementation stage (1) Method 2.

Method 5

The compound in which R2is an amino group or a mono - or di(lower alkyl)amino group, can be obtained by the amidation reaction carboxy-compound (I) is carried out in a known manner.

Alternatively, this compound can be obtained by reaction of the ester-amide exchange between ether compound (IV), (IX) or (X) and the appropriate amine or ammonia.

The reaction of the carboxy amidation of compound (I) is carried out, for example, by conversion of this compound into the acid chloride using, for example, thionyl chloride, followed by addition of an appropriate amount of amine or ammonia.

oC to room temperature.

Method 6

The compound (II) in which a is accelerograph can be obtained by reaction of the corresponding hydroxyhexane-2,3-dione with the appropriate alkylating agent in the presence of a base. This reaction can be carried out, mainly, in a solvent such as DMF, DMSO, THF, acetonitrile or acetone. As grounds, it is preferable to use an organic base (e.g. potassium carbonate or sodium hydride).

Method 7

The compound (I) in which R1is carbamoyl group, can be obtained in a known manner by treating the corresponding derivative (I) having as R1the cyano, acidic or basic conditions. For example, this compound can be obtained by reaction of the cyano-derivative with an acid, such as hydrochloric acid, sulfuric acid or formic acid, or by reaction in basic conditions, for example aqueous hydrogen peroxide solution or sodium hydroxide.

Thus obtained compounds of the present invention is isolated and purified as a free compound or its salts.

The allocation of PTS and the Ktsia, concentration, evaporation, crystallization, filtration, recrystallization, various methods of chromatography, etc.

The compound of the present invention has a high degree of affinity for AMPA-receptor; strong activity that reduces the neurotoxicity induced by kainic acid; and anticonvulsant action aimed at the suppression of the auditory reflex epileptic seizures in mice DBA/2.

Therefore, the compound of the present invention possess valuable pharmaceutical properties, can be used, in particular, as a psychotropic drug for the prevention and treatment horii's disease, Parkinson's disease, epilepsy, Alzheimer's disease or senile dementia; as well as anti-ischemic agent for the prevention and treatment of conditions associated with cell death caused by cerebral ischemia; hypoxia; temporary cardiac arrest; degeneration of nervous tissue observed after hypoglycemia or epileptic seizure; and the lack of mental and motor functions.

Test method

Determination of the activity of inhibiting the binding of [3H] AMPA and overwhelming neurotoxic action of kainic activity inhibiting the binding of [3H]-AMPA:

While cooling with ice water, 0.5 ml (total) of the reaction liquid mixture containing about 45 nm [3H]-AMPA (2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid), 300 mg of the sample meninges rats, and the test compound was subjected to reaction for 45 minutes. The number of [3H] -AMPA associated with AMPA-receptor was measured by the filtration method. The number of specific binding took part (of the total related amounts), substituted 10 μm kiskaloo acid. Evaluation of the test compound was carried out by determining the degree of inhibition of specific binding. As a result of this determination, for example, found that the value of Ki for compounds of Example 1 is to 0.73 μm, for compounds of Example 9 it is 0,093 μm, and compounds of Example 19 this value is 0,070 mm, which suggests that these compounds are strong inhibitors.

2) Measurement of activity, inhibiting neurotoxicity of kainic acid:

The inhibitory activity of the compounds of the present invention, directed to suppress the neurotoxicity of kainic acid, was investigated using first the and 18-20-day fetal rats cut the hippocampus and were treated with papain and Dnazol 1 for dispersing cells. Thus obtained cells were placed in a MEM medium containing 10% serum, and then inoculable on 48-well plate, pre-treated poly-1-lysine at a concentration of 4105CL /cm/. After 24 hours, the serum was replaced with serum-free medium. The medium was replaced twice a week. Cells were cultured for at least 6 days, and then spent the next test.

(2) Inhibition of neurotoxicity induced by kainic acid:

Neurotoxicity was expressed in the form of lactate dehydrogenase activity released into the culture medium due to cell death. As control was used neurons treated for 24 hours in serum-free medium containing 30 μm kainic acid. Neurons were exposed to the effect of each of the tested compounds with 300 μm kainic acid for 24 hours, and then evaluated the inhibitory activity of each of the compounds aimed prevent neuronal death caused by kainic acid.

As a result of these tests it was found, for example, that the IC50for compounds of Example 1 is 0.8 μm; IC50for compounds of Example 9 is 0.96 μm; and the IC50for with the missing action.

(3) Measurement of inhibitory actions aimed at the suppression of the auditory reflex epileptic seizures in mice DBA/2:

Ten 21-28-day Masha-males were subjected to auditory stimulation sound at 12 kHz and 120 dB sound test chamber for 1 minute or until until the mice will not occur tonic seizures. The test compound suspended in 0.5% solution of methylcellulose or dissolved in physiological solution, and the resulting suspension or solution was injected into mice intraperitoneally 15 minutes before the start of stimulation by sound. The effectiveness of the drugs was evaluated by the appearance and in the absence of seizures, and to identify the minimum effective dose (MED).

The results of these evaluations showed that the compound of Example 1, the compound of Example 9 and the compound of Example 19 was suppressed hearing epileptic seizure in mice at concentrations of 3 mg/kg, 10 mg/kg and 1 mg/kg, respectively.

(4) Measurement of solubility:

Receive buffer:

To a 0.1 M aqueous solution of monopotassium phosphate potassium was added 0.1 M aqueous solution of monopotassium phosphate sodium; received buffers, which had a pH of 5, 6, 7 and 8, respectively.

shivali in four glass test tubes was added in 0.1 ml phosphate buffer, having a pH of 5, 6, 7 and 8, respectively, after which the tube was intensively shaken. Solubility was defined as the value obtained from the following equation:

< / BR>
The results of these measurements are presented in Table 1.

The compound of Example 9 had a solubility 4100 mg/ml at pH 6. Thus, the connection of the present invention has high solubility even at neutral or near-neutral pH values. Accordingly, the compound of the present invention can be successfully included as an active ingredient in preparations for pills of administration, such as tablets and capsules, or in preparations for parenteral administration such as injection.

In addition, the compound of the present invention has a high, so high solubility in the blood even when the clinical introduction, and not subject to easy deposition in organs that give this connection a special value.

Table 1, see end of text.

Pharmaceutical preparation containing one or more compounds of the present invention or its salt as an effective ingredient, obtained using a carrier or filler and other Donatelli, used for the manufacture of pharmaceutical preparations can be solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, Arabic gum, olive oil, sesame oil, cacao butter, ethylene glycol and other standard carriers or fillers.

In accordance with the present invention, as a solid composition for oral administration can be used in tablets, powders, granules, etc. In such solid compositions may contain one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or metasilicate aluminum-magnesium. In addition to the inert diluent, this composition may contain additives, for example, a lubricant such as magnesium stearate; a disintegrator such as calcium glycolate, cellulose; a stabilizer such as lactose; or solubilizers agent or solubilizers additive, such as glutamic acid or aspartic acid. Tablets or pills may be coated, made from the gastro - or enteroscope the vines.

As examples of liquid compositions for oral administration can serve as pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elexir, which usually contain the commonly used inert diluent such as purified water or ethanol. In addition to the inert diluent, the liquid composition may also contain an adjuvant, such as solubilizers agent or solubilizers additive, wetting agent or suspendisse agent, sweetening agent, flavoring, flavouring agent, or antiseptic agent.

Examples of the composition for parenteral administration by injection can serve as a sterile aqueous and non-aqueous solutions, suspensions and emulsions. As the solvent for the aqueous solution or aqueous suspension can be used distilled water suitable for injection, saline solution. Examples of the diluent for anhydrous solution or anhydrous suspension can serve as propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohol such as ethanol, and Polysorbate 80" (trade mark). In addition, this composition may also contain additives such as an agent for imparting to the solution is stabilizator (for example, lactose), and solubilizers agent or solubilizers additive. These compositions can be sterilized, for example, by filtration through a bacterial filter, through the introduction of insecticide, or by irradiation. The preparation for injection can also be made in the form of sterile solid compositions, which can then be directly before using it, dissolved in sterile water or sterile solution suitable for injection.

The above compositions can be introduced in any manner, for example orally in the form of tablets, pills, capsules, granules, powders or solutions; parenterally, by injection, such as intravenous or intramuscular injection; in the form of suppositories; or transcutaneous. Injected dose must be determined separately in each case depending on the symptoms, age and sex of the patient. However, in General, for an adult, the dose, if perepelinogo introduction, is in the range from 1 to 1000 mg/day, and preferably from 50 to 200 mg/day and can be entered once a day or portions several times a day; or, in the case of intravenous administration, the dose is in the range from 1 mg to 500 mg per day, and can

Examples

In more detail, the present invention is described in the following Examples, it should be borne in mind that these Examples should not be construed as a limitation of the present invention. In addition, in these Examples are also described receiving the main source connections.

Example 1

1) To a mixture containing 13,96 g of the hydrochloride of the ethyl ester of glycine, 30 ml of tetrahydrofuran, 10 and 11 g of triethylamine and 30 ml of dimethylformamide, was added 15,91 g of 2,4-deformirovannoe, and the mixture was heated under reflux for three hours in a stream of argon gas. The reaction mixture was cooled and diluted with ethyl acetate, after which the precipitated nerastvorimaya substance was removed by filtration. The filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, then washed with water and brine, then drained basw is from ethanol, resulting received 17,32 g (71,5%) of ethyl ester of N-(2-nitro-5-forfinal) glycine.

MC (m/z): 242 (M+).

Spectrum of nuclear magnetic resonance

(NMR-spectrum (CDCl3internal standard TMS): of 1.33 (3H, t, J=6.5 Hz), Android 4.04 (2H, d, J=4.9 Hz), or 4.31 (2H, square, J=6.5 Hz), 6,34 (1H, DD, J=2,4, and 11.0 Hz), 6,44 (1H, m), of 8.25 (1H, DD, J=6,1 and 9.7 Hz), 8,55 (1H,c).

2) a Mixture containing of 6.52 g of ethyl ester of N-(2-nitro-5-forfinal) glycine, 100 ml of tetrahydrofuran, 50 ml of methanol and 500 mg of 10% palladium-on-charcoal, stirred in hydrogen atmosphere, which restored the nitrogroup. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the obtained residue was added 200 ml of chloroform and 7,54 ml of triethylamine, and the mixture was dissolved. To the obtained mixture in an argon atmosphere under ice cooling and with stirring, one drop was added to a solution containing 30 ml of chloroform in 7,35 g etylchlorhydrine. After complete addition, stirring was continued for one hour at room temperature, and then the mixture was diluted with chloroform. The diluted solution is then washed with water, saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride and SOLEV the scientists to the residue was added 150 ml of ethanol and 1 ml of concentrated hydrochloric acid, and then the mixture was heated under reflux for one hour. After cooling, the resulting crystals were collected by fillratio and was dried under reduced pressure, resulting in a received 5,80 g (80%) of ethyl-2-(7-fluoro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) acetate.

MC (m/z): 266 (M+).

NMR spectrum (DMSO-d6internal standard-TMC): : 1,22 (3H, t, J=7,3 Hz), 4,17 (2H, square, J=7,3 Hz), of 4.95 (2H, s), of 7.70 (IH, m), 7,22 (1H, DD, J= 5,4, 8,8 Hz), was 7.36 (1H, DD, J=2.4 and 11.2 Hz), 12,20 (1H, s).

3) In 15 ml of concentrated sulfuric acid at a temperature below 0oC dissolved 1.20 g ethyl-2-(7-fluoro-2,3-di-oxo-1, 2, 3, 4 - tetrahydroquinoxalin-1-yl) acetate. To the resulting solution, with stirring, was added drop of 0.21 ml of fuming nitric acid (d=1,52), and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was poured into ice water. Precipitated crystals thus collected by filtration, washed with water, and dried under reduced pressure, resulting in a received 1.35 g (96%) of ethyl-2-(7-fluoro-6-nitro-2,3-dioxo-1,2,3,4 - tetrahydroquinoxalin-1-yl) acetate.

MC (m/z): 312 (M++ 1).

NMR spectrum (DMSO-d6, internal standard TMS): 1,24 (3H, t, J=7,3 Hz), 4,18 (2H, q, J=7,3 Hz), 5,02 (2H, s). 7,74 (1H, d, J=13.5 Hz), Salin-1-yl) acetate, 450 mg of imidazole and 10 ml of dimethylformamide, was stirred for six hours at a temperature of 120oC. After cooling, the reaction mixture was poured into ice-cold water. The obtained crystals were collected by filtration, washed with water, and dried under reduced pressure.

The compound obtained was added to 5 ml of 1 n.. an aqueous solution of sodium hydroxide at room temperature, and then the mixture was stirred for 15 minutes for hydrolysis of ester. The reaction mixture is brought to pH 3.5 by adding 1 n.. hydrochloric acid. Precipitated crystals thus collected by filtration, washed with water, and dried under reduced pressure, resulting in a received 473 mg (40%) 2-[12,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4 - tetrahydroquinoxalin-1-yl] acetic acid HCl 1 1,2 H2O.

So pl.: 225oC (Razlog.).

Elemental analy for C13H9N5O6HCl 1,2 H2ABOUT:

Calculated: C 40,11; H 3,21; N 17,99; Cl 9,11 (%):

N. ideno: C 40,01; H 3,11; N 17,86; Cl 9,02 (%).

MC (m/z): 332 (M++1).

NMR spectrum (DMSO-d6, internal standard TMS): : 4,89 (2H, s), 7,88 (1H, s), 8,01 (1H, s), 8,08 (1H, s), of 8.28 (1H, s), 9,43 (1H, s), 12,89 (1H, s), 13,1-14,2 (1H, Shir.S.).

Example 2

1) 14,58 g (80%) of methyl-3-(5-fluoro-2-neither the g of methyl ester hydrochloride-alanine, 20 ml of dimethylformamide, 12.0 g of 2,4-deformirovannoe, 7,58 g of triethylamine and 20 ml of tetrahydrofuran.

MC (m/z: 242 (M+).

The NMR spectrum (CDCl3, internal standard TMS): : 2,73 (2H, t, J=6.6 Hz), 3,61 (2H, t, J=6.6 Hz), 3,74 (3H, s), 6,36-6.42 per (1H, m), of 6.52 (1H, DD,J =2,9 and 11.7 Hz), by 8.22 (1H, DD, J=5,9, and 9.3 Hz), a 8.34 (1H, s).

2) of 5.84 g (55%) of ethyl-3-(2,3-dioxo-7-fluoro-1,2,3,4-tetrahydroquinoxalin-1-yl)propionate was obtained by the method described in Example 1-2, except that he used to 6.19 g of methyl-3-(5-fluoro-2-nitrophenylamino)propionate.

MC (m/z): 280 (M+).

NMR spectrum (DMSO-d6, internal standard TMS): of 1.27 (3H, t, J=6.8 Hz), and 2.79 (2H, t, J=7,6 Hz), 4,18 (2H, square, J=6,8 Hz), of 4.45 (2H, t, J=7,6 Hz), 6,94-6,99 (1H, m), 7,07 (1H, DD, J=2,4, 9.7 Hz), 7,30 (1H, DD, J=4,5, 9.7 Hz), 11,23 (1H, s).

3) 1,58 g (91%) of ethyl-3-(2,3-dioxo-7-fluoro-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl) propionate was obtained by the method described in Example 1-3, except that the used of 1.50 g of ethyl-3-(2,3-dioxo-7-fluoro-1,2,3,4-tetrahydroquinoxalin-1-yl) propionate.

MC (m/z): 326 (M++ 1).

NMR spectrum (DMSO-d6, internal standard TMS): : 1,21 (ZN, t, J=7,1 Hz) to 2.67 (2H, t, J=7,3 Hz), 4,08 (2H, q, J=7,1 Hz), 4,32 (2H, t, J=13.3 Hz), 7,78 (1H, d, J=13,8 Hz), 7,89 (1H, d, J=7,3 Hz), to 12.3 (1H, s).

4) 704 mg (48%) of 3-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-of 1-4, except that used 1.20 g of ethyl-3-(7-fluoro-6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)propionate, 502 mg of imidazole and 10 ml of dimethylformamide.

So pl.: 281-282oC (Razlog.).

Elemental analysis for C14H11N5O6HCl H2O (%):

Calculated: C 42,07; H 3,53; N 17,52; Cl 8,87

N. ideno: C 41,98; H of 3.78; N 17,63; Cl 8,65.

MC (m/z): 346 (M++ 1).

NMR spectrum (DMSO-d6, internal standard TMS): : to 2.65 (2H, t, J=7.8 Hz), the 4.29 (2H, t, J=7.8 Hz), to $ 7.91 (1H, s), with 8.05 (1H, s), 8,07 (1H, s), of 8.25 (1H, s) to 9.57 (1H, s), 12,72 (1H, s), 12,1-13,2 (1H, Shir.S.).

Example 3

1) 9,72 g (61%) of ethyl-4-(5-fluoro-2-nitrophenylamino)butyrate was obtained by the method described in Example 1-1, except that the used of 9.55 g of the hydrochloride of the ethyl-aminobutyrate, 20 ml of tetrahydrofuran, was 6.73 g of triethylamine, 10 ml of dimethylformamide, and of 9.45 g of 2,4-deformirovannoe.

MC (m/z): 270 (M+).

The NMR spectrum (CDCl3), internal standard TMS): : of 1.28 (3H, t, J=7.0 Hz), 2,02-of 2.08 (2H, m), 2,47 (2H, q, J=7,1 Hz), the 3.35 (2H, t, J=7.0 Hz), 4,17 (2H, t, J=6.0 Hz), 6,35-6,41 (1H, m), of 6.52 (1H, DD, J=2,4, and 11.6 Hz), 8,21 (1H, DD, J=5,1, 9,2 Hz).

2) to 5.93 g (85%) of ethyl-4-(2,3-dioxo-7-fluoro-1,2,3,4-tetrahydroquinoxalin-1-yl) butyrate was obtained by the method described in Example 1-2, except that UB>6, internal standard TMS): : of 1.28 (3H, t, J=7.4 Hz), 2,04 is 2.10 (2H, m), 2,52 (2H, t, J=6,7 Hz), 4,18-4.26 deaths (2H, m), 6,93-6,98 (1H, m), 7,26-to 7.35 (2H, m), 11,59 (1H, s).

3) of 2.81 g (92%) of ethyl-4-(2,3-dioxo-7-fluoro-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl)butyrate was obtained by the method described in Example 1-3, except that used 2.64 g ethyl-4-(2,3-dioxo-7-fluoro-1,2,3,4-tetrahydroquinoxalin-1-yl)butyrate.

MC (m/z): 340 (M++ 1).

NMR spectrum (DMSO-d6, internal standard TMS): : of 1.29 (3H, t, J =7,3 Hz), 1,98-of 2.05 (2H, m), 2,52 (2H, t, J=6,7 Hz), 4,15-4,24 (4H, m), 7,56 (1H, d, J=12.9 Hz), 8,03 (1H, d, J=6,7 Hz).

4) 1.42 g (80%) 4-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl] butyric acid 1HCl of 0.1 H2Oh was obtained by the method described in Example 1-4, except that the used of 1.50 g of ethyl-4-(7-fluoro-6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)butyrate, 632 mg of imidazole and 10 ml of dimethylformamide. So pl.: > 300oC.

Elemental analysis for C15H13N5O6HCl of 0.1 H2O (%):

Calculated: C 45,32; H of 3.60; N 17,62; Cl 8,92

N. ideno: C 45,20; H 3,68; N 17,57; Cl 8,96.

MC (m/z): 360 (M++ 1).

NMR spectrum (DMSO-d6, internal standard TMS): : to 1.86 (dt, J=6,8, 7,4 Hz), of 2.38 (2H, t, J=6.8 Hz), of 4.12 (2H, t, J=7.4 Hz), 7,92 (1H, s), 8,02 (1H, s), 8,07 (1H, s), of 8.25 (1H, s), of 9.56 (1H the output in Example 1.

1) to 7.59 g (47%) of ethyl ester of N-(4-fluoro-2-nitrophenyl)glycine was obtained using a 9.25 g of the hydrochloride of the ethyl ester of glycine, 10,55 g (to 66.3 mmol) of 2,5-deformirovannoe, 35 ml of tetrahydrofuran, 9,29 ml of triethylamine, and 5 ml of DMF.

The NMR spectrum (CDCl3, internal standard TMS): : to 1.32 (3H, t, J=7.4 Hz), 4,08 (2H, d, J=5.5 Hz), the 4.29 (2H, square, J=7,4 Hz), of 6.68 (1H, DD, J=4,3, and 9.1 Hz), 7.24 to 7,29 (1H, m), 7,92 (1H, DD, J=3,0, 9.1 Hz), of 8.27 (1H, Shir., C. ).

2) a Mixture containing 7,41 g (30,6 mmol) of ethyl ester of N-(4-fluoro-2-nitrophenyl)glycine, 120 ml of tetrahydrofuran, and 0.5 g of 10% palladium-on-charcoal, stirred at room temperature under normal pressure in a hydrogen atmosphere. After completion of the reaction the catalyst was removed by filtration. To the filtrate was added 150 ml of tetrahydrofuran and 19.5 ml of triethylamine. To the resulting mixture under ice cooling for one drop was added to a mixture containing 19 g of etylchlorhydrine and 20 ml of tetrahydrofuran and then stirred. The reaction mixture was heated to room temperature and was stirred overnight. Precipitated crystals thus was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added 150 ml of ethanol and 1.5 ml of concentrated hydrochloric acid, and the mixture was heated with obival ethanol and was dried under reduced pressure, resulting received 6,77 g (83%) of ethyl-2-(2,3-dioxo-6-fluoro-1,2,3,4-tetrahydroquinoxalin-1-yl)acetate.

NMR spectrum (DMSO-d6, internal standard TMS): : 1,22 (3H, t, J=7,3 Hz) to 4.17 (2H, q, J=7,3 Hz), equal to 4.97 (2H, s), 7,00 (1H, DD, J= 3,0, 9,2 Hz), 7,02-7,06 (1H, m), 7,35 (1H, DD, J= 4,9, 9,2 Hz), 12,25 (1H, s).

3) to 2.74 g (96%) of ethyl-2-(2,3-dioxo-6-fluoro-7-nitro-1,2,3,4 - tetrahydroquinoxalin-1-yl)acetate was obtained with the use of 2.45 g (of 9.21 millimoles) of ethyl-2-(2,3-dioxo-6-fluoro-1,2,3,4-tetrahydroquinoxalin-1-yl)acetate, 15 ml of concentrated sulfuric acid, and 0.5 ml of fuming nitric acid.

NMR spectrum (DMSO-d6, internal standard TMS): : to 1.23 (3H, t, J=6,7 Hz), 4,19 (2H, q, J=6,7 Hz), of 5.05 (1H, s), 7,19 (1H, d, J=11,6 Hz), 8,10 (1H, d, J=6,7 Hz), 12,68 (1H, s).

4) 2.24 g (96%) of ethyl-2-[2,3-dioxo-6-(1H-imidazol-1-yl)-7-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl] acetate was obtained using 2,02 g ethyl-2-(2,3-dioxo-6-fluoro-7-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl) acetate, 1,33 g of imidazole and 15 ml of DMF.

NMR spectrum (DMSO-d6, internal standard TMS): : a 1.25 (3H, t, J=7,3 Hz), is 4.21 (2H, q, J=7,3 Hz), 5,09 (1H, s), 7,11 (1H, s), 7,26 (1H, s), 7,45 (1H, s), to 7.93 (1H, s), 8,21 (1H, s), 12,3-13,0 (1H, Shir.C).

5) 1.88 g (84%) of 2-[2,3-dioxo-6-(1H-imidazol-1-yl)-7-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl] acetic acid, HCl H2O received with use of 2.09 g of the solution of sodium hydroxide.

So pl.: 217-218oC.

Elemental analysis for C13H9N5O6HCl H2O (%):

Calculated: C 40,48; H 3,14; N 18,16; C 19,19.

N. ideno: C 40,17; H 3.04 from; N 18,08; Cl 9,20.

Example 5

1) Mixture of 1.30 g of ethyl-2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]-acetate, 80 ml of tetrahydrofuran, 20 ml of methanol and 600 mg of 10% palladium-on-charcoal, stirred in an atmosphere of hydrogen for 36 hours; after filtration of the reaction mixture, the filtrate was concentrated under reduced pressure, resulting in a received 1,02 g (86%) ethyl-2-[6-amino-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]-acetate.

NMR spectrum (DMSO-d6, internal standard TMS): : 1,14-1,22 (3H, m), 4.09 to 4,18 (2H, m), 4,88 (2H, s), of 5.05 (2H, s) of 6.71 (1H, s), 7,11 (1H, s), 7,16 (1H, s), 7,30 (1H, s), 7,74 (1H, s), 12,11 (1H, s).

2) To 1.5 ml of 1 n.. an aqueous solution of sodium hydroxide was added 150 mg of ethyl-2-[6-amino-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4 - tetrahydroquinoxalin-1-yl] acetate at room temperature, and the mixture was stirred for two hours. The reaction mixture is brought to pH 6 by adding 1 ad . of hydrochloric acid. Precipitated crystals thus collected by filtration, washed with water and dried under reduced pressure, acid 1,7 H2O.

So pl.: > 300oC.

MS (m/z): 302 (M++ 1).

Spectrum of nuclear magnetic resonance (DMSO-d6, internal standard TMS): : 4,78 (2H, s), 5,04 (2H, Shir.C.), of 6.71 (1H, s), 7,11 (2H, s), 7,29 (1H, s), 7,73 (1H, s), 12,09 (1H, s).

Example 6

To 6 ml of an aqueous solution of ammonia was added 100 mg of ethyl-2-[2,3-dioxo-7- (1H-imidazol-1-yl)-6-nitro-1,2,3,4-Tetra-hydrogenation-1-yl] acetate at a temperature of -5oC, and the resulting mixture was stirred for 3 hours at a temperature of 0oC, and then concentrated under reduced pressure. The concentrate was washed with water and dried under reduced pressure, resulting in a received 90 mg (89%) of 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4 - tetrahydroquinoxalin-1-yl]ndimethylacetamide of 0.5 NH 1,3 H2O.

So pl.: 245oC (Razlog.).

MS (m/z): 331 (M++1).

NMR spectrum (DMSO-d6, internal standard TMS): : of 4.77 (2H, s), 6,3-6,9 (1H, Shir. C.), 7,07 (1H, s), 7,22-7,33 (2H, m), of 7.36 (1H, s), to 7.64 (1H, s), 7,80-7,87 (2H, m).

Example 7

A mixture containing 465 mg of ethyl-2-[6-amino-2,3-dioxo-7-(1H-imidazol-1-yl)- 1,2,3,4-tetrahydroquinoxalin-1-yl]-acetate, 160 mg of formalin, 30 ml of water, 3 ml of 1 N. hydrochloric acid and 100 mg of 20% palladium-on-charcoal, stirred in hydrogen atmosphere for 8 hours, and then filtrowa sodium hydroxide at room temperature, and this mixture was stirred for one hour. The reaction mixture is brought to pH 6 by addition of 1 N. hydrochloric acid. Precipitated crystals thus collected by filtration, washed with water, and dried under reduced pressure, and then purified on a column with HP20, resulting received 33 mg (6%) 2-[2,3-dioxo-7- (1H-imidazol-1-yl)-6-methylamino-1,2,3,4-tetrahydroquinoxalin-1-yl]acetic acid 1HCl 1,45 H2O.

So pl.: > 300oC.

MS (m/z): 316 (M++1).

NMR spectrum (DMSO-d6, internal standard TMS): : to 2.65 (3H, s), 4,74 (2H, s), to 5.58 (1H, Shir.C.), to 6.57 (1H, s), 7,51 (1H, s), 7,78 (1H, s), to 7.84 (1H, s), 9,24 (1H, s), 12,18 (1H, s), at 13.0 to 13.1 (1H, Shir.S.).

Example 8

395 mg (44%) of 2-[6-dimethylamino-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl] acetic acid and 0.7 H2Oh was obtained by the method described in Example 7, except that used 0,93 g ethyl-2-[6-amino-2,3-pixo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate, 0,92 g of formalin, 50 ml of water, 5 ml of 1 N. hydrochloric acid and 600 mg of 10% palladium-on-charcoal grill.

So pl.: > 300oC.

MC (m/z): 329 (M+).

NMR spectrum (DMSO-d6, internal standard TMS): : 2,40 (6H, s), to 4.87 (2H, s), 6,97 (1H, s), 7,10 (1H, s), 7,31 (1H, s), 7,42 (1H, s), 7,88 (1H, s), 12,14 (1H, s).

The NMR spectrum (CDCl3, internal standard TMS): : and 1.54 (9H, s), 3,98 (2H, d, J= 4.9 Hz), 6,46 (1H, d, J=a 12.7 Hz), 8,54 (1H, d, J=7.8 Hz), 8,76 (1H, Shir.S.).

2) a Mixture containing 9,36 g (27,7 mm) tert-butyl ether N-(5-fluoro-2-nitro-4-triptoreline)glycine, rate of 7.54 g of imidazole and 30 ml of DMF, was stirred for 2 hours in an oil bath at a temperature of 60oC. After cooling, the reaction mixture was concentrated under reduced davidiana then washed with water and ethyl ether, and then was dried under reduced pressure, resulting in received of 8.95 g (84%) of tert-butyl ether N-[5-(1H-imidazol-1-yl)-2-nitro-4 - triptoreline]glycine.

The NMR spectrum (CDCl3, internal standard TMS): : of 1.52 (9H, s), was 4.02 (2H, d, J=4.9 Hz), to 6.67 (1H, s), 7,14 (1H, s), 7,21 (1H, s), to 7.64 (1H, s), 8,66 (1H, s), 8,76 (1H, Shir.S.).

3) a Mixture containing is 3.08 g (7,98 mmol) tert-butyl ether N-[5-(1H-imidazol-1-yl)-2-nitro-4-triptoreline]glycine, 100 ml of tetrahydrofuran, 50 ml of methanol and 350 mg of 10% palladium-on-charcoal, stirred in hydrogen atmosphere at normal pressure and at room temperature. After completion of the reaction, palladium-on-coal was removed by filtration and then the filtrate was concentrated under reduced pressure. To the obtained residue was added 150 ml of chloroform and 2.46 ml of triethylamine. To the obtained mixture under stirring and under cooling with ice for one drop was added to the mixture to 2.29 g (of 16.7 mmol) of etylchlorhydrine and 20 ml of chloroform. After complete addition, the reaction mixture was left to warm to room temperature and then was stirred overnight. After this was added 200 ml of chloroform. The resulting mixture was sequentially washed with water and saline, dried with anhydrous sodium sulfate and koncentrirane was heated under reflux for 10 hours. After cooling, the reaction mixture was concentrated under reduced pressure. To the residue was added 15 ml triperoxonane acid, and the mixture was stirred at room temperature for 6 hours. The resulting reaction mixture was concentrated under reduced pressure, and then brought to pH 7 by adding 1 N. aqueous sodium hydroxide solution and saturated aqueous sodium bicarbonate solution. The resulting solution was purified by using "HP-20" (product of Mitsubishi Chemical Corporation; eluting solvent: water/methanol). Thus obtained purified product was recrystallized from 1 N. aqueous solution of hydrochloric acid, resulting in a received 1,31 g (40%) 2-[2,3 - dioxo-7-(1H-imidazol-1-yl)-6-trifluoromethyl-1,2,3,4-tetrahydroquinoxalin-1-yl] acetic acid 1HCl 1H2O.

So pl.: 226-227 of theoC.

MC (m/z)- 354 (M+).

NMR spectrum (DMSO-d6, internal standard TMS): : a 4.86 (1H, s), 7,89 (1H, s), to $ 7.91 (1H, d, J=1.5 Hz), of 8.04 (1H, s), 8,13 (1H, s), 9,54 (1H, s), 12,89 (1H, s) 12,5-14,0 (1H, Shir.S.).

The target compounds of Examples 10-12 were obtained by the method described in Example 9.

Example 10

1) to 4.01 g (86%) tert-butyl ether N-(4-acetyl-5-fluoro-2-nitrophenyl)glycine was obtained using 2.50 g hydroglider-5-nitroacetophenone.

The NMR spectrum (CDCl3, internal standard TMS): : 1,53 (9H, s), 2,58 (3H, d, J = 4.3 Hz), 3,98 (2H, d, J=4.9 Hz), 6,34 (1H, d, J=12.9 Hz), of 8.90 (1H, d, J=8,2 Hz) and 10.7 (1H, Shir.S.).

2) 3.80 g (87%) of tert-butyl ether N-[4-acetyl-5-(1H-imidazol-1-yl)- 2-nitrophenyl]glycine was obtained with the use of 3.77 g (12.1 mmol) tert-butyl ether N-(4-acetyl-5-fluoro-2-nitrophenyl)glycine, 3.28 g of imidazole and 15 ml of dimethylformamide.

The NMR spectrum (CDCl3, internal standard TMS): : 1,53 (9H, s), and 2.14 (3H, s), was 4.02 (2H, d, J=5,1 Hz), to 6.57 (1H, s), to 7.09 (1H, s), 7,25 (1H, s), 7,63 (1H, s), a total of 8.74 (1H, s), 8,76 (1H, Shir.S.).

3) In this stage used tert-butyl ether N-[4-acetyl-5-(1H-imidazol-1-yl)-2-nitrophenyl] glycine (3,63 g), 120 ml of tetrahydrofuran and 360 mg 10% palladium-on-charcoal, and conducted the reaction of recovery. Then received of 1.32 g (37%) of 2-[6-acetyl-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4 - tetrahydroquinoxalin-1-yl] acetic acid 1H2O using a 7.1 ml of triethylamine and 6,89 g etylchlorhydrine.

So pl.: 225-226oC (Razlog.).

NMR spectrum (DMSO-d6, internal standard TMS): : to 2.40 (3H, s), the 4.90 (2H, s), 7,73 (1H, s), 7,81 (1H, s), to 7.84 (1H, s), to 7.99 (1H, s), 9,16 (1H, s) 12,70 (1H, s), 12,9-14,3 (1H, Shir. C.).

Example 11

1) of 2.27 g (28%) of 2-(4-tert-butoxycarbonylmethylene-2-fluoro-5-nitrophenoxy)acetate was obtained the ester of glycine, 40 ml of tetrahydrofuran, 10 ml of dimethylformamide and 3 ml of triethylamine.

The NMR spectrum (CDCl3, internal standard TMS): : to 1.31 (3H, t, J=6.8 Hz), of 1.52 (9H, s), of 3.94 (2H, d, J=4.5 Hz), 4,28 (2H, q, J=6.8 Hz), with 4.64 (2H, s), of 6.45 (1H, d, J=a 12.7 Hz), 7,83 (1H, d, J=8,8 Hz), 8,42 (1H, s).

2) 1.88 g (78% of ethyl-2-[4-tert-butoxycarbonylamino-2-(1H-imidazol-1-yl)-5-nitrophenoxy] acetate was obtained with the use of 2.13 g (5,73 mmol) of 2-(4-tert-butoxycarbonylmethylene-2-fluoro-5-nitrophenoxy)acetate, 1.56 g of imidazole and 15 ml of DMF.

The NMR spectrum (CDCl3, internal standard TMS): : to 1.31 (3H, t, J=8.7 Hz), of 1.52 (9H, s), 3,98 (2H, d, J=5.4 Hz), 4,27 (2H, q, J=8.7 Hz), of 4.66 (2H, s), of 6.65 (1H, s), 7,20 (1H, s), 7,39 (1H, s), 7,39 (1H, s), 7,83 (1H, s), 8,01 (1H, s), of 8.37 (1H, Shir.S.).

3) In this stage used ethyl-2-[(4-tert-butoxy-carbonylmethyl) amino-2-(1H-imidazol-1-yl)-5-nitrophenoxy] acetate (1.75 g, 4,71 mmol), 100 ml of tetrahydrofuran and 0.3 g of 10% palladium-on-charcoal, and conducted the reaction of recovery. 1,03 g (53%) of 2-[6-carboxymethoxy-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl] acetic acid was obtained with the use of 3.3 ml of triethylamine and 3.22 g of etylchlorhydrine.

So pl.: > 300oC (Razlog.).

MS (m/z): 360 (M+).

NMR spectrum (DMSO-d6, internal standard TMS): : to 4.81 (2H, s), 4,88 (2H, s), the silt ester of N-(4-etoxycarbonyl-5-fluoro-2-nitrophenyl)glycine was obtained using 3,63 g of the hydrochloride tert-butyl ester of glycine, 25 ml of tetrahydrofuran, 3.03 g of triethylamine, 5 ml of dimethylformamide and 5.0 g (21.6 mmol) of ethyl-2,4-debtor-5-nitrobenzoate.

The NMR spectrum (CDCl3, internal standard TMS): : of 1.39 (3H, t, J=8,3 Hz) of 1.53 (9H, s), 3,98 (2H, d, J=4.9 Hz), 4,37 (2H, q, J=8,3 Hz), 6,36 (1H, d, J=a 12.7 Hz), a total of 8.74 (1H, Shir.C.), 8,88 (1H, d, J=8.7 Hz).

2) 7,01 g (97%) tert-butyl ether N-[4-etoxycarbonyl-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine was obtained using 6,35 g (18.5 mmol) of tert-butyl methyl ether M-(4-etoxycarbonyl-5-fluoro-2-nitrophenyl)glycine, of 5.05 g of imidazole, and 20 ml of DMF.

The NMR spectrum (CDCl3, internal standard TMS): : of 1.18 (3H, t, J=7,3 Hz), of 1.52 (9H, s) to 4.01 (2H, d, J= 5.4 Hz), 4,19 (2H, q, J=7,3 Hz), to 6.58 (1H, s), 7,07 (1H, s) 7,19 (1H, s), 7,60 (1H, s), is 8.75 (1H, Shir. C.), 8,96 (1H, s).

3) a Mixture containing at 6.84 g (17.5 mm) tert-butyl ether N-[4-etoxycarbonyl-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine, 150 ml of tetrahydrofuran and 0.5 g of 10% palladium-on-charcoal, stirred at normal pressure and at room temperature in a hydrogen atmosphere. After completion of the reaction the catalyst was removed by filtration. To this filtrate was added to 12.3 ml of triethylamine. To the obtained mixture under stirring and under cooling with ice for one drop was added to the mixture 11,96 g etylchlorhydrine and 20 ml of tetrahydrofuran. The reaction mixture Ally was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added 100 ml of ethanol, and the resulting mixture was heated under reflux for three hours. After cooling, the precipitated crystals were collected by filtration, then washed with ethanol and diethyl ether and then dried under reduced pressure. To the resulting compound were added 30 ml triperoxonane acid, and the mixture was stirred over night at room temperature. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added 10 N. aqueous sodium hydroxide solution and 1 N. aqueous sodium hydroxide solution to bring the pH to a value of 9-10, and then was stirred overnight. To bring the pH to 2-3, the reaction mixture was added concentrated hydrochloric acid and 1 N. aqueous solution of hydrochloric acid. Precipitated crystals were collected by filtration. The compound obtained was recrystallized from 1 N. aqueous solution of hydrochloric acid, resulting in received of 3.65 g (63%) of 2-[6-carboxy-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl] acetic acid and 0.15 HCl for 1.5 H2O.

So pl.: > 300oC.

MC (m/z): 330 (M+).

NMR spectrum (DMSO-d6,
1) To a mixture containing 6,86 g 2,4-debtor-5-nitrobenzonitrile, was 22.67 of triethylamine, and 40 ml of DMF and 40 ml of tetrahydrofuran under ice cooling was added 5.20 g of the hydrochloride of the ethyl ester of glycine, and the resulting mixture was stirred at the same temperature for 4 hours. To the reaction mixture was added water, and the product was extracted with chloroform. The extract was sequentially washed with water and saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 80-20), resulting in a received 4,85 g (49%) of ethyl ester of N-(4-cyano-5-fluoro-2-nitrophenyl)glycine.

The NMR spectrum (CDCl3, internal standard TMS): : 1,22 is 1.48 (3H, m), 4,08 (2H, d, J =5.3 Hz), 4,19-4,50 (2H, m), 6,46 (1H, d, J=11.3 Hz), to 8.57 (1H, d, J=6,7 Hz), 8,80-9,05 (1H, Shir.).

2) a Mixture containing 2.50 g of ethyl ester of N-(4-cyano-5-fluoro-2-nitrophenyl)glycine, of 0.67 g of imidazole, 7,40 g of pyridine and 40 ml of DMSO was stirred for four hours at a temperature of 80oC. After adding water, the reaction product was extracted with chloroform. The extract was sequentially washed with water and brine, and then dried with anhydrous sodium sulfate and is silicagel (eluent: chloroform:methanol=95:5), resulting received 2,82 g (92%) of ethyl ester of N-[4-cyano-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine.

NMR spectrum (DMSO-d6, internal standard TMS): : 1,15-of 1.26 (3H, m), 4,10-is 4.21 (2H, m), of 4.45 (2H, d, J=5.5 Hz), 7,15-7,22 (2H, m), 7.68 per-7,73 (1H, m), 8,17 (1H, s), is 8.75 (1H, s), cent to 8.85-to 8.94 (1H, m).

3) a Mixture containing 2.00 g of ethyl ester of N-[4-cyano-5-(1H-imidazol-1-yl)-2-nitrophenyl] glycine, 40 ml of tetrahydrofuran (THF, 8 ml of methanol and 200 mg of 10% palladium-on-charcoal, stirred in hydrogen atmosphere for nitrogroup reduction. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure. Then to the residue was added 50 ml of chloroform and 4,43 ml of triethylamine, the resulting mixture, while cooling with ice, drop by drop was introduced 1,69 ml of etylchlorhydrine. After stirring at room temperature for 20 hours the reaction mixture was diluted with chloroform. The diluted mixture was washed with saline, dried with anhydrous sodium sulfate and concentrated under reduced pressure. To the obtained residue was added 60 ml of ethanol and 0.5 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 3 hours. After cooling, the resulting crystals were collected by filtration and was dried under reduced da-yl]acetate.

NMR spectrum (DMSO-d6, internal standard TMS): : 1,15-1,25 (3H, m), 4,10-4,20 (2H, m), 4,99 (2H, s), to 7.84 (1H, s), of 7.90 (1H, s), of 8.04 (1H, s), 8,16 (1H, s), for 9.47 (1H, s), 12,83 (1H, s).

4) To 6 ml of 1 N. aqueous sodium hydroxide solution was added 672 mg of ethyl 2-[6-cyano-2,3-dioxo-7-(1H-imidazol-1 - yl)-1,2,3,4-tetrahydroquinoxalin-1-yl] acetate at room temperature, and the mixture was stirred one hour for hydrolysis of ester. The reaction mixture is brought to pH 1 by addition of 1 N. hydrochloric acid. Precipitated crystals thus collected by filtration, washed with water, and dried under reduced pressure, resulting in a received 417 mg (62%) of 2-[6-cyano-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4 - tetrahydroquinoxalin-1-yl]acetic acid 1,7 H2O.

So pl.: 283-285oC (Razlog.).

NMR spectrum (DMSO-d6, internal standard TMS): : of 4.95 (2H, s), 7,17 (1H, s), a 7.62 (2H, s), 7,74 (1H, s), of 8.06 (1H, s), 12,54 (1H, s), 13,2-13,4 (1H, Shir.).

Compounds of Examples 14-20 received by the method described in Example 13.

Example 14

1) 2.70 g (61%) of ethyl ester of N-(5-fluoro-4-methyl-2-nitrophenyl)glycine was obtained using 3.00 g of 2,4-debtor-5-nitrotoluene, 8,77 g of triethylamine, and 40 ml of dimethylformamide and 40 ml of tetrahydrofuran, and to 2.42 g of the hydrochloride of the ethyl ester of glycine.

2) 470 mg (39%) of ethyl ester of N-[5-(1H-imidazol-1-yl)-4-methyl-2-nitrophenyl] glycine was obtained with the use of 1.00 g of ethyl ester of N-(5-fluoro-4-methyl-2-nitrophenyl)-glycine, 266 mg of imidazole and 10 ml of pyridine.

The NMR spectrum (CDCl3, internal standard TMS): : 1,26-of 1.36 (3H, m), of 2.15 (3H, s), of 4.05 (2H, d, J=5.5 Hz), 4,23-to 4.33 (2H, m), 6,55 (1H, s), to 7.09 (1H, s), 7,24 (1H, s), 7,63 (1H, s), to 8.20 (1H, s), 8,32 (1H, Shir.).

3) 221 mg (44%) of ethyl-2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-methyl-1,2,3,4-tetrahydroquinoxalin-1-yl] acetate was obtained with the use of 467 mg of ethyl ester of N-[5-(1H-imidazol-1-yl)-4-methyl-2-nitrophenyl]glycine.

NMR spectrum (DMSO-d6, internal standard TMS): : to 1.21 (3H, t, J=7,3 Hz), 2,17 (3H, s), 4,10-4,19 (2H, m), 7,25 (1H, s), of 7.70 (1H, s), 7,89 (1H, s), 7,98 (1H, s), 12,45 (1H, s).

4) 180 mg (79%) of 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-methyl-1,2,3,4-tetrahydroquinoxalin-1-yl] acetic acid 1HCl 0,4 H2O received with use of 218 mg of ethyl-2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-methyl-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate.

So pl.: > 300oC.

MC (m/z): 301 (M++1).

NMR spectrum (DMSO-d6, internal standard TMS): : 2,17 (3H, s), a 4.83 (2H, s), 7,25 (1H, s), 7,72 (1H, s), of 7.90 (1H, s), to 7.99 (1H, s), 9,34 (1H, s), 12,46 (1H, s), of 13.1 and 13.3 (1H, Shir.).

Example 15

1) of 0.59 g ( g of triethylamine, 25 ml of DMF, 25 ml THF, and 1.58 g of the hydrochloride of the ethyl ester of glycine.

The NMR spectrum (CDCl3, internal standard TMS): : 1,20-of 1.45 (3H, m), a 4.03 (2H, d, J=5.3 Hz), 4,15-4,47 (2H, m), 6.48 in (1H, DD, J=12.2 and 6.6 Hz), 8,10 (1H, DD, J=10.6 and an 8.4 Hz), to 8.3 and 8.6 (1H, Shir.).

2) of 0.41 g (59%) of ethyl ester of N-[4-fluoro-5-(1H-imidazol-1-yl)-2-nitrophenyl] glycine was obtained with the use of 0.59 g of ethyl ester of N-(4,5-debtor-2-nitrophenyl)glycine, 155 mg of imidazole, of 1.80 g of pyridine and 10 ml of DMSO.

The NMR spectrum (CDCl3, internal standard TMS): : 1,20-of 1.46 (3H, m), a 4.03-4,48 (4H, m), of 6.66 (1H, d, J=6,1 Hz), 7,20-7,40 (2H, m), of 7.90 (1H, Shir. ), 8,10-at 8.60 (2H, m).

3) 154 mg (35%) ethyl-2-[2,3-dioxo-6-fluoro-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl] acetate was obtained with the use of 406 mg of ethyl ester of N-[4-fluoro-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine.

NMR spectrum (DMSO-d6, internal standard TMS): : 1,16-of 1.29 (3H, m), 4,12-4,22 (2H, m), to 4.98 (2H, s), 7,33 (1H, d, J=10,8 Hz), 7,81-of 7.96 (2H, m), of 8.06 (1H, s), 9,36 (1H, s), to 12.58 (1H, s).

4) 90 mg (61%) of 2-[2,3-dioxo-6-fluoro-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetic acid 1H2O received using 152 mg of ethyl-2-[2,3-dioxo-6-fluoro-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate.

So pl.: > 300oC.

MS (m/z): 305 (M++ 1).

NMR spectra(1H, C) at 13.0 and 13.2 (1H, Shir.).

Example 16

1) 0.66 g (7%) of ethyl ester of N-(4-chloro-5-fluoro-2-nitrophenyl)glycine was obtained using 6,32 g of 5-chloro-2,4-deformirovannoe, to 9.91 g of triethylamine, 60 ml of DMF, and 60 ml of tetrahydrofuran, and 4,56 g of the hydrochloride of the ethyl ester of glycine.

The NMR spectrum (CDCl3, internal standard TMS): : to 1.16 to 1.47 (3H, m), Android 4.04 (2H, d, J=5.3 Hz), 4,16 is 4.45 (2H, m), 6,47 (1H, d, J=11,1 Hz), 8,25-8,67 (2H, m).

2) of 0.44 g (57%) of ethyl ester of N-[4-chloro-5-(1H-imidazol-1-yl)-2-nitrophenyl] glycine was obtained using 0.66 g of ethyl ester of N-(4-chloro-5-fluoro-2-nitrophenyl)glycine, 162 mg of imidazole and 4 ml of pyridine.

The NMR spectrum (CDCl3, internal standard TMS): : 1,16-of 1.44 (3H, m), 4,07 (2H, d, J=5,2 Hz), 4,16-4,48 (2H, m), of 6.65 (1H, s), 7,15-7,37 (2H, m), 7,76 (1H, s), 8,35-8,63 (2H, m).

3) 235 mg (50%) ethyl-2-[6-chloro-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl] acetate was obtained with the use of 442 mg of ethyl ester of N-[4-chloro-5-(1H-imidazol-1-yl)-2 - nitrophenyl]glycine.

NMR spectrum (DMSO-d6, internal standard TMS): 1,17-1,24 (3H, m), 4,12-4,20 (2H, m), is 4.93 (2H, s), of 7.48 (1H, s), 7,81 (1H, s), to $ 7.91-7,98 (2H, m), 9,23 (1H, s), 12,54 (1H, s).

4) 163 mg (79%) of 2-[6-chloro-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl] acetic acid and 0.7 H2O received using 225 mg S="ptx2">

MS (m/z): 321 (M++1).

NMR spectrum (DMSO-d6, internal standard TMS): : the 4.90 (2H, s), to 7.15 (1H, s), 7,37-7,47 (2H, m), to 7.67 (1H, s), 7,92 (1H, s), 12,40 (1H, s).

Example 17

1) of 10.5 g (60%) of ethyl ester of N-(4-bromo-5-fluoro-2-nitrophenyl)glycine was obtained with the use to 7.61 g (of 54.5 mmol) of the hydrochloride of the ethyl ester of glycine, 15 ml of tetrahydrofuran, to 7.64 ml of triethylamine, 10 ml of DMF and 11.8 g (49,6 millimoles) of 5-bromo-2,4-deformirovannoe.

The NMR spectrum (CDCl3, internal standard TMS): : to 1.33 (3H, t, J=7.4 Hz), Android 4.04 (2H, d, J= 4.9 Hz), 4,30 (2H, q, J = 7.4 Hz), 6,46 (1H, d, J = 10,9 Hz), 8,44 (1H, d, J = 7,3 Hz), 8,49 (1H, Shir. C.).

2) 3.50 g (90%) of ethyl ester of N-[4-bromo-5-(1H-imidazol-1-yl)-2-nitrophenyl] glycine was obtained using 3,36 g (10.5 millimoles) of ethyl ester of N-(4-bromo-5-fluoro-2-nitrophenyl)glycine, 2.86 g of imidazole and 20 ml of dimethyl-formamide.

The NMR spectrum (CDCl3, internal standard TMS): : to 1.32 (3H, t, J=7.4 Hz), of 4.05 (2H, DD, J=5,2, to 14.9 Hz), the 4.29 (2H, q, J=7.4 Hz), only 6.64 (1H, d, J= 9.1 Hz), 7,19 (1H, s), 7.23 percent (1H, s), 7,72 (1H, s), 7,72 (1H, s), to 8.45 (1H. Shir.C.), to 8.57 (1H, s).

3) a Mixture containing 3,24 g (8,78 mmol) of ethyl ester of N-[4-bromo-5- (1H-imidazol-1-yl)-2-nitrophenyl] glycine, 70 ml of tetrahydrofuran, 50 ml of methanol, and about 0.5 g of Nickel catalyst Raney, was stirred at room temperature the filtrate was concentrated under reduced pressure. To the residue was added 100 ml of chloroform and 3.1 ml of triethylamine. To the resulting mixture while cooling with ice and with stirring drop by drop was added to the mixture to 3.02 g of etylchlorhydrine and 20 ml of chloroform. The reaction mixture was heated to room temperature and then was stirred overnight. The reaction mixture was diluted with 150 milliliters of chloroform, then washed with water, 5% aqueous sodium bicarbonate solution and brine, and then dried with anhydrous sodium sulfate, and concentrated under reduced pressure. After adding 100 ml of ethanol and 1.5 ml of concentrated hydrochloric acid the mixture was heated under reflux for 6 hours.

After cooling, the reaction mixture was concentrated under reduced pressure. To this mixture was added 15 ml of 1 N. aqueous sodium hydroxide solution, and then stirred for two hours. The reaction mixture is brought to pH 2-3 by adding 1 N. aqueous solution of hydrochloric acid, and precipitated thus the connection was collected by filtration. The compound obtained was recrystallized from 1 N. aqueous solution of hydrochloric acid, resulting in a received 2,02 g (55%) of 2-[6-bromo-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetic to the R-range DMSO-d6, internal standard TMS): : 4,84 (2H, s), of 7.75 (1H, s), to 7.93 (1H, s), 8,02 (1H, s), 8,03 (1H, s), 9,48 (1H, s), was 12.75 (1H, s), 12,6-14,0 (1H, Shir.).

Example 18

1) 0.52 g (13%) of ethyl ester of N-(5-fluoro-4-methoxy-2-nitrophenyl)glycine was obtained using 2,78 g 2,4-debtor-5-nitrophenylamino ether of 4.45 g of triethylamine, 30 ml of DMF, 30 ml of THF, and 2,05 gatilova ester of glycine.

The NMR spectrum (CDCl3, internal standard TMS): : 1,19-of 1.45 (3H, m), 3,80-4,46 (7H, m), of 6.45 (1H, d, J = 13.1 Hz), 7,81 (1H, d, J=8,8 Hz), to 8.3 and 8.6 (1H, Shir.).

2) 200 mg (41%) of ethyl ester of N-[5-(1H-imidazol-1-yl)-4-methoxy-2-nitrophenyl

glycine was obtained using 420 mg of ethyl ester of N-(5-fluoro-4-methoxy-2-nitro-phenyl)glycine, 420 mg of imidazole, and 2.5 ml of dimethylformamide.

The NMR spectrum (CDCl3, internal standard TMS): : of 1.27 to 1.37 (3H, m), 3,88 (3H, s), 4.09 to (2H, d, J=5.5 Hz), 4,25-4,34 (2H, m), only 6.64 (1H, s), 7,20 (1H, s), 7,27 (1H, s), a 7.85-7,94 (2H, m), 8,32-to 8.40 (1H, m).

3) 46 mg (22%) ethyl-2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-methoxy-1,2,3,4 - tetrahydroquinoxalin-1-yl]acetate was obtained with the use of 196 mg of ethyl ester of N-[5-(1H-imidazol-1-yl)-4-methoxy-2-nitrophenyl]glycine.

NMR spectrum (DMSO-d6, internal standard TMS): : 1,17-1,25 (3H, m), 3,85 (3H, s), 4,11-4,20 (2H, m), 4,94 (2H, s), to 7.09 (1H, s), of 7.75 (1H, s), 7,79 (1H, s), 7,92 (1H, s), 9,24 (1H, s), 12,37 (1H, s).

4) poluchili using 44 mg of ethyl-2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-methoxy-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate.

So pl.: > 300oC.

MS (m/z): 317 (M++1).

NMR spectrum (DMSO-d6, internal standard TMS): : 3,81 (3H, s), 4,91 (2H, s), 7,02 (1H, s), 7,12 (1H, J), 7,43-7,51 (2H, m), to 7.99 (1H, s), 12,23 (1H, s), at 13.0 and 13.3 (1H, Shir.).

Example 19

1) 454 mg (8%) of ethyl ester of N-(4-benzyloxy-5-fluoro-2 - nitrophenyl)glycine was obtained with the use to 4.41 g of benzyl-2,4-debtor-5-nitrophenylamino ether of 5.05 g of triethylamine, 30 ml of DMF, 30 ml of THF, and 2,32 g of the hydrochloride of the ethyl ester of glycine.

The NMR spectrum (CDCl3, internal standard TMS): : to 1.32 (3H, t, J = 7,3 Hz), a 4.03 (2H, d, J=5.5 Hz), 4,25-to 4.33 (2H, m) 5,09 (2H, s), 6,44 (1H, d, J= and 12.2 Hz), 7,30-of 7.48 (5H, m), to 7.99 (1H, d, J=8.5 Hz), 8,40 (1H, Shir.).

2) 331 mg (65%) of ethyl ester of N-[4-benzyloxy-5-(1H-imidazol-1-yl)-2-nitrophenyl] glycine was obtained using 448 mg of ethyl ester of N-(4-benzyloxy-5-fluoro-2-nitrophenyl)glycine, 350 mg of imidazole and 2 ml of DMF.

NMR sectr (CDCl3, internal standard TMS): : to 1.32 (3H, t, J=7,3 Hz), 4,08 (2H, d, J=5.5 Hz), 4,25-4,34 (2H, m), 5,09 (2H, s), 6,63 (1H, s), 7,20 (1H, s), 7,25-7,40 (6H, m), 7,92 (1H, s), 8,00 (l1H, C), 8,31-of 8.37 (1H, m).

3) 70 mg (66%) of ethyl-2-[6-benzyloxy-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl] acetate was obtained using 100 mg of ethyl ester of N-[4-benzyloxy-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine.

NMR SN, m), 7,94-8,08 (1H, m), 9,36-9,48 (1H, m), 12,47 (1H, s).

4) 86 mg (62%) of 2-[6-benzyloxy-2,3-dioxo-7-(1H-imidazol-1-yl)- 1,2,3,4-tetrahydroquinoxalin-1-yl] acetic acid HCl 0,5 1,4 H2O received using 134 mg ethyl-2-[6-benzyloxy-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate.

So pl.: 275oC (Razlog.).

MC (m/z): 393 (M++ 1).

NMR spectrum (DMSO-d6, internal standard TMS): : 4,88 (2H, s) to 5.17 (2H, s), 7,13 (1H, s), 7,30-of 7.48 (6H, m), of 7.64 (1H, s), 7,74 (1H, s), 8,66 (1H, s), 12,32 (1H, s).

Example 20

1) of 2.44 g (99%) of ethyl ester of N-(5-fluoro-4-methylsulphonyl-2-nitrophenyl) glycine was obtained using 1,82 g 2,4-debtor-5-nitrophenyl methylsulfone, 0,78 g of triethylamine, 4 ml of DMF, 8 ml of THF and 1.07 g of the hydrochloride of the ethyl ester of glycine.

The NMR spectrum (CDCl3, internal standard TMS): : 1,15-of 1.55 (3H, m), 3,19 (3H, s), 3,93-4,50 (4H, m), of 6.49 (1H, d, J=12.0 Hz), 8,76 - 9,07 (2H, m).

2) 0.35 g (67%) of ethyl ester of N-[5-(1H-imidazol-1-yl)-4-methylsulphonyl - 2-nitrophenyl] glycine was obtained with the use of 1.00 g of ethyl ester of N-(5-fluoro-4-methylsulphonyl-2-nitrophenyl)glycine, 0.85 grams of imidazole and 5 ml of dimethylformamide.

NMR spectrum (DMSO-d6, internal standard TMS): : 1,08-of 1.32 (3H, m), of 2.86 (3H, s) to 4.16 (2H, q, J=7,3 Hz) to 4.41 (2H, d, J=6.0 Hz), 7,09-of 7.23 (2H, m), 7,Il - 1,2,3,4-tetrahydroquinoxalin-1-yl] -acetate was obtained with the use of 345 mg of ethyl ester of N-[5-(1H-imidazol-1-yl)-4-methylsulphonyl-2-nitrophenyl]glycine.

NMR spectrum (DMSO-d6, internal standard TMS): : 1,16-1,25 (3H, m), 3,18 (3H, s), 4,12-4,20 (2H, m), of 4.95 (2H, s), 7,83 (1H, s), 7,94-of 8.06 (3H, m), 9,37 (1H, s), was 12.75 (1H, s).

4) 106 mg (68%) of 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-methylsulphonyl - 1,2,3,4-tetrahydroquinoxalin-1-yl] acetic acid 0,6 HCl 1,2 H2O was obtained by using 150 mg of ethyl-2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-methylsulphonyl-1,2,3,4 - tetrahydroquinoxalin-1-yl]acetate.

So pl.: > 300oC.

MC (m/z): 365 (M++ 1).

NMR spectrum (DMSO-d6, internal standard TMS): : a 3.06 (3H, s), 4,88 (2H, s), to 7.59 (1H, s), 7,82 (1H, s), 7,88-7,98 (2H, m), 8,84 (1H, s), 12,68 (1H, s), of 13.1 to 13.5 (1H, Shir.).

Example 21

A mixture containing 1.63 g ethyl-2-[2,3-dioxo-7-fluoro-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate, 4 ml of 50% aqueous dimethylamine and 10 ml of dimethylformamide, was heated and stirred in an oil bath (100oC) in argon atmosphere for 5 hours. After cooling, the reaction mixture was concentrated under reduced pressure. To the obtained residue were added 15 ml of 1 N. aqueous sodium hydroxide solution, and then stirred for 3 hours at a temperature of 30oC. the Reaction mixture was concentrated under reduced pressure to half the original volume, and then added 3 N. solenopotes filter, washed with 1 N. hydrochloric acid and was dried under reduced pressure. The crude crystals are recrystallized from 1 N. hydrochloric acid, resulting in a received 742 mg (45%) of 2-[7-dimethylamino-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl] acetic acid, and 0.5 H2O.

So pl.: > 300oC. MS (m/z): 309 (M++ 1).

NMR spectrum (DMSO-d6, internal standard TMS): : 2,82 (6H, s), equal to 4.97 (2H, s), 6,83 (1H, s), 7,45 (1H, s), 12,17 (1H, Shir. C.).

Example 22

A mixture containing equal to 2.94 g of ethyl-2-[7-fluoro-2,3-dioxo-6-nitro - 1,2,3,4-tetrahydroquinoxalin-1-yl] acetate, of 1.36 g of imidazole and 20 ml of dimethylformamide, was stirred under heating at a temperature of 120oC for 3 hours. After cooling, the reaction mixture was poured into ice-cold water. Precipitated crystals thus collected by filtration, washed with water and dried under reduced pressure, resulting in received of 3.45 g (99%) of ethyl-2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl] -acetate 0,65 H2O.

So pl. 159-160oC (Razlog.).

MC (m/z): 359 (M+).

NMR spectrum (DMSO-d6, internal standard TMS): : to 1.21 (3H, t, J=7.2 Hz), of 4.16 (2H, q, J = 7.2 Hz), to 5.03 (2H, c), to 7.09 (1H, c), 7,39 (1H, c), of 7.75 (1H, c), 7,87 (1H, c), of 8.00 (1H, c), 12,60 (1H, Shir.S.).

MC (m/z): 314 (M+).

NMR spectrum (DMSO-d6, internal standard TMS): : 1,22 (3H, t, J=7.0 Hz), 4,18 (2H, q, J=7.0 Hz), is 5.06 (2H, s), 7,41 (1H, d, J=8.6 Hz), 7,60 (1H, DD, J=2.5 and 8.6 Hz), the 7.65 (1H, s), to 7.77 (1H, d, J=25 Hz), 8,13 (1H, s), 9,24 (1H, s), 12,47 (1H, s).

2) At a temperature of 0oC or below 0oC, 3,63 g ethyl-2-[2,3 - dioc the th acid. The resulting solution was heated to room temperature, was stirred for one hour, and poured into ice-cold water, then brought to a pH of 2.0 by adding an aqueous solution of sodium hydroxide. Received nerastvorimaya substance was removed by filtration. To this filtrate was added an aqueous solution of sodium hydroxide to bring the pH of the resulting liquid to a value of about 6.5. Received nerastvorimaya substance was collected by filtration, washed with water and dried under reduced pressure, resulting in a received 1.07 g (26%; purity: 95% (URGH analysis)) ethyl-2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate.

3) a Mixture containing 2,12 g ethyl-2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl] - acetate and 13 ml of 1 N. aqueous sodium hydroxide solution, stirred at room temperature in argon atmosphere. After completion of the reaction, the reaction mixture was brought to pH 3.0 by adding 0.5 ml of concentrated hydrochloric acid and the corresponding number of 1 N. hydrochloric acid. Precipitated crystals thus collected by filtration, washed with 1 N. hydrochloric acid and was dried under reduced pressure. Received neojidanno the 84%) of 2-[2,3-dioxo-7- (1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl] acetic acid 1HCl 1H2O.

So pl.: 248-250oC (Razlog.).

MC (m/z): 331 (M+).

NMR spectrum (DMSO-d6, internal standard TMS): : the 4.90 (2H, s), 7,89 (1H, s), 8,03 (1H, s), of 8.09 (1H, s) of 8.33 (1H, s), 9,48 (1H, s), 12,96 (1H, s).

Example 24

66 ml of 1 N. aqueous sodium hydroxide solution while cooling with ice was gradually added to 8.5 g of compound of Example 23 to its dissolution. To the obtained solution under cooling with ice was gradually added 44 ml of 1 N. aqueous solution of hydrochloric acid.

Precipitated crystals were collected by filtration and dried, resulting in a received 6.8 g of 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetic acid in the form of crystals.

Elemental analysis for C13H9N5O60,2 H2O 0,2 H2O (%):

Calculated: C 46,63; H 2,83; N 20,92;

Found: C 46,51; H-2.91 In; N 21,00.

NMR spectrum (DMSO-d6, internal standard TMS): : of 4.95 (2H, s), 7,10 (1H, s), 7,40 (1H, s), 7,73 (1H, s), 7,88 (1H, s), of 8.00 (1H, s), to 12.58 (1H, s), and 13.4 (1H, Shir.S.).

Example 25

1) To a mixture containing of 5.06 g (32.9 millimoles) of 2,4-deformirovannoe, of 5.24 g of the hydrochloride of 5-aminovaleric acid and 20 ml of tetrahydrofuran was added 9,24 ml of triethylamine, and the mixture was heated under reflux in the Lyali by filtration. The filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate/ethyl ether, which was given to 4.73 g (56%) of 5-(3-fluoro-6-nitrophenyl) aminovaleric acid.

MC (m/z): 256 (M+).

NMR spectrum (DMSO-d6, internal standard TMS): : 1,78 of-1.83 (4H, m), 2,44-2,48 (2H, m), 3,29 (2H, q, J=7.0 Hz), 3,34-3,39 (1H, m), 6,45-of 6.49 (1H, m), 8,16-8,23 (1H, m).

2) a Mixture containing 2,19 g (8,55 mmol) 5-(3-fluoro-6-nitrophenyl) aminovaleric acid, 100 ml of 2-propanol and 5 ml of 4 N. hydrochloric acid in dioxane was heated under reflux for two hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified using column chromatographie on silica gel (manifesting solvent: hexane/ethyl acetate= 9: 1 - 6:1), as a result, we got to 2.55 g (stechiometric. Qty) isopropyl-5-(3-fluoro-6-nitrophenyl) aminovaleric.

MC(m/z): 298 (M+).

The NMR spectrum (CDCl3, internal standard TMS): : 1,24 (6N, d, J=6.4 Hz), 1,76-2,82 (4H, m), a 2.36 (2H, t, J=6.8 Hz), or 3.28 (2H, d, J=5.4 Hz), to 5.03 (1H, q, J=6.4 Hz), 6,33-to 6.39 (1H, m), 6,47 (1H, DD, J=2.5 and an 11.7 Hz), 8.17-a 8,23 (1H, m).

3) Mixture of 2.53 g (8,48 mmol) isopropyl-5-(3-fluoro-6-nitrophenyl)aminomalonate, 100 ml of tetrahydrofuranate for 5 hours. After completion of the reaction the catalyst was removed by filtration. To the filtrate was added 5,94 ml of triethylamine, and the mixture was stirred under ice cooling in an argon atmosphere. To the resulting solution, with stirring, one drop was added a mixture consisting of 5.49 g of etylchlorhydrine and 15 ml of tetrahydrofuran. After stirring for one hour, nerastvorimaya substance was removed by filtration, and the filtrate was concentrated under reduced pressure. To the obtained residue was added 150 ml of ethanol, and the mixture was heated under reflux for 18 hours. After cooling, the reaction mixture was concentrated under reduced pressure to 1/3 the original volume. To the obtained residue was added 100 ml of ethyl ether. Besieged thus nerastvorimaya substance was collected by filtration and was dried under reduced pressure, resulting in a received 2.17 g (79%) isopropyl-5-[2,3-dioxo-7-fluoro-1,2,3,4-tetrahydroquinoxalin-1-yl]-valerate.

MC (m/z): 322 (M+).

NMR spectrum (DMSO-d6, internal standard TMS): : to 1.16 (6H, d, J=6,1 Hz), 1.60-to of 1.62 (4H, m), 2,32 (2H, t, J=6,7 Hz), 4,01-4,08 (2H, m), to 4.87 (1H, q, J= 6,1 Hz), 7,01-7,05 (1H, m), 7,18 (1J, DD, J=5,5, 8.6 Hz), 7,32 (1H, DD, J=2,7, 11 Hz), to 12.0 (1H, s).

4) In 10 ml kontsentrirovannoe-5-[2,3-dioxo-7-fluoro-1,2,3,4-tetrahydroquinoxalin-1-yl] valerate. To the resulting mixture at a temperature equal to -5oC or below, one drop was added 300 μl of fuming nitric acid and then the mixture was stirred for 30 minutes. The reaction mixture was poured into ice-cold water. Besieged thus nerastvorimaya substance was collected by filtration, washed with water, and dried under reduced pressure, resulting in received of 2.06 g (93%) isopropyl-5-[2,3-dioxo-7-fluoro-6-nitro-1,2,3,4 - tetrahydroquinoxalin-1-yl] valerate.

MS (m/z): 367 (M+).

NMR spectrum (DMSO-d6, internal standard TMS): : to 1.16 (6H, d, J=6.3 Hz), 1,61-to 1.63 (4H, m), 2,30 of-2.32 (2H, m), as 4.02-to 4.14 (2H, m), 4,88 (1H, q, J=6.3 Hz), 7,66 (1H, d, J=13,7 Hz), of 7.90 (1H, d, J= 7,3 Hz), and 12.2 (1H, s).

5) the Mixture containing 1.88 g (5,11 mmol) isopropyl-5-[2,3-dioxo-7-fluoro-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]valerate, 765 mg of imidazole and 15 ml of DMF was stirred while heating in an oil bath (70oC) within ten hours in a stream of argon. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to half of the original volume. The obtained residue was poured into ice water. Besieged nerastvorimaya substance was collected by filtration, washed with water and dried under reduced pressure. Around hydroxide sodium, and this mixture was stirred for 5 hours. The reaction mixture is brought to pH 5-6 by adding an aqueous solution of hydrochloric acid. After deposition of nerastvorimogo substances, the reaction mixture was heated to obtain a homogeneous solution and then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from 10 ml of water, resulting in received of 1.15 g of 5-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl] valerianic acid 1HCl 0,2 H2O (54%).

So pl.: 236-237oC.

Elemental analysis for C16H15N5O6HCl 0,2 H2O (%):

Calculated: C 46,49; H 4,00; N 16,94; C 18,56

found: C 46,34; H 3,95; N 16.88 In; Cl 8,69

Example 26

for 9.64 g (86%) of ethyl-6-(5-(fluoro-2-nitrophenylamino)hexanoate was obtained by the method described in Example 1-1, except that used 7,38 g of the hydrochloride of the ethyl-6-aminohexanoate, 100 ml of tetrahydrofuran, to 26.3 ml of triethylamine in 35 ml of dimethylformamide and 6.00 g of 2,4-deformirovannoe.

MS (m/z): 298 (M+).

The NMR spectrum (CDCl3, internal standard TMS): 1: 1,10-1,97 (9H, m), of 2.34 (2H, t, J=6.5 Hz), 3,10-of 3.42 (2H, m), 4,14 (2H, q, J=7,1 Hz), 6.22 per 6,62 (2H, m), 8,00-8,35 (2H, m).

2) of 1.75 g (32%) of ethyl-6-(2,3-dioxo-7-fluoro-1,2,3,4-t is built of 5.00 g of ethyl-6-(5-fluoro-2-nitrophenylamino)hexanoate.

MC (m/z 323 (M++1).

NMR spectrum (DMSO-d6, internal standard TMS): : 0,95-to 1.83 (9H, m), 2,10-of 2.45 (2H, m), 3,86-to 4.28 (4H, m), 6.90 to-7,46 (3H, m), 11,95-12,15 (1H, Shir.).

3) 1.04 g (91%) of ethyl-6-(2,3-dioxo-7-fluoro-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl)hexanoate was obtained by the method described in Example 1-3, except that he used to 1.00 g of ethyl-6-(2,3-dioxo-7-fluoro-1,2,3,4-tetrahydroquinoxalin-1-yl)hexanoate. MC(m/z): 368 (M++1).

NMR spectrum (DMSO-d6, internal standard TMS): : 0,90-1,82 (9H, m), 2,02-of 2.50 (2H, m), 3,76-to 4.33 (4H, m), 7,66 (1H, d, J= 13,7 Hz), of 7.90 (1H, d, J= 7,4 Hz), 12,13-12,40 (1H, Shir.).

4) 318 mg (74%) of 6-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl] hexanoic acid 0,9 H2Oh was obtained by the method described in Example 1-4, except that used 392 mg ethyl-6-(2,3-dioxo-7 - fluoro-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl)hexanoate, 160 mg of imidazole and 2.5 ml DMF.

So pl.: 120-123oC.

Elemental analysis for C17H17N5O60,9 H2O (%):

Calculated: C 50,60; H 4,70; N OF 17.35

found: C 50,63; H to 4.38; N 17,32.

MC (m/z): 388 (M++ 1).

NMR spectrum (DMSO-d6, internal standard TMS): : 1,20-1,32 (2H, m); 1,48-to 1.59 (2H, m), 1.77 in-1,89 (2H, m), 2,19 (2H, T,J=7,3 Hz), 4,34 (2H, t, J= 7,3 Hz), to 7.09 (1H, s), the 7.43 (1H, what about the hydrogen peroxide solution and 1.2 ml of 1 N. an aqueous solution of sodium hydroxide was added 150 mg of 2-[6-cyano-2,3-dioxo-7-(1H-imidazol-1-yl-1,2,3,4-tetrahydroquinoxalin-1-yl] acetic acid, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture is brought to pH 1 by addition of 1 N. hydrochloric acid. Precipitated crystals thus collected by filtration, washed with water and dried under reduced pressure, resulting in a received 138 mg (81%) of 2-(6-carbarnoyl-2,3-dioxo-7-(1H-imidazol-1-yl-1,2,3,4 - tetrahydroquinoxalin-1-yl]acetic acid 1,4 H2O.

So pl.: > 300oC.

Elemental analysis for C14H11N5O51,4 H2O (%):

Calculated: C 47,44; H to 3.92; N 19,76

found: C 47,36; H 3,82; N fall of 19.88.

MC (m/z): 330 (M++1).

NMR spectrum (DMSO-d6, internal standard TMS): : 4,94 (2H, s),? 7.04 baby mortality (1H, s), 7,26-7,34 (2H, m), 7,45 (1H, s), 7,51 (1H, s), 7,72-7,80 (2H, m), KZT 12.39 (1H, s).

Example 28

1) In 16 ml of concentrated sulfuric acid was dissolved 3,29 g (to 11.8 mmol) of ethyl-4-(2,4-divergence)benzoate at a temperature not exceeding 5oC. To the obtained mixture under stirring was added 520 microliters fuming nitric acid at a temperature of -5oC or below, and then this mixture was stirred for 30 minutes at the about was collected by filtration. The compound obtained was dissolved in chloroform. Then the solution is then washed with water and saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (manifesting solvent: hexane: ethyl acetate = 8:1), resulting in a received 2,42 g (63%) of ethyl-4-(2,4-debtor-5-nitrophenoxy)-benzoate.

The NMR spectrum (CDCl3, internal standard TMS): : of 1.40 (3H, t, J=7,3 Hz), to 4.38 (2H, q, J=7,3 Hz), 7,02 (2H, d, J=9,2 Hz), 7,21 (1H, t (DD), J= 9.8 Hz), to $ 7.91 (1H, t(DD), J=7,6 Hz), 8,08 (2H, d, J=9,2 Hz).

MS (m/z): 323 (M+).

2) Mixture of 2.38 g (7.36 mmol) of ethyl-4-(2,4-debtor-5 - nitrophenoxy)benzoate, of 1.03 g of the hydrochloride of the ethyl ester of glycine, 30 ml of tetrahydrofuran, 10 ml of dimethylformamide, and to 2.06 ml of triethylamine was heated under reflux for 10 hours. After cooling, the reaction mixture was diluted with ethyl acetate. Nerastvorimaya substance was removed by filtration and then the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate. The resulting solution was sequentially washed with water and brine, and then dried with anhydrous sodium sulfate, and concentrated the Commissioner solvent: hexane/dichloromethane/ethyl acetate = 8:2:1), in the result received is 1.81 g of ethyl ester of N-[4-(4-ethoxycarbonylphenyl)- 5-fluoro-2-nitrophenyl] glycine (61%).

MS (m/z): 406 (M+).

The NMR spectrum (CDCl3, internal standard TMS): : to 1.34 (3H, t, J=7,3 Hz) to 1.38 (3H, t, J=7.0 Hz), 4.09 to (2H, d, J=2,9 Hz), 4,32 (2H, q, J=7,3 Hz), 4,36 (2H, q, J=7.0 Hz), of 6.52 (2H, d, J=and 12.2 Hz), to 6.95 (2H, d, J=9.1 Hz), 8,03 (2H, d, J=9.1 Hz), 8,11 (1H, d, J=11,6 Hz), 8,51 (1H, Shir.S.).

3) a Mixture containing 1.78 g (4,39 mmol) of ethyl ester of N-[4-(4-ethoxycarbonylphenyl)-5-fluoro-2-nitrophenyl] -glycine, 896 mg of imidazole and 20 ml of DMF was stirred while heating in an oil bath (70oC) within 12 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate. Then the solution is then washed with water and saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (manifesting solvent: chloroform +0-1% methanol) and received 1,49 g (75%) of ethyl ester of N-[4-(4-ethoxycarbonylphenyl)-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine.

MC (m/z 454 (M+).

NMR spectrum (DMSO-d6, internal standard TMS); : of 1.34 (3H, t, J=7,3 Hz) to 1.37 (3H, t, J=7.2 Hz), 4,14 (2H, is), 8,46-9,48 (1H, m).

4) Mixture of 1.46 g (3,19 mmol) of ethyl ester of N-[4-(4-ethoxycarbonylphenyl)-5-(1H-imidazol-1-yl)-2-nitrophenyl] glycine, 100 ml of tetrahydrofuran, and 410 mg of 10% palladium-on-charcoal, stirred at room temperature and under normal pressure in an atmosphere of hydrogen for 6 hours. After completion of the reaction the catalyst was removed by filtration. To the filtrate was added 2,02 ml of triethylamine, and the mixture was cooled by ice in the stream of argon gas. To the reaction mixture under stirring drop by drop was added to a mixture of 1.37 ml of etylchlorhydrine and 15 ml of tetrahydrofuran. The resulting reaction mixture was stirred for another two hours. After removal of nerastvorimogo substances by filtration, the filtrate was concentrated under reduced pressure. To the obtained residue was added 100 ml of ethanol, and the mixture was heated under reflux for 18 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (manifesting solvent: chloroform + 5-10% methanol), resulting in a received 1.19 g (78%) of ethyl-2-[2,3-dioxo-6-(4-ethoxycarbonylmethoxy)-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate.

MC (m8 (2H, kV, J=7,0 Hz), 4,28 (2H, q, J=7.0 Hz), 5,04 (2H, s), 6,98 (1H, s). ? 7.04 baby mortality-was 7.08 (3H, m), 7,41 (1H, s), 7,71 (1H, s), 7,88 (1H, s), of 7.90-to 7.93 (3H, m), 12,24 (1H, s).

Example 29

1) In 20 ml of dimethylformamide was dissolved 500 mg of 7-fluoro-1-hydroxy-6-nitro-2,3(1H, 4H)-khinoksalinona. To the resulting solution were added 83 mg of sodium hydride, and the mixture was stirred for 10 minutes. To the reaction mixture was added 218 ml ethylbromoacetate, and then carried out the reaction in two days. The resulting reaction mixture was poured into a saturated aqueous solution of ammonium chloride, and then three times were extracted with chloroform. The organic layer was concentrated, after which the concentrate was recrystallized from 2-propanol, resulting in received 481 mg of ethyl-2-[2,3-dioxo-7-fluoro-6-nitro-1,2,3,4-tetrahydroquinoxaline) oxy]acetate.

MC (m/z): 328 (M++1).

NMR spectrum (DMSO-d6, internal standard TMS): : to 1.23 (3H, t, J=7.2 Hz), 4,19 (2H, q, J=7.2 Hz), 4,96 (2H, s), 7,73 (1H, d, J=12,4 Hz), to $ 7.91 (1H, d, J=6,8 Hz).

2) Ethyl-2-[(2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4 - tetrahydroquinoxaline)oxy] acetate was obtained by the method described in Example 4-4, except that used ethyl-2- [(2,3-dioxo-7-fluoro-6-nitro-1,2,3,4-tetrahydroquinoxaline) oxy]acetate.

MC (m/z): 376 (M++1).

NMR-CE), for 7.78 (1H, s), 7,95 (1H, s).

3) 2-[(2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4 - tetrahydroquinoxaline)oxy]acetic acid 2 H2Oh was obtained by the method described in Example 4-5, except that used ethyl-2-[(2,3-dioxo-7-fluoro-6-nitro-1,2,3,4 - tetrahydroisoquinoline)oxy]acetate.

So pl.: > 300oC.

NMR spectrum (DMSO-d6, internal standard TMS): : to 4.41 (2H, s), was 7.08 (1H, s), 7,40 (1H, s), 7,88 (1H, s), 7,92 (1H, s), 8,30 (1H, s).

Example 30

1) Ethyl ester of N-(6-chloro-3-nitropyridine-2-yl)glycine was obtained by the method described in Example 1-1, except that used 2,6-dichloro-3-nitropyridine and the hydrochloride of the ethyl ester of glycine.

MC (m/z): 260 (M++1).

The NMR spectrum (CDCl3internal standard TMS): : to 1.32 (3H, d, J=7,2 Hz), 4,28 (2H, q, J=7.2 Hz), 4,36 (2H, d, J=5,2 Hz), 6,70 (1H, d, 3=8.0 Hz), scored 8.38 (1H, d, J=8.0 Hz).

2) Ethyl ester of N-(6-1H-imidazol-1-yl)-3-nitro-pyridine-2-yl)glycine was obtained by the method described in Example 28-3, except that used the ethyl ester of N-(6-chloro-3-nitropyridine-2-yl)glycine.

MC (m/z): 292 (M++1).

NMR spectrum (DMSO-d6, internal standard TMS): : of 1.18 (3H, d, J=7,2 Hz), 4,14 (2H, q, J=7.2 Hz), 4,32 (2H, d, J=5,2 Hz), 7,17 (1H, s), 7.23 percent (1H, d, J=9,2 Hz), 7,94 (1H, s), 8,58 (1H, s) 8,64 (1H, d, is the way described in Example 1-2, except that used the ethyl ester of N-(6-(1H-imidazol-1-yl)-3-nitropyridine-2-yl)glycine.

MC (m/z): 316 (M++ 1).

NMR spectrum (DMSO-d6, internal standard TMS): : 1,19 (3H, d, J=6.0 Hz), of 4.16 (2H, q, J=6.0 Hz), is 5.06 (2H, s), 7,14 (1H, s), to 7.64 (1H, d, J=6.8 Hz), of 7.70 (1H, d, J=6.0 Hz), 7,92 (1H, s), 8,53 (1H, s).

4) In 30 ml of acetonitrile was dissolved 730 mg of ethyl-2-(2,3-dioxo-6-(1H-imidazol-1-yl)-1,2,3,4-tetrahydropyrido-[2,3-b] pyrazin-4-yl)acetate. While cooling in an ice bath, to the mixture was added 615 mg tetrafluoroborate nitronium. After stirring in an ice bath for 2 hours, the reaction mixture was concentrated. To this concentrate was added 1 N. aqueous solution of potassium hydroxide, and then the mixture was stirred for 2 hours. The reaction mixture is neutralized 1 N. hydrochloric acid, and then was purified by chromatography on a column with C18, resulting received 364 mg of ammonium 2-(2,3-dioxo-6-(1H-imidazol-1-yl)-7-nitro-1,2,3,4-tetrahydropyrido [2,3-b] pyrazin-4-yl)-acetate H2O

So pl.: 241-245oC

NMR spectrum (DMSO-d6, internal standard TMS): : 4,58 (2H, s), 7,05 (1H, s), 7,45 (1H, s), to 7.99 (1H, c) to 8.12 (1H, c).

Example 31

2-(2,3-Dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4 - tetrahydroquinoxaline)propiononitrile and the hydrochloride of the ethyl ester of alanine.

So pl.: 129-133oC.

NMR spectrum (DMSO-d6, internal standard TMS): : 2,50 (2H, d, J=5.6 Hz), 4,24 (1H, q, J=5.6 Hz), 6.89 in (1H, s), 7,79 (1H, s), 7,88 (1H, s), to 7.99 (1H, s), at 8.36 (1H, s).

Example 32

Ethyl-2-(2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4 - tetrahydroquinoxaline)-3-(4-nitrophenyl)propionate was obtained by the method described in Example 1, except that used 2,4-diplomarbeit and the hydrochloride of the ethyl ester of phenylalanine.

MC (m/z): 495 (M++ 1).

NMR spectrum (DMSO-d6, internal standard TMS): : 0,90-1,30 (3H, Shir. ), 3,15-of 3.12 (2H, W), 4,10-and 4.40 (1H, W), 4,58 (1H, W), of 6.52 (1H, d, J= 10,8 Hz), was 7.36 (1H, d, J=6.0 Hz), of 7.48 (2H, d, J=8.0 Hz), 7,71 (1H, s), 7,83 (1H, s), of 7.96 (1H, s), 8,13 (2H, d, J=6,8 Hz).

Example 33

The final by-product of the Example 23-2 recrystallized from 1 N. aqueous solution of hydrochloric acid, which was obtained 2-[2,3-dioxo-7-(1H-imidazol-1-yl)-5-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl] acetic acid HCl 0,5 0,5 H2O.

Melting point: 268oC (Razlog.) (1 N. HCl)

Elemental analysis for C13H9N5O60,5 HCl 0.5 H2O

Calculated: C 43,56; H 2,95; N 19,54; Cl 4,94

found: C 43,81; H 2,88; N 19,57; Cl 5,17.

MC (n/z): 332 (M++ 1)

NMR spectrum (DMSO-d6, internal stogo compounds obtained in the Examples presented in the tables at the end of the text.

Each of the following compounds can be obtained by a method basically similar to the methods of production are illustrated in this description or in the Examples, or these compounds may be obtained by methods with minor modifications, obvious to every specialist

1) 2-[2,3-dioxo-7-(4-carboxyphenoxy)-6-(1H-imidazol-1-yl)-1,2,3,4 - tetrahydroquinoxalin-1-yl]acetic acid;

2) 2-[2,3-dioxo-7-(4-carboxymethoxy)-6-(1H-imidazol-1-yl) - 1,2,3,4-tetrahydroquinoxalin-1-yl]acetic acid;

3) 5-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4 - tetrahydroquinoxalin-1-yl]-2,2-dimethylpentane acid;

4) Ethyl-5-[2,3.-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4 - tetrahydroquinoxalin-1-yl]valerate;

5) 5- [2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4 - tetrahydroquinoxalin-1-yl] pentanone;

6) 5-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4 - tetrahydroquinoxalin-1-yl]-2,4-dimethylpentane acid;

7) 5-[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4 - tetrahydroquinoxalin-1-yl]-4-phenylpentane acid.

8) 4-[(2,3. -dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4 - tetrahydroquinoxaline)oxy]butyric acid.

Examples of compositions

The lower the SS="ptx2">

Liofilizovannye the drug in the same vessel:

Connection Example 1 - 50 mg (0.5%)

Citric acid 210 mg (2.1 per cent)

D-mannitol 100 mg (1,0 %)

Only 10 ml

In 800 ml of water was sequentially added to dissolve 5 g of compound of Example 1, 21 g of citric acid and 10 g of D-mannitol. Then add water to obtain a total quantity of 1000 ml.

After sterile filtration, 10-ml portion of the solution was poured into a vessel made of dark glass and liofilizovane, resulting received the concentrated preparation for injection, which must be dissolved immediately before use.

1. Derivatives of 1,2,3,4-tetrahydroquinoxaline the following formula I

< / BR>
where X is a nitrogen atom or a group of the formula CH;

R - imidazolidine group or a di(lower alkyl)amino group;

R1- (1) a halogen atom, a nitro-group, cyano, carboxyl group, amino group, mono - or di(lower alkyl)amino group, a lower alcoolica group, lower alkylsulfonyl group or carnemolla group; (2) a lower alkyl group or lower CNS group which may be substituted by halogen atoms, a carboxyl group or phenyl group; (3) fenoxaprop, Kotor is a strong group, amino group;

And the lowest Allenova group which may be substituted nitroanilines group, or a group of the formula-O-and - lowest Allenova group;

provided that excluded the case when R is imidazolidinyl group, R1represents a cyano, a represents an ethylene group, and R2is a hydroxyl group;

or a salt, hydrate or solvate.

2. Compounds or salts under item 1, where R is imidazolidinyl group, and R1represents: (1) a halogen atom, a nitro-group, a cyano, a carboxyl group, a mono - or di(lower alkyl)amino, lower alkylsulfonyl group or karbamoilnuyu group; (2) a lower alkyl group or lower CNS group which may be substituted by a carboxyl group or phenyl group; (3) fenoxaprop, which may be substituted by lower alkoxycarbonyl group.

3. Compounds or salts under item 1, where R is a 1-imidazolidinyl group, X represents a group of formula CH, R1represents a halogen atom, a nitro-group, triptorelin group, a cyano or benzyloxy.

4. Connection on p. 1, vybrannoi its salt, 2-(2,3-dioxo-7-(1H-imidazol-1-yl)-6-trifluoromethyl-1,2,3,4-tetrahydroquinoxalin-1-yl)acetic acid or its salt, 2-(6-benzyloxy-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl)acetic acid or its salt.

5. Pharmaceutical composition having activity of inhibiting the binding of AMPA receptor and overwhelming neurotoxic action of kainic acid and auditory reflex epileptic seizures, containing the active ingredient and pharmaceutically acceptable carrier, characterized in that it contains as active ingredient an effective amount of the compounds under item 1 or its pharmaceutically acceptable salt.

6. The pharmaceutical composition according to p. 5, characterized in that is an antagonist of glutamate receptor.

7. The pharmaceutical composition under item 5 or 6, characterized in that is an antagonist of AMPA-receptor.

8. The pharmaceutical composition under item 5 or 6, characterized in that an inhibitor of neurotoxicity induced by kainic acid.

Priority points and features:

27.09.94 on PP.1 - 8 X - group SN, R - imidazolidine group, R1- the nitro-group, A - lowest Allenova group, R2- gidroiingeo, carboxyl group, amino group, mono - or di(lower alkyl)amino group, a lower alcoolica group, or a lower alkyl or lower CNS group which may be substituted by a halogen atom, a carboxyl group or phenyl group, R2lowest CNS group, amino group, And the lowest Allenova group.

 

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Substituted pyrrole // 2141960

The invention relates to new substituted pyrrole General formula I

< / BR>
where R is hydrogen, hydroxyl;

R1and R2- together group of the formula -(CH2)nand R7is hydrogen, or R1and R7- together group of the formula -(CH2)nand R2is hydrogen;

R3is phenyl, naphthyl which may be substituted with halogen, C1-C7- alkoxy, CF3or benzofuranyl, benzo(b)thienyl, indolyl, substituted by 1-3 substituents selected from the group comprising halogen, C1-C7-alkyl, C1-C7-alkoxy; R4, R5and R6is hydrogen, halogen, C1-C4-alkoxy, C1-C7-alkyl,

R8a group of the formula -(CH2)p-R9or -(CH2)q-R100;

R9is hydrogen, C1-C7-alkylsulphonyl, C1-C7-alkylsulfonyl, aminocarbonyl;

R10is hydroxyl, amino, C1-C7-alkylamino, di(C1-C7)-alkylamino, three(C1-C7)-alkylamino, azido, C1-C7-alkoxy-carbylamine, isothiocyanate, C1-C7-alkylcarboxylic, C1-C7-alkylsulfonate, 6-membered nitrogen-containing saturated gets the SUB>2; W is amino; one of X and Y - O-atom, and the other is O or (H,H);

Z - group-CH - or N-atom;

m, p and q is a number from 0 to 5, n is a number from 1 to 5, provided that m and q represent the number from 2 to 5 when Z Is N-atom, and their pharmaceutically acceptable salts

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert
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