Derivatives finokalia, the retrieval method and tool quisqualate-antagonistic action based on them


(57) Abstract:

Usage: in medicine as a drug for the treatment of diseases of the Central nervous system. Products: derivatives finokalia F.-ly (I), where R1- replaced remaining R2: C1- C12- alkyl, C2-C12alkenyl or quinil, C3- C7- cycloalkyl or (CH2)n-phenyl, R2- COR3or ROCH, and R2meets one to two times, R4- H or R1, R5- R8same or different: hydrogen, halogen, nitro, a group NR9R10, NHCOR11, cyano, CF3C1-C6- alkyl, C1- C4-alkoxy -, or imidazole, n = 0 to 5, R3is hydroxyl, C1- C6-alkoxy or NR9R10x and y are hydroxyl, C1- C6- alkoxy, C1- C4- alkyl or NR9R10R9and R10- H, C1- C4- alkyl, R11- C1- C6- alkyl. Reagent I: compound of formula (II), where R1, R5, R6, R7and R8have the meanings specified for compounds of the formula (I), which is subjected to cyclization with reactive derivatives of oxalic acid, and, if necessary, the resulting mating R4with the exception of hydrogen. The compounds of formula I is non-toxic and have improved quicklet - antagonistic activity. 3 S. and 2 C.p. f-crystals.

The invention relates to the derivatives of cinoxacin, but rather to derive hinoksidin-carboxylic and phosphonic acids, their preparation and use as pharmaceuticals.

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

Currently, it is found that proposed according to the invention compounds in comparison with the known from European patent A-315 959 and WIPO 91/138 78 khinoksalinona have a good ability to associate with quisqualate-receptors.

Proposed according to the invention compounds are derivatives of cinoxacin formula 1.

< / BR>

R1denotes a substituted residue R2- C1- C12- alkyl; substituted residue R2- C2- C12alkenyl; substituted residue R2C2- C12- quinil; substituted residue R2C3- C7- tipmost residue R2or/CH2/n- heteroaryl, in which heteroaryl or alkyl residue substituted with residue R2;

R4denotes hydrogen; substituted residue R2C1- C12- alkyl; substituted residue R2C2- C12alkenyl; substituted residue R2C2- C12-quinil; /CH2/n- A /C6- C12/ - aryl, in which aryl or alkyl residue substituted with residue R2; or/CH2/n- heteroaryl, in which heteroaryl or alkyl residue substituted with residue R2;

R5, R6, R7and R8are identical or different and denote hydrogen, halogen, nitro, NR9R10, NHCOR11, SO2R12C3- C7- cycloalkane, COR13, cyano, CF3C1- C6- alkyl, C1- C4- alkoxy or, if necessary, replaced by a cyano group, a C1- C4- alkyl or COO - C1-C6- alkyl imidazole, or

R5and R6or R7and R8are secondinstance benzene ring, and

R2denotes-CO-R3or-PO-XY and R2meets once before and two is one is NR9R10;

X and Y are identical or different and denote hydroxyl, C1- C6-alkoxy, C1- C4- alkyl or NR9R10and

R9and R10are identical or different and denote hydrogen, C1- C4- alkyl or together with the nitrogen atom form a saturated 5 - or 6-membered heterocycle, which can contain another oxygen atom, sulfur or nitrogen;

R11represents C1- C6- alkyl or phenyl;

R12denotes hydrogen, C1- C4- alkyl, NH2N(C1-C4- alkyl)2and

R13denotes hydroxyl, C1- C6- alkoxy, C1-C6- alkyl or NR9R10,

as well as their isomers, or salts, and if R4, R5, R6, R7and R8denote hydrogen, R1may not be carbamoylmethyl, 1-carboxy-1-phenylmethyl or linear C1- C6- alkyl, in which 1-position substituted with-COOH or-COO-(C1- C6) - alkyl, and

if R1denotes a linear C1- C6- alkyl, in which 1-position substituted with-COOH or-COO-(C1- C6/ - alkyl, R6and/or R7the meet is listwan, cannot signify hydrogen, and

if R1denotes-CH2- COOH,

a/ R6and R7cannot simultaneously denote methyl or

b/ R6and R7can't designate the group NO2and R4oC R8depending on the circumstances, may not denote hydrogen.

Compounds of General formula 1 include also the possible tautomeric forms and cover E - or Z-isomers, if there is a chiral center, the racemates or enantiomers.

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

Deputy R2found oneoC twice, the same or different is in any position in the alkyl, Alchemilla, alchenilla, cycloalkyl, heteroaryl or aryl residue.

Under alkyl, depending on the circumstances, you need to understand linear or branched alkyl residue, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert.-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, and C1-C6- alkyl residues are preferred.

Alkenyl includes, in particular, C2- C6- alkeline residues, which can be linear or rashotte etkinlik residues suitable in particular, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl with 2-4 C-atoms.

Under C3-C7- cycloalkyl, depending on the circumstances, understand cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, in particular, C3-C5- cycloalkyl.

As the aryl residue should be called, for example, phenyl, naphthyl, biphenylyl and indenyl in particular /CH2/nis phenyl with n=0,1 or 2.

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

Under the halogen should be understood fluorine, chlorine, bromine and iodine.

If R9and R10together with the nitrogen atom form a saturated a heterocycle, for them to understand, for example, piperidine, pyrrolidine, morpholine, thiomorpholine or piperazine.

If R1represents C1-C12- alkyl and R2denotes COR3, R5oC R8in particular, represent substituents as NO2, NR9R10, NHCOR11, SO2R12C3- C7- cycloalkane, COR13, cyano, CF3C1-C4- alkoxyl, if necessary, the Y have a very good solubility in water.

Under physiologically compatible salts need to understand salt of organic and inorganic bases, such as, for example, soluble salts of alkali and alkaline earth metals and N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, Tris-hydroxy-methyl-aminomethane, aminopropanol, Sovak base, 1-amino-2,3,4-butanetriol.

The compounds of formula 1 and their physiologically compatible salts, based on their affinity to quisqualate-receptors, applicable as a drug. Based on your profile of actions proposed in the invention compounds are suitable for treating diseases that are caused by hyperactivity of the excitatory /annoying/ amino acids as glutamate or aspartate. Since the new compounds act as antagonists of excitatory amino acids and have a high specific affinity for AMPA-receptors in that they displace radioactively labeled specific agonists /RS/ - - amino-3-hydroxy-5-methyl-4-isoxazoline /AMPA/ of AMPA receptors, they are particularly suitable for treatment of such diseases which can be influenced through the receptors of excitatory am who I am, hypoglycemia, psychosis, muscle rigidity, vomiting, pain condition, anoxia and deficits after ischemia.

The new compounds are not toxic and are different from the prior art in that they are not antagonists of glycine, as disclosed in WO 9113878 on page 3 for stated there connections. Compared to the one described in EPA-0315959 connections according to the invention are characterized by improved efficiency. Improved quisqualate-antagonistic activity compared with the prior art follows from the following data:

Connection - Efficiency of binding of AMPA 1C50, µmol

A - 2,22

B - 1,79

C - 64,82

D - 7,31

E - 2,6

F - 1,6

A=1-(trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)- acetic acid

B= 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)- propane 1-phosphonic acid

C= 1-(1-carboxy)butyl)quinoxaline-2,3(1H,4H)-dione (example 8, U.S. patent 5 166 155)

D = 1-(1-carboxy)hexyl-6-bromoquinoline-2,3(1H,4H)-dione (example 15, U.S. patent 5 166 155)

E = 1-carboxymethyl-6-nitroquinazoline-2,3(1H,4H)-dione (example 7, U.S. patent 5 166 155)

F = 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)- propionic acid

U.S. patent 5 166 155 is identical to Europatent EPA-0315959.

The Izod terguride, bromkriptin, derivative of amantadine, memantine and its derivatives described in European patent A-351 352 compounds, as well as a combination with L-DOPA, respectively, L-DOPA and benserazide. In combination reduced used the usual dose of a drug and its action is increased synergistically.

Affinity proposed according to the invention compounds to the Central AMPA receptors was tested in vitro classical studies linking. They bind with high affinity with marked using the3H-AMPA seats binding.

To test the quality of action and efficacy in vivo of the compounds were tested after intravenous administration to mice. After preprocessing using offer in the invention compounds antagonizers depending on the dose release due to intracerebroventricular injection of AMPA spasms.

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

As the main systems can also be applied to surface-active auxiliary substances, such as salts of Gallic the STI.

For oral administration especially suitable tablets, coated tablets or capsules with talc and/or hydrocarbon base or binder, as, for example, lactose, corn or potato starch. The application can also be in liquid form, as, for example, in the form of juice, to which if necessary is added sweetener.

The dose of the biologically active substances may vary depending on route of administration, age and weight of the patient, type and severity of curable diseases and similar factors. The daily dose is 0.5-1000 mg, preferably 50-200 mg, and the dose can be given in the form of directly injected single dose or divided into two or more daily doses.

Getting proposed according to the invention compounds is carried out by known methods. For example, the compounds of formula I get the fact that

and the compound of formula II:

< / BR>

R1, R5, R6, R7and R8have the above significance, cyclist with reactive derivatives of oxalic acid and, if necessary, enter into interaction with R4'-X, where X denotes a halogen, tosylate, mesilate or triflate and R4'has R6, R7and R8have the above significance, enter into interaction with R1- X with obtaining compounds of formula I and desirable in the case of the ester group omelet or acid group atrificial to ester or lidiruyut or restore the nitro group to the amino group or amino group alkylate or acelerou or amino group exchanged for halogen or cyano group or amino group enter into interaction with 2-Isobutanol formula IV:

< / BR>

U and V are a volatile group, and R11denotes hydrogen, cyano or COO-/C1-C6/-alkyl and R12denotes hydrogen or C1- C6- alkyl,

obtaining imidazole derivative, or isomers share, or get salt.

The cyclization of compounds of formula II with a reactive derivative of oxalic acid is carried out in one stage or in two stages. As a preferred need to consider the two-stage method, in which the diamine is injected into the interaction of with a derivative of oxalic acid as the partial ester - acid chloride oxalic acid in polar solvents, such as dimethylformamide or cyclic or acyclic ethers, or the halo of the project, as organic amines, such as triethylamine, pyridine, base Chenega or diethylaminopropyl. Subsequent cyclization can be accomplished in basic or acidic medium, preferably, however, in an acidic medium, and the solvent can be added alcohol.

The introduction of substituents R1and R4carry out conventional methods of alkylation by the fact that hinoksidin enter into interaction with R1- X or R4- X, where X = toilet, mesilate or especially triflate or halogen, in the presence of bases, at room or elevated temperature in an aprotic solvents. You can also obtain the anion, before adding R1- X or R4'- X. as a reason suitable, for example, compounds of alkali metals such as potassium carbonate; sodium hydroxide; alkali metal alcoholate, especially hydrides of metals, such as sodium hydride. Compounds of alkali metals can also enter into interaction in conditions of phase transfer. If you get a mixture of compounds with substituent R1accordingly, R4their usual share.

Usable solvents are aprotic polar solvents, such as dimethylformamide way b/ interact with 2 moles of R1- X under similar reaction conditions, at the same time introducing the substituents R1and R4.

If necessary, subsequent saponification of the ester group can be performed in the main or preferably in an acidic environment, the fact that hydrolyzing at elevated temperatures up to the boiling temperature of the reaction mixture in the presence of acids, as more highly concentrated acid or alcohols. Esters of phosphonic acid is preferably hydrolyzed by heating in concentrated aqueous acid, such as concentrated hydrochloric acid or by treatment with trimethylsilylpropyne and subsequent treatment with water.

The esterification of carboxylic acids or phosphonic acids is carried out in a known manner using the appropriate alcohol in the acid or in the presence of an activated derivative of the acid. As an activated derivative of the acid take into account, for example, acid chloride, imidazole or acid anhydride. In the case of phosphonic acids can interact with a complex of ortho esters of the corresponding alcohol. Also the interaction with the product's accession dicyclohexylcarbodiimide is with diazomethane.

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

The restoration of the nitro group to the amino group carried out catalytically in polar solvents at room or elevated temperature under hydrogen pressure. As catalysts suitable metals, such as Raney Nickel, or catalysts based on noble metals, such as palladium or platinum, if necessary, on the media. Instead of hydrogen can also known to use ammonium formate. Can also be used reductants, as the chloride of tin-II or chloride of titanium-III, and complex metal hydrides, in some cases in the presence of salts of heavy metals. It may be preferable introduction the reduction of the ester group.

If it is desirable alkylation of amino group, you can alkilirovanii conventional methods, for example, using alkylhalogenide. It is also possible reductive amination using an aldehyde and reducing agents, as Ciano the th environment in the presence of a base, entering into interaction with the corresponding anhydrides or halogenide acids.

The introduction of the cyano group can be accomplished through reaction of Sandmeier; for example, the intermediate formed from amino-compounds with nitrite diazonium salts can be administered during interaction with cyanide in the presence of copper cyanide-1 or K2Ni /CN/4.

The introduction of Halogens - chlorine, bromine or iodine through the amino group can be performed in aqueous or non-aqueous medium; for example, according to Sandmeyer in the aquatic environment the fact that the intermediate formed with nitrite diazonium salts enter into interaction with the chloride of copper-I or copper bromide-I in the presence of the corresponding acid is hydrochloric or Hydrobromic acid, or potassium iodide. When carrying out the reaction in non-aqueous environment hydrochloride in a known manner enter into interaction with soumillion and, for example, metilfenidato or bromoform in aprotic solvents, such as dimethylformamide. Introduction fluorine is carried out, for example, by reaction Balz-Schiemann with disneytheatrical.

The interaction of amino groups with 2-isobutane formula IV with getting imidazole derivatives is carried out in the presence of acids SUB>1- C3- dialkylamide as dimethyl-, diethyl - and dipropylamine, and cyclic amines, as pyrrolidine.

The interaction is carried out, for example, so that the amino-derivative and azadian in organic acid, such as formic acid, acetic acid, propionic acid or triperoxonane acid, is first stirred at room temperature and then heated up to the boiling temperature of the reaction mixture /approximately 120oC/.

Acid can serve both as a reagent and as a solvent. However, it is also possible to add a solvent, such as alcohols, ethers, ketones, esters like ethyl acetate, hydrocarbons like toluene, or kalogeropoulou as carbon tetrachloride.

The amount of acid may vary within wide limits, however, the acid is used in excess. Preferably choose a 3-10-fold excess of acid per amine and azadian.

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

Obtaining salt by assetco compounds of alkali or alkaline earth metal, which if necessary is used in the form of a solution, and the precipitate was separated or usual solution process.

Since the starting compounds is not described, these are known or can be obtained analogously to known compounds or methods described here.

For example, the compounds of formula II can be obtained by the fact that 2,4-dinitroaniline get method Sanger, due to the fact that O-halo-nitro-aromatic compounds, preferably, o-fluoro-nitro-aromatic compounds, such as, for example, dinitrophenol, in an aqueous medium is injected into the interaction with derivatives of amino acids in the presence of a base like sodium carbonate or sodium bicarbonate, at temperatures from 0oC to the boiling temperature under reflux and then restore. This reaction also can be transferred to other substituted 2-nitrogenase connection. Also Ullmann reaction from dinitrochlorobenzene with aromatic amine can be obtained diarylamino connection. For this reaction used high-boiling solvents, such as dimethylformamide or kallidin, and solid potassium carbonate and copper powder as the base. You can also get the corresponding o-nitroaniline p is the restoration of the 0-nitro-group flows, if there are multiple nitro groups, selectively due to sodium sulfide in the presence of ammonia and ammonium chloride, in a polar solvent at room temperature or at elevated temperature. In some cases it is preferable to interact with esters and in the last stage to hydrolyze.

The separation of enantiomers can be done at the last stage or in intermediate stages through optically active auxiliary bases such as brucine or 1-phenylethylamine, or, however, also by chromatography over optically active media. Enantiomers, however, can also be obtained synthetically by reacting the corresponding optically active amino acids with the corresponding vernetroyersextape connections by way of Sanger and by further processing aminonicotinic compounds, as described above.

The following examples should clarify proposed in the invention method.

Example 1. Methyl ester of 3-/6-nitro-2,3-dioxo-1,2,3,4 - tetrahydroquinoxalin-1-yl-methyl/-benzoic acid methyl ester 3-/7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl/-benzoic acid

1,03 g /5 is formamide, at room temperature. To a mixture of 330 mg /11 mmol/ hydrate sodium /80%/ three portions. Then stirred for 1 hour at room temperature. To the mixture was added dropwise 1.26 g /5.5 mmol/ methyl ester 3-bromomethylphenyl acid in 5 ml of dimethylformamide and additionally stirred for 3.5 hours. After concentration the residue is distributed in the mixture, acidified with acetic acid, water/ethyl acetate. The organic phase is separated, dried, filtered and concentrated. The remainder chromatographic through silica gel using a mixture of dichloromethane/ethanol = 95: 5. Get along with 211 mg of methyl ester of 3-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl/- benzoic acid, which is purified still further, 222 mg of the methyl ester 3-/7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl/- benzoic acid with so pl. 265-267oC.

Similarly get:

methyl ester 4-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1- -yl-methyl/-benzoic acid with so pl. 308-314oC;

methyl ester 4-/7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl/-benzoic acid with so pl. > 300oC;

ethyl ester of 2-in/6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl/-benzoic acid with so pl. 279oC/ 283-284o what Asa cleaning is processed next;

1-/3-methoxycarbonyl-2-propenyl/-6-nitrophenoxy-2,3- /1H, 4H)-dione with so pl. 256-265oC with decomposition;

1-/3-ethoxycarbonylphenyl/-6-nitrophenoxy-2,3-/1H, 4H)-dione with so pl. 215-217oC;

1-/3-ethoxycarbonylphenyl/-7-nitrogenation-2,3-/1H, 4H)-dione with so pl. 215-217oC;

diethyl ether 4-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl/-phenylphosphonic acid so pl. 114oC/ 129-131oC;

diethyl ether 4-/7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl/-phenylphosphonic acid is further processed without purification/;

diethyl ether 3-/6-trifluoromethyl-2,3-dioxo-1,2,3,4 - tetrahydroquinoxalin-1-yl-prop-1-EN-1-phosphonic acid;

diethyl ether 3-/6-trifluoromethyl-2,3-dioxo-1,2,3,4 - tetrahydroquinoxalin-1-yl-prop-1-yl-1-phosphonic acid;

diethyl ether 3-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-propane-1-phosphonic acid;

tert.-butyl ester 1-/6-trifluoromethyl-2,3-dioxo-1,2,3,4 - tetrahydroquinoxalin-1-yl/-Methocarbamol acid.

Example 2. With the introduction of twice the amount of methyl-3-bromoethylamine and the rest when the same test as in example 1, in addition, it is possible to allocate 503 mg 3-/4-/3-methoxycarbonylbenzyl/-6-nitro-2,3-dioxo-1,2,3,4 - Tetra is/BR> methyl ester 4-/4-/4-methoxycarbonylbenzyl/-6-nitro-2,3 - dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl/-benzoic acid with so pl. 225-227oC;

ethyl ester of 2-/4-/2-ethoxycarbonylmethyl/-6-nitro-2,3 - dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl/-benzoic acid with so pl. 230-234oC;

1,4-bis-/3-methoxycarbonyl-2-propenyl/-6-nitrophenoxy-2,3- /1H,4H)-dione with so pl. 181-183oC.

Example 3.

A/Ethyl ester 4-/2,4-dinitrophenyl/-aminobenzoic acid

1.01 g /5 mmol/ 1-Chloro-2,4-dinitrobenzene, 1.01 g /6 mmol/ ethyl ester of 4-aminobenzoic acid, 13 mg /0.2 mmol/ copper powder and 961 mg /7 mmol/ potassium carbonate /powder/ in 5 ml of absolute dimethylformamide is stirred for 25 minutes at a bath temperature of 180oC in argon atmosphere and in the absence of moisture.

After concentrating bring in water, alkalinized with ammonia and shaken out with ethyl acetate, and the organic phase is dried, filtered and concentrated. The remainder chromatographic through silica gel using a mixture of cyclohexane/ethyl acetate = 8:2. Get 768 mg of ethyl ether 4-/2,4-dinitrophenyl/-aminobenzoic acid so pl. 99-102oC.

Similarly get:

ethyl ester of 3-/2,4-dinitrogen the slots, which without further purification process next;

ethyl ester of 2-/2,4-dinitrophenyl/-aminobenzoic acid, which without further purification process next.

B Ethyl ester 4-/2-amino-4-nitrophenylamino/-benzoic acid

566 mg /1.7 mmol/ Ethyl ether 4-/2,4-dinitroaniline/- benzoic acid, 761 mg /12.2 mg/ DL of ammonium chloride, 0.68 ml of concentrated ammonia, 15 ml of ethanol and 6 ml of distilled water combine together when the internal temperature of 78oC /bath temperature 90oC/. Three portions added 1.27 g /5,68 mmol/ sodium sulphide /35%/ and additionally stirred for 1 hour. The mixture is sucked off at room temperature and first washed with water and then ether. Get 535 mg of ethyl ether 4-/2-amino-4-nitrophenylamino/-benzoic acid in the form of raw product is processed further without further purification/.

Similarly get:

ethyl ester of 3-/2-amino-4-nitrophenylamino/-benzoic acid with so pl. 145-150oC;

ethyl ester of 3-/2-amino-4-nitrophenylamino/-phenylphosphonic acid so pl. 160-163oC.

In/. Ethyl ester of 4-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl/-benzoic acid

582 mg /2.3 mmol/ Ethyl is tetrahydrofuran (THF) with a bath temperature of +4oC in argon atmosphere and in the absence of moisture. To the mixture was added dropwise a solution of 659 mg /4.8 mmol/ ethyl ester - acid chloride oxalic acid and 8 ml of anhydrous tetrahydrofuran and stirred at room temperature for 2 hours. Additionally, add 0.2 ml of triethylamine and 0.1 ml ethyl ester-acid chloride oxalic acid and stirred for 1 hour at room temperature. The mixture is filtered and the filtrate concentrated. The remainder is distributed in a mixture of water/ethyl acetate. The organic phase is evaporated. The residue in 25 ml of 1N. hydrochloric acid and 25 ml of ethanol is refluxed for 2 hours. Usageprice the product is sucked off, washed with water and dried. Obtain 220 mg of ethyl ether 4-/6-nitro-2,3-dioxo - 1,2,3,4-tetrahydroquinoxalin-1-yl/-benzoic acid/ /without treatment treated next.

Similarly get:

ethyl ester of 3-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl/benzoic acid with so pl. 258-263oC;

ethyl ester of 3-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl/phenylphosphonic acid.

Example 4.

A/. 2-/2,4-dinitrophenyl/-aminobenzoic acid

1,37 g /10 mmol/ 2-Aminobenzoic acid with 2 g /18,7 with 1.86 g /10 mmol/ 2,4-dinitrofluorobenzene and stirred for 2 hours. The mixture is diluted with about 400 ml of water and precipitated with 4h. HCl. The product is sucked off, washed with water and dried. Obtain 2.8 g of 2-/2,4-dinitrophenyl/-aminobenzoic acid so pl. 266-270oC.

Similarly get:

3-/2,4-dinitroaniline/-propionic acid with so pl. 134-137oC;

4-/2,4-dinitroaniline/-phenylphosphonate acid so pl. 271-272oC with decomposition;

2-/2,4-dinitroaniline/-phenylphosphonate acid, which without purification process next;

/2,4-dinitroaniline/-metaphosphate acid so pl. 225-227oC;

2-/2,4-dinitroaniline/-acanthostega acid, which without purification process next;

3-/2,4-dinitroaniline/-phenylphosphonate acid;

/2-nitro-1-naphthylamine/-metaphosphate acid;

/1-nitro-2-naphthylamine/-metaphosphate acid;

1-/2-nitro-1-naphthylamine/-ethane-1-phosphonic acid;

1-/1-nitro-2-naphthylamine/-ethane-1-phosphonic acid;

/2-nitro-4-trifluoromethyl-phenylamino/-metaphosphate acid;

1-/2-nitro-4-trifluoromethyl-phenylamino/-ethane-1-phosphonic acid;

1-/2,4-dinitroaniline/-ethane-1-phosphonic acid;

3-/2,4-dinitroaniline/-propane-1-phosphonic acid;

4-/2,4-dinitroaniline the amino/-methane-phosphonic acid;

/2-nitro-4-brompheniramine/-methane-phosphonic acid;

/2-nitro-4-methylphenylamine/-methane-phosphonic acid;

1-/2-nitro-4-forgenerating/-ethane-1-phosphonic acid;

1-/2-nitro-4-chlorpheniramine/-ethane-1-phosphonic acid;

1-/2-nitro-4-brompheniramine/-ethane-1-phosphonic acid;

1-/2-nitro-4-methylphenylamine/-ethane-1-phosphonic acid;

1-phenyl-1-/2-nitro-4-trifluoromethyl-phenylamino/-metaphosphate acid;

1-methyl-1-/2-nitro-4-trifluoromethyl-phenylamino/-ethane-1-phosphonic acid;

1-/2-nitro-4-trifluoromethyl-phenylamino/-hexane-1-phosphonic acid;

1-methyl-2-/2-nitro-4-trifluoromethyl-phenylamino/-ethane-1-phosphonic acid;

2-/2-nitro-4-trifluoromethyl-phenylamino/-propane-1-phosphonic acid;

1-methyl-2-/2-nitro-4-trifluoromethyl-phenylamino/-propane-1-phosphonic acid;

1-/2-nitro-4-trifluoromethyl-phenylamino/-cyclopropane-1-phosphonic acid;

/+/-1-/2-nitro-4-trifluoromethyl-phenylamino/-ethane-1-phosphonic acid;

/-/-1-/2-nitro-4-trifluoromethyl-phenylamino/-ethane-1-phosphonic acid;

P,P-dimethyl-/2,4-dinitroaniline/methane-phosphine oxide;

P-methyl-/2,4-dinitroaniline/-metaphosphate acid;

1-/5-/imidazol-1-yl/-2,4-dinitroaniline/-methylphosphonous acid;

1-/is openline/-ethane-1 - phosphonic acid

600 mg of 5-fluoro-2,2-dinitropropanol make in 30 ml of water and 10 ml of ethanol at 40oC dropwise and mixed with a solution of 376 mg of racemic aminoethylphosphonic acid in 10 ml of water and 600 mg of sodium carbonate. Stirred for 1.5 hours at the same temperature. After distillation of the ethanol is extracted with acetic acid. The aqueous phase is mixed with 200 mg of imidazole and heated at 110oC for 2 hours. Then again add 200 mg of imidazole and heated at 110oC for 2 hours. Acidified with 4n. hydrochloric acid, filtered off from nerastvorimaya part and the filtrate washed with ethyl acetate. The aqueous phase is concentrated and boiled with ethanol. Ethanol extract was concentrated and chromatographic through silica gel using methanol/butanol/water/ammonia = 75: 25:17:3. Receive 300 mg 5-/imidazol-1-yl/-2,4-dinitrophenyl-/1-amino-ethyl-phosphonic acid/.

In/. 2-/2-Amino-4-nitrophenylamino/-benzoic acid

1,80 g /6 mmol/ 2-/2,4-Dinitroaniline/-benzoic acid, 2.66 g /42,6 mmol/ ammonium chloride, 2.4 ml of concentrated ammonia, 52 ml of ethanol and 21 ml of distilled water are mixed together at an internal temperature of 78oC /bath temperature 90oC/. Three portions to the mixture of 4.44 g /20 mmol/ sulf and washed successively with water and ether. The filtrate is concentrated until the aqueous phase and shaken out with ethyl acetate. The organic phase is dried, filtered and concentrated. The aqueous phase is acidified with 1N. hydrochloric acid and sucked off. Obtain 1.1 g 2-/2-amino-4-nitrophenylamino/benzoic acid /process without purification/.

Similarly receive and process without further purification:

3-/2-amino-4-nitrophenylamino/-propionic acid;

4-/2-amino-4-nitrophenylamino/-phenylphosphonate acid;

2-/2-amino-4-nitrophenylamino/-phenylphosphonate acid;

/2-amino-4-nitrophenylamino/-methylphosphonous acid;

/2-amino-4-nitrophenylamino/-ethylphosphonic acid;

1-/2-amino-4-nitrophenylamino/-ethane-1-phosphonic acid;

3-/2-amino-4-nitrophenylamino/-propane-1-phosphonic acid;

4-/2-amino-4-nitrophenylamino/-butane-1-phosphonic acid;

1-/2-amino-4-triptoreline/-cyclopropane-1-phosphonic acid;


P-methyl-/2-amino-4-nitrophenylamino/-metaphosphate acid;

1-/5-/imidazol-1-yl-2-amino-4-nitrophenylamino/-methylphosphonous acid.

G/. /2-Amino-4-trifluoromethyl-phenylamino/-metanfetamina acid

894 g /2-Nitro-4-trif the room temperature under normal pressure of hydrogen. The reaction mixture is sucked off from the catalyst and the filtrate concentrated. The residue without further purification used in stage D/.

In principle, similarly get:

1-/2-amino-1-naphthylamine/-ethane-1-phosphonic acid;

1-/2-amino-2-naphthylamine/-ethane-1-phosphonic acid;

1-/2-amino-1-naphthylamine/-metaphosphate acid;

1-/2-amino-2-naphthylamine/-metaphosphate acid;

1-/2-amino-4-triptoreline/-ethane-1-phosphonic acid;

1-/2-amino-4-triptoreline/methane-1-phosphonic acid;

/2-amino-4-methylphenylamine/-metaphosphate acid;

1-/2-amino-4-methylphenylamine/-ethane-1-phosphonic acid;

1-phenyl-1-/2-amino-4-triptoreline/-metaphosphate acid;

1-methyl-1-/2-amino-4-triptoreline/-ethane-1-phosphonic acid;

1-/2-amino-4-triptoreline/-hexane-1-phosphonic acid;

1-methyl-2-/2-amino-4-triptoreline/-ethane-1-phosphonic acid;

2-/2-amino-4-triptoreline/-propane-1-phosphonic acid;

1-methyl-2-/2-amino-4-triptoreline/-propane-1-phosphonic acid;

/+/-1-/2-amino-4-triptoreline/-ethane-1-phosphonic acid;

/-/-1-/2-amino-4-triptorelin is a melamine/-ethane-1-phosphonic acid;

/4-fluoro-2-aminophenylamino/-metaphosphate acid;

/5-/imidazol-1-yl/-4-trifluoromethyl-2-amino-phenylamino/- methylphosphonous acid;

1-/4-fluoro-2-aminophenylamino/-ethane-1-phosphonic acid.

D/. 3-/6-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl/- propionic acid

211 mg /0.9 mmol/ 3-/2-Amino-4-nitrophenylamino/-propionic acid is mixed with 200 mg /2 mmol/ triethylamine in 20 ml of anhydrous tetrahydrofuran at a bath temperature of +4oC in argon atmosphere and in the absence of moisture. To the mixture was added dropwise a solution of 270 mg /2 mg/ DL ethyl ester-acid chloride oxalic acid and 5 ml of anhydrous tetrahydrofuran and stirred for 2 hours at room temperature. Additionally, add 0.05 ml of triethylamine and 0.05 ml ethyl ester-acid chloride oxalic acid and stirred for 1 hour at room temperature. The mixture is filtered and the filtrate concentrated. The remainder is distributed in a mixture of water/ethyl acetate. The organic phase is concentrated. The residue is treated with 15 ml of ethanol and 15 ml of 1N. hydrochloric acid and refluxed for 2 hours at a bath temperature of 110oC. the Mixture is concentrated, treated with a small amount of water and sucked off. Receive 120 mg of 3-/6-nitro-2,3-magicnum way get:

2-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl/- benzoic acid with so pl. > 255oC;

4-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl/-phenylphosphonate acid so pl. > 252oC;

2-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl/- phenylphosphonate acid so pl. > 310oC;

/6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl/- metaphosphate acid so pl. 180-200oC with decomposition;

2-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl/- acanthostega acid so pl. 304-308oC with decomposition;

/2,3-dioxo-1,2,3,4-tetrahydrobenzo/./-cinoxacin-4-yl/- metaphosphate acid;

/2,3-dioxo-1,2,3,4-tetrahydrobenzo/. /cinoxacin-4-yl/-ethane-1-phosphonic acid;

/2,3-dioxo-1,2,3,4-tetrahydro-benzo/. /cinoxacin-1-yl - methane-phosphonic acid;

/2,3-dioxo-1,2,3,4-tetrahydro-benzo/. /cinoxacin-1-yl/-ethane-1-phosphonic acid;

/6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl/- metaphosphate acid so pl. 202oC;

1-/6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- acanthostega acid so pl. 274oC;

1-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/-ethane-1-phosphonic acid so pl. 297-300oC with decomposition;

3-/6-nitro-2,3-dioxo-1,-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl-butane-1-phosphonic acid so pl. 285-287oC;

/6-fluoro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- metaphosphate acid;

/6-chloro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- metaphosphate acid;

/6-bromo-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- metaphosphate acid;

/6-methyl-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- metaphosphate acid;

1-/6-fluoro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/-ethane-1-phosphonic acid so pl. 259oC;

1-/6-chloro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/-ethane-1-phosphonic acid;

1-/6-bromo-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/-ethane-1-phosphonic acid;

1-/6-methyl-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/-ethane-1-phosphonic acid;

1-/6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/ -1-phenyl-methane-1-phosphonic acid so pl. 245oC;

1-/6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/ -1-methyl-ethane-phosphonic acid;

1-/6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- hexane-1-phosphonic acid;

1-methyl-2-/6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/-ethane-1-phosphonic acid;

2-in/6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl-propane-1-phosphonic acid;

1-methyl-2-/6-trifluoromethyl-2,3-hydro-cinoxacin-1-yl/ -cyclopropane-1-phosphonic acid;

/+/-1-/6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/-ethane-1-phosphonic acid; [20546] = +7,4o/ c = worn: 0.505; water/;

/-/-1-/6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/-ethane-1-phosphonic acid; [20546] = -5,9o/ c = 0,510, water/;

P-methyl-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl - methane-phosphonic acid so pl. 320 or 325oC with decomposition;

/P, P-dimethyl-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/-metapontines, so pl. 325-330oC with decomposition;

/6-nitro-7-/imidazol-1-yl/-2,3-dioxo-1,2,3,4-tetrahydro - cinoxacin-1-yl/-methylphosphonous acid;

/6-trifluoromethyl-7-/imidazol-1-yl/-2,3-dioxo-1,2,3,4-tetrahydro - cinoxacin-1-yl/-methylphosphonous acid.

Example 5.

3-/6-Nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl-methyl/- benzoic acid

211 mg /0.6 mmol/ Methyl ester of 3-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl/-benzoic acid mixed with 4 ml of 4n. hydrochloric acid, 4 ml triperoxonane acid and stirred for 3.5 hours at a bath temperature of 110oC. the Reaction mixture after cooling to room temperature, diluted with water and sucked off. The balance of the filtrate washed with water and ethanol is L. > 330oC.

Similarly get:

3-/7-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl-methyl/- benzoic acid with so pl. > 330oC;

3-/4-/3-carboxybenzoyl/6-nitro-2,3-dioxo-1,2,3,4-tetrahydro - cinoxacin-1-yl/-methyl/-benzoic acid with so pl. 298-300oC;

2-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl-methyl/- benzoic acid with so pl. 329-334oC with decomposition;

2-/7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl/- benzoic acid with so pl. 328-330oC;

2-/4-/2-carboxy benzyl/-6-nitro-2,3-dioxo-1,2,3,4 - tetrahydroquinoxalin-1-yl-methyl/-benzoic acid with so pl. > 300oC;

4-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl/- benzoic acid with so pl. > 310oC;

4-/7-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl-methyl/- benzoic acid with so pl. 320-324oC with decomposition;

4-/4-/4-carboxymethylated/-6-nitro-2,3-dioxo-1,2,3,4 - tetrahydro-cinoxacin-1-yl-methyl/-benzoic acid with so pl. > 310oC;

4-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- benzoic acid with so pl. > 345oC;

3-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- benzoic acid with so pl. > 250oC;

1-/3-carboxy-2-propenyl/-6-nitro-cinoxacin-2,3-/1H, 4H/-DRI decomposition;

1-/3-carboxypropyl/-6-nitro-cinoxacin-2,3-/1H, 4H)-dione with so pl. 230-232oC;

1-/3-carboxypropyl/7-nitro-cinoxacin-2,3-/1H, 4H)-dione with so pl. 325-327oC with decomposition;

1-/6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- acetic acid so pl. 320oC.

Example 6.

4-/6-Nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl-methyl/- phenylphosphonate acid

582 mg /1.4 mg/ DL Ethyl ester 4-/6-nitro-2,3-dioxo-1,2,3,4 - tetrahydro-minoxidin-1-yl-methyl/-phenylphosphonic acid in 6 ml of concentrated hydrochloric acid is refluxed for 2 hours. After cooling, the reaction mixture is mixed with water and sucked off. The filter residue is dried. Get 253 mg 4-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl-methyl/- phenylphosphonic acid so pl. 253-265oC with decomposition.

Similarly get:

4-/7-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl-methyl/- phenylphosphonate acid so pl. > 250oC;

3-/6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- phenylphosphonate acid so pl. 304-307oC with decomposition;

3-/6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl - prop-1-in-1-phosphonic acid;

3-/6-tripteronotus, as well as diethyl ether /6-nitro-2,3-dioxo-1,2,3,4 - tetrahydro-cinoxacin-1-yl/-metaphosphates acid

To 300 mg /6-Nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- metaphosphates acid in 5 ml of absolute dimethylformamide at -15oC was added dropwise to 0.29 ml /476 mg/ thionyl chloride. After the addition was finished the reaction mixture was stirred for 20 minutes at a bath temperature of +4oC. Then, to the reaction mixture of 0.35 ml /276 mg/ ethanol and stirred for 1.5 hours at room temperature. After concentration in vacuum chromatografic the residue through silica gel using a mixture of toluene/glacial acetic acid/water = 10:10:1.

First get 100 mg of diethyl ether /6-nitro-2,3-dioxo - 1,2,3,4-tetrahydro-cinoxacin-1-yl/-metaphosphates acid so pl. 220-260oC and then obtain 36 mg of monoethylene ether /6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/-metaphosphates acid so pl. 197oC.

Similarly get:

mono-N, N-dimethyl-amide and bis-N, N-dimethylamide /6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/-metaphosphates acid.

Example 8.

1-/6-Amino-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- metanfetamina acid

300 mg 1-/6-NITR the zhota sequentially mixed with 50 mg of Pd /C 10%, 300 mg of ammonium formate and 18 ml of water and heated at 80oC for 1 hour. After cooling, is filtered off from the catalyst, the filtrate is evaporated and the residue is subjected to drying by freezing. Receive 200 mg 1-/6-amino - 2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl-/metaphosphates acid in a solid white color.

Similarly get:

1-/6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl/- acanthostega acid.

Example 9.

1-/6-/4-Carbethoxy-imidazol-1-yl/-2,3-dioxo-1,2,3,4-tetrahedrally-1-yl/-metaphosphates acid

200 mg of 1,4-bis-dimethylamino-3-carbethoxy-2-isobutane-1,4 mixed with 3 ml of glacial acetic acid under mild cooling and stirred for 10 minutes at room temperature. Then 100 mg 1-/6-amino-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/-metaphosphates acid dissolved in 3 ml of glacial acetic acid, is added to the reaction mixture and stirred over night at room temperature. Then heated 4 hours at a bath temperature of 110oC. After concentrating receive 50 mg 1-/6-/4 - Kurbatsky-imidazol-1-yl/-2,3-dioxo-1,2,3,4-tetrahedrally-1-yl/- metaphosphates acid in the form of butter.

Similar to the way the slot.

Example 10.

1-/6-Iodine-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- metanfetamina acid

180 mg 1-/6-Amino-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- metaphosphates acid was added dropwise to 10 ml of 25% sulfuric acid. After stirring for 5 minutes to form a suspension of the salt, which is cooled to 0oC. thereto was added dropwise a solution of 60 mg of sodium nitrite in 2 ml of water. After stirring for 15 minutes at 0oC the reaction mixture is almost dissolved. Thereto was added dropwise a solution of 180 mg of potassium iodide in 2 ml of water. The ice bath is removed and heated for 2 hours at 100oC. the Cooled reaction mixture is neutralized with concentrated ammonia solution and evaporated to dryness. The residue is boiled with ethanol and a small amount of water, filtered and the filtrate concentrated. After chromatography through silanizing silica gel using a mixture of water/methanol = 4: 1 receive 40 mg 1-/6-iodine-2,3-dioxo - 1,2,3,4-tetrahydro-cinoxacin-1-yl/metaphosphates acid so pl. 295-297oC.

Similar, respectively, are known from the literature, receive:

1-/6-iodine-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/-ethane-1-phosphonic acid;


1-/6-cyano-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- metaphosphate acid.

Example 11.

6-Iodine-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl-metanfetamina acid

100 mg of 6-Amino-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl - metaphosphates acid dissolved in concentrated hydrochloric acid and concentrated to dryness. Hydrochloride is well dried, bring in 10 ml of dimethylformamide and mixed successively with 4 ml of methylaniline and 0.6 ml of isoamylamine. After heating for 2 hours at a bath temperature of 80oC all is dissolved. Concentrate in the tube with ball expansion in vacuum and the residue chromatographic through silanizing silica gel 60 /reversed phase using a mixture of water/methanol = 4:1 as solvent. Receive 20 mg of 6-iodine-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl-metaphosphates acid so pl. 295-297oC.

Similarly get:

6-bromo-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl-metaphosphate acid;

1-/6-iodine-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- acanthostega acid;

1-/6-bromo-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/- acanthostega acid.

Example 12. 100 mg 1-/6-Amino-2,3-dioxo-1,2,3,4 - tetrahydroxy the values of 9.5 and mixed with 0.2 ml of acetanhydride. After stirring for one hour concentrated, dissolved in possible small amount of water is transferred to the ion exchanger /1R 120, strongly acidic/ and elute with water: appropriate faction unite, concentrate, and dried. Obtain 110 mg of 1-/6-acetylamino-2,3 - dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl/-metaphosphates acid so pl. 120oC.

1. Derivatives finokalia General formula I

< / BR>
where R1- replaced remaining R2WITH1- C12-alkyl, C2- C12alkenyl,2- C12-quinil,3- C7-cycloalkyl or (CH2)n-phenyl, in which phenyl or alkyl residue substituted for a residue R2;

R4is hydrogen or R1;

R5- R8same or different is hydrogen, halogen, nitro, a group NR9R10, NHCOR11, cyano, CF3WITH1- C6-alkyl, C1- C4-alkoxy -, or imidazole, if necessary substituted by cyano, C1- C4the alkyl or SOOS1- C6-alkyl, or R5and R6or R7and R8- precondensation benzene ring;

R2- COR3or POXY, and R2meets one to two times, and avlee NR9R10;

X and Y, same or different, a hydroxyl,1- C6-alkoxyl,1- C4-alkyl or NR9R10,

R9and R10the same or different, is hydrogen, C1- C4-alkyl,

R11- C1- C6-alkyl,

their isomers, or salts,

moreover, in the case when R4- R8is hydrogen, R1cannot specify carbamoylmethyl, 1-carboxy-1-phenylmethyl or linear C1- C6-alkyl, which is substituted in the first position-COOH or-SOOS1- C6-alkyl, and if R1- linear WITH1- C6-alkyl, which is in the first position is substituted by-COOH or SOOS1- C6-alkyl, R6and/or R7, R6and R8can't denote fluorine, chlorine or bromine, and R4- R8depending on the circumstances, may not designate hydrogen, and, if R1- -CH2-COOH, and R6and R7at the same time cannot signify methyl or (b) R6or R7cannot signify NO2and R4- R8depending on the circumstances, may not be hydrogen.

2. Derivatives under item 1, which represents a methyl ester of 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl)-benzoic shall trihydroxysilyl-1-yl-methyl)-phenylphosphonic acid, ethyl ester of 2-[4-(2-ethoxycarbonylethyl)-6-nitro-2,3-dioxo-1,2,3,4 - tetrahydro-cinoxacin-1-yl-methyl]-benzoic acid, ethyl ester 4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)-benzoic acid; 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl)-propanolol acid, (6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl)-methylphosphonous acid, 4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl-methyl)-vinylphosphonate acid (6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydro - cinoxacin-1-yl)-metaphosphate acid, 1-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl)-acanthostega acid, (+)-1-(6-trifluoromethyl-2,3-dioxo - 1,2,3,4-tetrahydro-cinoxacin-1-yl)-acanthostega acid, (-)-1-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl)-acanthostega acid, 1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl)-ethane-1-phosphonic acid, 4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl-)-butane-1-phosphonic acid, 1-(6-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydro - cinoxacin-1-yl)-1-Penilaian-1-phosphonic acid, P-methyl-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl)-methane-phosphonic acid, (P,P-dimethyl)-(6-nitro-2,3-dioxo-1,2,3,4 - tetrahydro-cinoxacin-1-yl)-metaphosphate acid, 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrasol acid, 1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl)-meth - apostolou acid, 1-(6-carbethoxy-imidazol-1-yl)-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl)-metaphosphate acid, 1-(8-trifluoromethyl-2,3-dioxo-1,2,3,4 - tetrahydro-cinoxacin-1-yl)acetic acid, 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydro-cinoxacin-1-yl)-propane-1-phosphonic acid.

3. Derivatives under item 1 as antagonists quisqualate receptors.

4. The tool, showing antagonistic activity against quisqualate receptors containing the active substance and conventional additives, characterized in that the active substance it contains derivatives of cinoxacin formula I under item 1 in the amount of 0.5 - 1000,0 mg.

5. The method of obtaining derivatives of cinoxacin General formula I on p. 1, characterized in that the compound of General formula

< / BR>
where R1, R5- R8are specified in paragraph 1 values;

subjected to cyclization with a reactive derivative of oxalic acid and, if necessary, the resulting compound is treated with R4-X, where X is halogen, tosylate, mesilate or triphala, R4'matter R4with the exception of hydrogen, followed by separation of the target product


Same patents:

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

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

< / BR>
in whichisor, R6represents H or alkyl, and R7and R8are each H, alkyl, nitro or phenyl, or alternatively, R7and R8taken together, represent butadiene or 1,4-butylene; R2and R3are each H, F, cyano, acyl, nitro, alkyl, morpholino or one of the above definitions for R1; R4and R5are each H, hydroxyl, alkyl, cycloalkyl, heterocycle, phenyl, or Y-substituted alkyl; Y represents a hydroxyl, acyloxy, F - substituted methyl, cycloalkyl, tetrahydrofuranyl, carboxyl, alkoxycarbonyl or

The invention relates to new cycloalkenes and cycloalkanes, suitable as pharmaceutically active substances, more particularly to derivatives of 1,3-substituted of cycloalkene and cycloalkane formula (I)

Z-CH2-Y (I)

where Z stands for a group

< / BR>

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

Y - group

< / BR>
where R is the specified value,

mixtures of their isomers or the individual is

The invention relates to pharmaceutical facilities intended for use orally, in particular to the pharmaceutical agent in the form of microcapsules and method thereof

The invention relates to heterocyclic amines of formula I:


in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to the compounds and their pharmaceutically acceptable salts and methods for treating HIV infections and related viruses and/or treatment of acquired immunodeficiency syndrome (AIDS)

The invention relates to a new use some diphenylmethyl-piperazinecarboxamide, in particular amperozide, 4 [4,4-bis(forfinal)butyl] N-ethyl-1-piperazinecarboxamide and their salts in the treatment of substance abuse

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: medicine, cardiology.

SUBSTANCE: it is suggested to apply cortisol antagonists in addition to clonidine while manufacturing preparation to treat heart failure. Moreover, one should introduce cortisol antagonist or a product that includes cortisol antagonist along with the second medicinal preparation being a combined preparation to be applied either simultaneously, separately or successively. The present innovation provides decreased symptoms of heart failure at decreasing cardiac muscle's fibrosis and heart sizes due to preferable impact upon glucocorticoid receptors in patient's heart and/or kidneys.

EFFECT: higher efficiency of application.

12 cl, 2 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with medicinal preparations designed as solution and indicated for therapeutic needs. Eye drops contain ciprofloxacin hydrochloride monohydrate being equivalent to 0.3% free foundation, a buffer system that keeps pH within 3.5-5.5 interval, as a conserving agent - benzalconium chloride and a s a stabilizer - the salt of disodium ethylenediamine tetraacetic acid, moreover, their range of osmolality values correspond to 150-450 mM/kg H2O. Eye drops should be obtained by preparing buffer system in which mannitol should be dissolved followed by the salt of disodium ethylenediamine tetraacetic acid, benzalconium chloride, ciprofloxacin hydrochloride. Then one should perform the control for the quality of obtained solution to be then filtered by applying sterilizing elements and packed. This innovation provides treatment of eyes at creating the pressure in an eye and at certain desired osmolality.

EFFECT: higher efficiency of therapy.

4 cl, 1 ex

Endoparasitic agent // 2250779

FIELD: medicine.

SUBSTANCE: invention relates to endoparasitic agent containing cyclic depsipeptide of general formula 1 and piperazine of formula 2 .

EFFECT: endoparasitic agent with synergetic agent.

6 cl, 7 ex, 7 tbl

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating oncological diseases. It is suggested to apply bisdioxopiperazine (previously known as cardioprotector) to either treat or prevent tissue lesions caused due to sporadic transudation of cytotoxic poison for topoisomerase II (represented by anthracyclines, etoposide, teniposide, mitoxantrone daunorubicin, doxorubicin, etc.), medicinal remedies and pharmaceutical set of the same indication. It is, also, suggested to apply the method to treat or prevent tissue lesions caused by sporadic transudation of topoisomerase II poison. BisdioxopiperazineICRF-187 has impact due to catalytic inhibiting topo II. Signs for possible transudation of topoisomerase II poison (of local toxicity) usually include the availability of acute pain, erythema, development of ulcerations in area of transudation; due to the action of ICRF-187 the quantity of wounds is reduced, or the development of side effects is not observed.

EFFECT: higher efficiency of therapy.

59 cl, 12 dwg, 13 ex, 10 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of adamantane of the general formula:

wherein m = 1 or 2; each R1 represents independently hydrogen atom; A represents C(O)NH or NHC(O); Ar represents the group:


wherein X represents a bond, oxygen atom or group CO, (CH2)1-6, CH=, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n, S(O)nCH2, CH2S(O)n wherein n = 0, 1 or 2; R' represents hydrogen atom; one of R2 and R3 represents halogen atom, nitro-group, (C1-C6)-alkyl; and another is taken among R2 and R3 and represents hydrogen or halogen atom; either R4 represents 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system comprising one or two nitrogen atoms and oxygen atom optionally being heterocyclic ring system is substituted optionally with one or more substitutes taken independently among hydroxyl atoms, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7; or R4 represents 3-8-membered saturated carbocyclic ring system substituted with one or more substitutes taken independently among -NR6R7, -(CH2)NR6R7 wherein r = 1; R5 represents hydrogen atom; R6 and R7 each represents independently hydrogen atom or (C1-C6)-alkyl, or (C2-C6)-hydroxyalkyl group eliciting antagonistic effect with respect to R2X7-receptors. Also, invention describes a method for their preparing, pharmaceutical composition comprising thereof, a method for preparing the pharmaceutical composition and their applying in therapy for treatment of rheumatic arthritis and obstructive diseases of respiratory ways.

EFFECT: improved method for preparing and treatment, valuable medicinal properties of compounds.

13 cl, 88 ex

FIELD: medicine.

SUBSTANCE: at performing curative endoscopy one should apply pneumoapplication of granulated sorbent - diovine at the quantity of 0.2 g, the pressure being 15 atm. at the distance of 1.5 cm against the defect onto the surface of bleeding rupture of gastric mucosa. Diovine's coarse-grained structure enables to keep the integrity of mucous-bicarbonate barrier due to providing normal vapor exchange and moisture medium in the defect. Moreover, diovine's antimicrobial action helps to suppress gram-positive and gram-negative microflora that enables to shorten terms for defects healing and decrease the frequency of repeated hemorrhages.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a medicinal formulation consisting of a core and the stomach-dissolving envelope. The core comprises trimetazidine dihydrochloride as an active component, and starch, mannitol, povidone, magnesium stearate, croscarmelose and microcrystalline cellulose as accessory substances. The envelope comprises hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide, magnesium stearate and acid red as a dye. Also, invention describes a method for making the trimetazidine medicinal formulation. Trimetazidine tablets show high mechanical strength in the low pressing strength (3.5-5 kH). The composition of the medicinal formulation provides releasing 80% of trimetazidine for 30 min.

EFFECT: improved and valuable properties of formulation.

3 cl, 1 tbl, 1 ex

FIELD: medicine, neurology, pharmacy.

SUBSTANCE: invention proposes using levetiracetam and the corresponding levetiracetam-base pharmaceutical composition used in treatment of bipolar disorders, mania and migraine. Also, invention relates to a pharmaceutical composition based on levetiracetam and at least one inhibitor of GABA type A neuronal receptors that is used in treatment of epilepsy, alcohol withdrawal syndrome, tremor, bipolar disorders, obsessive-compulsive disorder, panic state, depression, headache, pain, ischemia and head trauma, to corresponding methods for treatment, to a method for selective enhancing the therapeutic effect of inhibitors of GABA type A neuronal receptors, to a method for treatment of patient with inhibitor of GABA type A neuronal receptors involving the combined administration of indicated inhibitor of GABA type A neuronal receptors with levetiracetam. Invention shows the possibility for using levetiracetam for treatment of chronic and neuropathic pain in lower doses as compared with doses causing secondary effects, and shows its property to enhance activity of inhibitor of GABA type A neuronal receptors.

EFFECT: improved and valuable medicinal properties of agent.

18 cl, 18 tbl, 7 ex