The derived 3-oxadiazolyl-5,6,7,8-tetrahydro-1,6 - naphthiridine and derived 5,6,7,8-tetrahydro-1,6 - naphthiridine

 

(57) Abstract:

Usage: as a medicinal product. Derivatives of 3-oxadiazolyl-5,6,7,8-tetrahydro-1,6-naphthiridine get intramolecular cyclization of the corresponding allselectbutton or 1,2-di(R-carbamoyl)of hydrazines in the presence of dehydrating. Product: 6-benzyl-3-(5-methylthio-1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-2(1H)-he, the yield of 55.5%, so pl. 215 - 217oC. 2 C. and 7 C.p. f-crystals, 8 PL.

The invention relates to 3-oxadiazolyl-5,6,7,8-tetrahydro-1,6-naphthyridinone used in medicine, method of its production and its use as a medicinal product and an intermediate product.

Benzodiazepine compounds such as diazepam, are widely used as protivovazdushna tools, and also as a remedy against insomnia. However, these compounds have a number of side effects, such as impaired coordination, sleepiness, muscle weakness, upset orientation or motor responses, in addition, their use is associated with a number of negative aspects, such as drug resistance and drug dependence in patients. To solve these is atarov brain.

One such nebenzodiazepinova compounds having the following formula, described in Journal of Medicinal Chemistry 34, page 2060 /1991/.

,

where

Rahydrogen atom, Rb-Rdrepresents a methyl group, and so on, Rerepresents a methoxy group, etc.

However, the compounds of formula I of the present invention never not been previously described.

The object of the present invention is 3-oxadiazolyl-5,6-7,8-tetrahydro-1,6-naphthyridinone corresponding to the formula I, or pharmaceutically acceptable salt is a product of acid accession, having affinity to the benzodiazepine receptor and used as medicines.

,

where

Het represents oxadiazole ring, R1is a hydrogen atom, acyl group, lower alkyl group or a group with the formula-CH2R1(in which R1there cyclessa ankylostoma lowest altergroup lowest Alchemilla, benzyl group, allograph or heteroaromatic group), R2represents a lower allilohreos, cyclonesue alkyl group, a lower altergroup, lower Altenilpe, aryl group, heteroaromatic SCHOU alkenylacyl, lower alkylthio or fenoxaprop.

Another object of the invention is the presentation of the method of obtaining the compounds of formula (I).

In addition, the subject invention includes a representation of a pharmaceutical composition containing these compounds as active ingredient and its use in medicine.

And later in the subject invention includes a representation of the intermediate product to obtain the compounds of formula (I).

We present herewith the invention compounds have the above formula /I/, however, more preferred are compounds of formula I, in which Het is a 1,2,4-oxadiazole ring or 1,3,4-oxadiazole ring, R1represents a group of formula-CH2R1, R1represents an aryl group or heteroaromatic group, R2is lower alkyl or cyclessa alkyl group, a lower alkenylphenol, aryl, heteroaromatic or lower alkoxygroup or lower alkoxygroup. In particular, the most preferred compounds of formula I in which Het represents a 1,3,4-oxadiazole ring, R1severely affected group is alogena, R2represents an alkyl group with 2 to 3 C-atoms, cyclo-, on drink or a methoxy group.

In the description and in the patent claims, the terms "lower alkyl", "lower alcocke" and "lower alkylthio" refers to Premiery or branched alkyl, alcoke, alkylthio, respectively having 1-5 C-atoms. The term "lower alkenyl", "lower quinil" and "lower alkenylacyl" implies premiani or branched alkenyl, alkinyl or alkenylamine, respectively having 2-5 C atoms. The term "cyclonite alkyl" represents cycloalkyl with 3-6 C-atoms. The term "acyl" denotes premiani or branched alkanoyl with 1-5 C-atoms, benzoyl, naphtol and so on, the Term "Ariel group"represents, for example, phenyl and dattilografare and similar groups, and these groups can have from 1 to 3 substituents selected from the group of a hydrogen atom, lower alkyl, triptoreline lower alcocke and the nitro-group. The name "heteroaromatic group" includes a 5-6-membered heteroaromatic group containing 1-2 heteroatoms selected from the group of nitrogen atom, oxygen atom, sulfur atom, such as thienyl, furyl, pyridinyl isoxazolyl and so on, and these heteroaromatic groups can have from 1 to 3 Deputy.

Pharmaceutically acceptable salts of the acid products of accession of the formula /I/, represents, for example, salts with inorganic acids /such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc./ or salts with organic acids /such as oxalate, maleate, fumarate, malonate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, tosylate and so on/.

Submitted by invention compounds can be obtained in various ways, are presented below.

Method 1. From the presented invention compounds (I) in connection with formula /Ia/,

,

where

R1has the above meaning, R2represents a group other than lower allylthiourea, can be obtained by subjecting the compound of formula (II),

,

in which

R2has the same meaning as R2with the exception of the lower allylthiourea, and R1has the above values, the intramolecular cyclodehydration.

This cyclization reaction is usually carried out by treating compound (II) dehydrating agent. Dehydrating agent can represent, for example, a combination of phosphoric /III/ connections /for example, triphenylphosphine and so on/ and d.D./, and similar compounds, however, more preferable is a combination /III/-basic phosphorus compounds and dialkyldithiocarbamate. The reaction can be carried out in a solvent or without it, but it is usually performed in an inert solvent which does not affect the reaction. Such solvents include, for example, ethers (tetrahydrofuran, dioxane and so on), aromatic hydrocarbons (benzoyl, toluene and so on ), gloriane hydrocarbons (dichloromethane, chloroform and so on) and others. The solvents can be used alone or a mixture of two or more solvents. If the reaction is carried out using combinations of compounds trehosnovnogo phosphorus and dialkyldithiocarbamate, in this case used for the reaction base. Under the grounds of having organic bases of triethylamine, tributylamine, Diisopropylamine, N-methylmorpholine, pyridine, etc. of the Reaction temperature varies depending on the initial connection, but usually it ranges from 0 to 110oC, preferably from 0 to 70oC. If the reaction using the compound of the formula (II) can be protected with suitable protecting group that can be removed after the reaction, the group of formyl, acetylcoa and so on), the lower alkoxycarbonyl group and benzyloxycarbonyl group. The cyclization reaction with a compound of phosphorus (III) and dialkyldithiocarbamato represents a new reaction.

Method 2. From the present by the present invention compounds (I), the compound of formula (I), where R2represents a lower allylthiourea, can be obtained by the method corresponding to the following reaction scheme.

,

in which

represents a lower alkyl group, M represents sodium or potassium and R1has the above values.

The compound (I) reacts with carbon disulfide in the presence of a base in accordance with the method described in Journal of Heterocyclic Chemistry T. 19, R. 541 /1982/ with obtaining the compound (II), after which the compound (II) interacts with an alkylating agent (for example, the lower alkylhalogenide and so on) according to the method described in Journal of Indiaan Chemistry Socicty so 68, R. 108 /1991/obtaining the compounds of formula /Ia/, representing a compound (Ia), where R2is a compound (Ia), where R2represents a lower allylthiourea. If the join /I/ RIrepresents an atom of odor is Ogii with method I.

Method 3. Of the present invention compounds (I), the compound of formula (Ib):

,

where

R2is not the lowest alkoxygroup, lower alkynylamino, fenoxaprop, lower alkylthiol RIhas the above values can be obtained by subjecting the compound of formula (III), which also is not the lowest alkoxygroup, lower alkynylamino, phenoxy and lower alkylthiol, and R2and RIhave the above values, the intramolecular cyclodehydration.

In addition, from the present to the present invention compounds (I), the compound of formula (Ic)

,

in which R2is not lower alkoxy, lower alkenylacyl, phenoxy and lower alkylthiol, and RIhas the above values can be obtained by subjecting the compound of formula (IV)

,

where

RIand have the above values, the intramolecular cyclodehydration.

The cyclization reaction of compound (III) and compound (IV) can be performed by processing the specified connection dehydrating agent is usually by heating in a suitable solvent, which does not affect the reaction. The solvent can be used, for example, is an etc. The solvents can be taken by themselves or to use a mixture of one or more solvents. The reaction temperature varies depending on the type of the original substance, but it usually ranges from 5 to 150oC, preferably from 80 to 120oC. If the reaction using the compound (III) and compound (IV) in which RIrepresents a hydrogen atom, these compounds may be protected by suitable protective groups which can be removed after completion of the cyclization. Protecting groups are, for example, the lowest alkanoglu (formyl, acetyl, and so on), low alkoxycarbonyl and benzyloxycarbonyl.

Method 4. Of the present invention compounds (I), the compound of formula (Ib), where R2represents a lower alkoxy-, lower allylthiourea, and RIhas the above values can be obtained by reaction of compounds of formula (V)

,

in which

represents a lower alkenylacyl-, alkoxy-, phenoxy or lower allylthiourea, and RIhas the values indicated above, with hydroxylamine in accordance with the method described in Journal of Heterocyclic Chemistry I. 18, page 1197, 1981.

The reaction is usually carried out in a suitable solvent, such as alcohols, my connection but is usually from 50 to 90oC.

Method 5. Of the compounds provided by the present invention, the compound of formula (IC), where R2represents a lower alkoxy-, lower alkenylacyl, phenoxy or lower allylthiourea, and RIrepresents the same groups that were described above can be obtained in accordance with the method described in Synthesis, page 843 /1986/, i.e., subjecting the compound of the formula /VI/

,

in which

RIand have the above values, and Ph represents a phenyl group, intramolecular cyclization.

The cyclization reaction is conducted by heating in a suitable solvent, for example aromatic hydrocarbons such as benzene, toluene and so on) and ethers (tetrahydrofuran, dioxane and so on). The reaction temperature varies depending on the type of the original compound, but is usually from 50 to 150oC, preferably 80-120oC.

Present invention the compound (I) obtained by the above methods 1-5, is isolated and purified using conventional methods such as chromatography, re-crystallization, pereosazhdeniya and so on

Submitted by invention compounds get in free reaction conditions, and so D. Salt-addition products of acids, is converted into the free base, using for this purpose the traditional methods, such as, for example, data bases, such as carbonates of alkali and alkaline earth metals, hydroxides of alkali and alkaline earth metals, and so on, Free base can be converted into their salts-acid products attach using traditional methods, such as processing their traditional methods, such as processing their inorganic or organic acids.

The method of obtaining the original connection.

The compounds used in the above method I, are new compounds and can be obtained in accordance with the following reaction scheme.

,

where

R represents a hydrogen atom or a lower alkyl group and R1and R2have the above values.

Synthesis of compound (II) from compound (III) is carried out by reaction of the compound (III) or its reactive derivative at the carboxyl group with a hydrazide of formula (where has the above values) in the usual manner.

Or the same compound (II) can be obtained by two-stage method, and asinam according to traditional methods with subsequent acylation product derived from carboxylic acids of the formula .

The compound (III) are obtained according to the method described in Arkiv foer kemi 26/41/, pages 489-495 Chemical Abstract, 67, 3261/1967/ or according to various other methods described below. described below.

Used in method 3, compound (III) are new compounds obtained in accordance with the following reaction scheme of the process.

,

where

R1and have the above values.

The compound (III) is obtained by reaction of the compound (IV) or its reactive derivative at the carboxyl group with amidoximes according to traditional methods. If the compound (IV) R1represents a hydrogen atom, the compound (IV) can be protected protecting group, as described below.

The compound (IV) obtained in accordance with method 3, are also novel compounds which can be obtained in accordance with the following reaction scheme of the process.

,

where

R1and have the above values.

The compound (IV) is reacted with hydroxylamine in the usual way of obtaining the compound (VII), which further reacts with a reactive derivative at carbox the cation of the compound (IV).

In the case of using the compound (VII), where R1represents a hydrogen atom, K1a group can be protected protecting group, as described below.

Used in method 4, the compound (V) are obtained according to the above scheme, where R1and have the above values.

.

The compound (IV) or its reactive derivative at the carboxyl group reacts with the salt of an alkali metal or ammonium salt titanoboa acid in a suitable solvent to obtain the compound (VIII), which is further subjected to alcoholism or handle lower alkylthio or its alkali metal salt in a suitable solvent to form compound (V). When using the compound (VIII), where R1represents a hydrogen atom, R1group can protect protecting group, as described below.

Used in method 5, the compound (VI) is a new compound obtained in accordance with the following reaction scheme, where R, R1and have these values, and Ph represents a phenyl group.

The compound (III) retrieve a reducing agent such as sodium borohydride, tetrabutylammonium the compounds (IX), which is further subjected to oxidation active dioxide magnesium in a suitable solvent to obtain compound (X).

The compound (X) is reacted with hydroxylamine under conditions of traditional education Akimov, to obtain the compounds (II), which interacts with the N-chlorosuccinimide according to the method described in Journal of Organic Chemistry. so 45 p. 3916/1980 with the formation of compound (XII).

The compound (XII) is reacted with sodium azide in a suitable solvent according to the method described in Synthesis, page 102/ 1979/ the formation of compound (XIII).

The compound (XIII) is reacted with the ether kalamurina acid or reactive derivative ester S - alkylthiophenes acid in a suitable solvent according to the method described in Synthesis cnh/ 843 /1986/, poluchenii compounds (XIV), which further reacts with triphenylphosphine to form compound (VI).

The compound (XII) can also be obtained by the method described in Syntesis page 102 /1079/, according to the reaction scheme below

,

where

R1has the above values.

The compound (IX) is reacted with a compound of phosphorus (for example, phosphorus trichloride, phosphorus oxychloride, and so on ) or thionyl chloride in Eiselstein acid in a suitable solvent with the formation of compound (XII).

The compound (III), the compound (IV) and compound (VI) is converted to the compound (II) 0 (VI) receive, in accordance with the method described Arkiv foer Kemi 26/41/, 489-495/1967// Chemical Abstract. so 67, 32611 z /1967/ or by the following reaction scheme

,

where

V represents a halogen atom, a lower alkoxygroup or denissow alkylamino, W and Z are the same or different meaning and each represent a cyano - or lower alkoxycarbonyl group. R1-lower alkyl, n is a number of 1-3, and R1has the above values.

The original compound (XVI) in the reaction scheme above, can be obtained in accordance with the method described in Journal of American Chemical so-85, page 207 /1963/. In addition, compound (XVI) is obtained by reaction with compound (XVII) in a solvent, for example alcohols such as methanol, ethanol and so on, ethers such as tetrahydrofuran, dioxane, etc., aromatic hydrocarbons (for example benzene, toluene, etc. at a temperature of from 0 to 120oC to obtain compound (XVIII), which further reacts with ammonia or an ammonium salt (e.g. ammonium acetate) in solvents, such as alcohols, for example methanol, ethanol and so on, ethers (for example, tetr the CLASS="ptx2">

If W and Z in the compound (XIX) are lower alkoxycarbonyl group, the compound (XIX) is heated in a solvent, such as alcohols, in particular methanol, ethanol and so on, ethers such as tetrahydrofuran, dioxane, etc. and aromatic hydrocarbons such as benzene, toluene, xylene, etc. at a temperature of from 50 to 120oC to obtain compound (III'), which is then hydrolized in alkaline or acidic conditions, traditional methods of obtaining the compound (IV).

If Z in the compound (XIX) represents cyano, the compound (XIX) is treated in the presence of a base in a suitable solvent, for example alcohols, such as methanol, ethanol and so on, ethers (e.g. tetrahydrofuran, dioxane and so on) and similar compounds at a temperature of from 0 to 100oC obtaining the compound (XIX), which subsequently reacts with nitrate under acidic conditions, for example 5 to 10% aqueous solution of hydrochloric acid or 5-20% aqueous solution of sulfuric acid at a temperature of from 0 to 20oC to obtain compound (III') if W in the compound (XX) is an ester group or the compound (VI) if W in the compound (XX) is Soboh the measures the thionyl chloride, with phosphorus pentachloride by phosphoroxychloride, polyphosphoric acid, and so on) in a solvent such as ethers: tetrahydrofuran, dioxane etc., aromatic hydrocarbons such as benzene, toluene and so on, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloromethane, etc. Specified compound (XXI) is obtained by reaction of a reactive derivative of the carboxy group of the compound (IV) with ammonia in the traditional way.

The compound (III) can also be obtained in accordance with the following reaction scheme.

,

where

represents lower alkyl, benzyl, lower alkoxycarbonyl or benzyloxycarbonyl group is not a hydrogen atom and an acyl group, as in the R1and R have the above values.

Deputy R1in the compound (III") and the substituent in the compound (III') can be converted into each other via the compound (XXII). The compound (III), where R1represents lower alkyl or benzyl group, can be converted to compound (XXII) in the processing of its 1-chloracidobacterium according to the method described in Journal of Organic Chemistry I. 49, page 2081 /1984/.

The compound (III), where PREDSTAVITEL in the presence of a catalyst (for example, of Raney Nickel, palladium on coal and so on) under normal pressure or under pressure at temperatures from 25 to 80oC in a suitable solvent, for example water, methanol, ethanol, acetic acid, dioxane, ethyl acetate, etc.

The compound (III"), which represents the lowest alkoxycarbonyl group or benzyloxycarbonyl group can also be converted into the compound (XXII) by treating it with an acid or a base in a suitable solvent. For example, the compound (III"), tertiary butoxycarbonyl group, process triperoxonane acid at a temperature of from 25 to 80oC in a solvent, for example dichloromethane, chloroform, etc. to obtain the compound (XXII).

Thus obtained compound (XXII) is converted into a compound (III') by reaction of compound (XXII) with an alkylating agent , respectively, where represents, for example, lower alkyl, allyl, propargyl, benzyl, naphthalenyl or heteroaromatic methyl group, in the presence of a basic compound, for example inorganic salts such as hydroxides of alkali metals (sodium hydroxide and potassium and so on), carbonates of alkali metals, carbonates of sodium, potassium and so on) and acid carbonates of alkali m is ritilin and so on, in a suitable solvent, for example acetone, methylethylketone, diethylketone, dimethylformamide, benzene, toluene, acetonitrile and the like, at a temperature of from 25 to 100oC. as the alkylating agent may be used, for example, alkylhalogenide.

Pharmacological properties present invention compounds /1/ data are illustrated in the following experiments.

Experience 1. Test the binding of benzodiazepine receptors.

In accordance with the method presented in Life Science, vol 20, page 2101, 1977, conduct the test for the binding of benzodiazepine receptors.

Raw fraction synaptosomal membranes isolated from rat brain of Winster (age 7-8 weeks), suspended in 15 mmol Tris-HCl buffer (pH 7,4) containing 118 mm NaCl, 4.8 mm KCl, 1.28 mmol of calcium chloride and 1.2 mmol of magnesium sulfate in a concentration of 1 g crude (weight) of the brain in 20 ml buffer, receiving the source membrane receptor. (3H) band is used as the labeled ligand.

The analyzed connection (known quantity), 3H-diazepam (final concentration of 1.5 nmol), a membrane receptor and the above buffer to the claim at 0oC for 20 minutes, after which the reaction mixture was rapidly filtered through a glass fiber filter GF/B Whatmann, connection device for collecting cells production Brandell. The collected labeled membrane receptor thrice washed with ice-cold 50 mm Tris-HCl-buffer (pH of 7.7, 5 ml). The radioactivity on the filter was measured liquid scintillation counter, determining the number of end (3H)-diazepam membrane receptor (total binding). Separately repeat the same procedure, except that type 1 mkmol diazepam, and measure the number of 3H-diazepam related in the membrane of the receptor (nonspecific binding). The amount of nonspecific binding is subtracted from the total binding and receive specific binding. On the basis of specific binding determine the inhibitory activity IR50(IC50) of the studied compounds. The value of the IC50represents the concentration of tested compound required to reduce specific binding of labeled ligand by 50%. The results obtained are presented in table 1.

Experience 2. Effect on clonic convulsion caused by pentylenetetrazole (anti-reserve-activity).

Experience the ard (of Anticonvulsant Drugs, J. Mercier, ed. pages 47-65, Pergamon Press, new York, 1973. In this test, antiepileptic drugs intended for the treatment of mild forms of epilepsy, and most benzodiazepine funds show positive results.

The test compound is administered orally to male mice Std-ddI weighing 20-25 g (five mice per group). After 2 hours subcutaneously injected pentylenetetrazole (85 mg/kg), after which the animals immediately placed in a plastic cage and within 30 minutes see the manifestation of clonic convulsions. In the absence of clonic convulsions establish that the test compound has an antagonistic activity. Results of observations are presented in table 2.

As shown by the above results, the present invention compounds exhibit external affinity to the benzodiazepine receptor and, in addition, show a pronounced antagonistic activity against clonic convulsions caused by pentylenetetrazole. From this we can conclude that the present invention compounds may be used as agonists of benzodiazepine receptors, such as protivovazdushna funds funds against epilepsy and the And case of use as antagonists of benzodiazepine receptors present invention compounds can be entered orally parenteral or rectal, however, oral introduction is more preferable. The dosage of the compounds of this varies depending on the method of administration, the patient's condition, age, purpose of treatment (prophylaxis or treatment), and so on, but usually the dose is from 0.01 to 10 mg/kg/day, preferably 0.02 to 5 mg/kg/day.

Present invention the compound is administered in the form of a conventional pharmaceutical composition in mixture with conventional pharmaceutically acceptable excipients or diluents. Pharmaceutically acceptable excipients and diluents can be a traditional substances used in the pharmaceutical industry, does not interact with the patented connection, such as lactose, glucose, mannitol, dextran, starch, white sugar, manualwinding, synthetic aluminum silicate, crystalline cellulose, Na-carboxymethylcellulose, Ca-carboxymethyl cellulose, ion-exchange resins, methylcellulose, gelatin, gum Arabic, hydroxypropylcellulose, hypromellose, nizkozameshhennoj hydroxypropylcellulose, polivinilpirolidon, polyvinyl alcohol, magnesium stearate, talc, carboxine is at, macrogol, vegetable oil, wax, liquid paraffin, white perolat, Nannie surfactants, propylene glycol, water, etc.

Pharmaceutical compositions are produced in the form of tablets, capsules, granules, powders, syrups, suspensions, suppositories, gels and compositions for injection, etc. For preparation of compositions using traditional methods. To prepare a liquid form of the drug first, it is prepared in solid form intended for subsequent dissolution or suspension in water. Tablets or granules also cover using traditional methods and composition for injection can be prepared by dissolving patented compound or its salt of the acid product of accession, in distilled water or natural sodium chloride solution, followed by solvent, if necessary, isotonic and adding a pH regulator, buffer and preservative.

Such pharmaceutical compositions may contain patentable compound in the amount of more than 0.01 % by weight, preferably 0.05 to 70 wt.%, and can be composed of several physiologically active components.

In more detail, the present S="ptx2">

Example 1. The obtained ethyl-6-benzyl-5,6,7,8-tetrahydro-2(1H)- oxo-1,6-naphthiridine-3-carboxylate.

1) Solution of 1-benzyl-4-piperidone (19g, 0.1 mol) and pyrrolidine (10.7 g, 0.15 mol) in toluene (200 ml) is refluxed for 5 hours, the water formed is removed by evaporation. The reaction solution is concentrated to dryness under reduced pressure and to the residue add anhydrous toluene (200 ml). To the mixture is added dropwise a solution atlatonementaustin (17 g, 0.1 mol) in anhydrous toluene (50 ml) under cooling with ice. The mixture is heated to room temperature and stirred overnight, then added dropwise concentrated hydrochloric acid (13 ml) under cooling with ice. The resulting hydrochloride is collected by a method of filtration, thoroughly washed with ethyl acetate and isopropyl ether. Hydrochloride is dissolved in ethylene (300 ml) and blown into the mixture under ice cooling gaseous ammonia until saturation. The mixture is heated to room temperature, incubated overnight, and then concentrated to dryness under reduced pressure. To the resulting residue add isopropanol, and the precipitated crystals emit by filtration, dried, receiving raw CRI 10% aqueous sodium hydroxide solution while cooling with ice. The mixture is heated to room temperature and stirred for 30 minutes, then to the resulting mixture under ice cooling, water is added (100 ml). Precipitated crystals are removed by filtration, washed with water and recrystallized from isopropanol to obtain ethyl-2-amino-6-benzyl-5,6,7,8-tetrahydro-1,6-naphthiridine - 3-carboxylate (8.5 g, as a colourless solid. The output of 27.3%, so pl. 141-143oC.

2). To a solution of the above ether compound (10 g, 32 mmol) in 10% solution of sulfuric acid (100 ml) is added dropwise slowly a solution of sodium nitrate (4.5 g, 65 mmol) in water (20 ml) under cooling with ice. After the addition the mixture is stirred for 2 hours. While continuing the stirring and using ice cooling, the mixture is alkalinized with 20% aqueous solution of sodium hydroxide, then extracted with chloroform. The extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove solvent. The resulting crystals recrystallized from zapopan obtaining a colorless solid (6.8 g). Yield 68%, so pl. 168-170oC.

Example 2. Obtain hydrochloride of 6-benzyl-5,6,7,8-tetrahydro - 2(1H)-oxo-1,6-naphthiridine-3-carboxylic acid. what one solution of hydrochloric acid (70 ml) is refluxed for 3 hours. After cooling, the precipitated crystals are removed by filtration, washed with water and recrystallized from methanol/water, getting the desired compound (7.0 g) as a colourless solid. The yield of 99.2%, so pl. 260-263oC.

2). A solution of 1-benzyl-4-piperidone /100 g of 0.53 mol/ and pyrrolidine (70 ml, 0,795 mol) in toluene (1.5 l) is refluxed for 5 hours with distillation of water. The mixture is concentrated to dryness under reduced pressure and the resulting residue added dioxane (1 l). While cooling with ice to the mixture add diethylethylenediamine (126 g of 0.58 mol) and the mixture refluxed for 6 hours. The mixture is cooled to room temperature, then add ammonium acetate (82 g, 1.06 mol) 82 g, 1.06 mol) and heated with stirring under reflux for 1 hour. The reaction solution is concentrated to dryness under reduced pressure, obtaining ethyl-6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-carboxy - lat, which is used at a later stage without isolation or further purification.

By the above ethyl ether are added 20% aqueous solution of hydrochloric acid /600 ml, and the mixture is boiled in reverse holodilnik.okna/water give the desired compound as a colourless solid (105 g). The yield of 61.9%, I. p. L. 260-263oC.

Example 3. Getting Atid-5,6,7,8-tetrahydro-2(1H)-oxo-1,6 - naphthiridine-3-carboxyglutamate.

To a solution of ethyl-6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6 - naphthiridine-3-carboxylate (8 g) in glacial acetic acid (360 Il) add 10% palladium catalyst on coal (200 mg), after which the mixture is subjected to catalytic hydrogenation at room temperature in a hydrogen atmosphere. After theoretical amount of hydrogen is consumed, the catalyst is removed by filtration. The filtrate is concentrated to dryness under reduced pressure. The residue is diluted with ethanol precipitated crystals are filtered out. After recrystallization from a mixture of ethanol/water get colorless compound as a solid (6.8 g). Yield 94%, so pl. 125-130oC.

Example 4. Ethyl-6-(3-terbisil)-5,6,7,8-tetrahydro-2(1H)-oxo - 1,6-naphthiridine-3-carboxylate.

A suspension of ethyl-5,6,7,8-tetrahydro-2(1H)oxo-1,6-naphthiridine-3-carboxyglutamate (2.0 g, 7.1 mmol), 3-ftorangidridy (1.7 g, 9 mmol) and acid sodium carbonate (2.0 g, 24 mmol) in methyl ethyl ketone (100 ml) is refluxed for 16 hours. The insoluble product is removed by filtration, and the filtrate concentri what Hayon CHP-20P (highly porous polystyrene resin, production Mitsubishi Kazei Corporation, Japan), elwira acetonitrile and water at high concentration gradient). After recrystallization from ethanol colorless solid connection (1,91 g). The yield of 81.4%, so pl. 276-280oC

Example 5. Getting 6-hydrochloride-(2-terbisil)-5,6,7,8 - tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-carboxylic acid.

1) dichloride phenylphosphorus acid (1 ml) is added at room temperature ethyl-6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-carboxylate (1.0 g, 3.3 mmol), and the mixture is stirred at a temperature of 150oC for one hour. After cooling, the mixture was diluted with diisopropyl ether. Deposited crystals are filtered off. The obtained crystals suspended in chloroform and the mixture is alkalinized by gradually adding 28% aqueous ammonia with stirring and ice cooling. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove solvent. The resulting oily product is processed through column chromatography with silica gel, elwira mixture of chloroform/methanol 200: 1 to obtain ethyl-6-benzyl-2-chloro-5,6,7,8-1,6-naphthiridine-3-carboxylate (9.7 g) in the form of bestbefore (200 ml) is added dropwise 1-chloroethylphosphonic (10.4 g, 72 mmol) at room temperature, and the mixture is refluxed for 20 hours. The mixture is concentrated to dryness under reduced pressure and the resulting residue diluted with methanol (200 ml). The mixture is heated under stirring for 2 hours at the temperature of the 4oC. the Reaction mixture is concentrated to dryness under reduced pressure and the resulting residue add isopropyl ether. Deposited crystals are filtered off and precrystallizer from ethanol, receiving 2-ethyl-5,6,7,8-tetrahydro-1,6-naphthiridine-3-carboxymethylated (21.2 g) in the form of the devil colored solid product. Output 85,8%, so pl. 153-156oC.

3) To a solution of the above hydrochloride (5.0 g, 18 mmol) and triethylamine (4.0 g, 40 mmol) in N,N-dimethylformamide (DMF) (50 ml) is added 2-florantyrone (3.1 g, 21 mmol) and the mixture heated with stirring at 60oC for 15 hours. The reaction solution is concentrated to dryness under reduced pressure and the resulting residue is dissolved in chloroform. The reaction mixture was washed with 10% aqueous potassium carbonate solution and then with water. The organic layer is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove solvent. The resulting oil is 1. Get ethyl-2-chloro-6-(2-terbisil)- 5,6,7,8-tetrahydro-1,6-naphthiridine-3-carboxylate (4.6 g) as a colourless oil. Output 73,3%

4) Solution of the above ester (4.6 g, 13 mmol) in 20% aqueous solution of hydrochloric acid (80 ml) is refluxed for 24 hours. After cooling, the deposited crystals are filtered, washed and precrystallizer from ethanol. Get the desired compound as a colourless solid (3.4 g). The output of 77.2 percent. so pl. 273-276oC.

Example 6. Getting 6-benzyl-3-(5-methoxy-1,3,4-oxadiazol-2-yl)-5,6,8,8 - tetrahydro-1,6-naphthiridine-2(1H)-it.

1) a Solution of the hydrochloride of 6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-carboxylic acid (3.0 g, 9.4 mmol) and N,N-carbonyldiimidazole (2.3 g, 14 mmol) in dimethylformamide (50 ml) is heated under stirring at 70oC for 3 hours. To the solution add methylcarbamate (1.0 g, 11 mmol) and the mixture is stirred at the same temperature for 2 hours. The reaction solution is concentrated to dryness under reduced pressure and the obtained residue add isopropanol and triethylamine. Deposited crystals are filtered off and precrystallizer from methanol. Get N1-methoxycarbonyl-6-lentil-5,6,7,8-thoseoC.

2) To a solution of the above product (2.0 g, 5.6 mmol), triphenylphosphine (3.0 g, 11 mmol) and triethylamine (2.0 g, 20 mmol) in anhydrous tetrahydrofuran (50 ml) is added dropwise with stirring a solution of diisopropylcarbodiimide (2.2 g, 11 mmol) in anhydrous tetrahydrofuran (10 ml) under cooling with ice. The mixture is stirred at room temperature for one hour and add a small amount of water, after which the mixture is concentrated to dryness under reduced pressure. To the residue add isopropanol and the precipitated crystals are filtered out. After recrystallization from acetonitrile obtain the desired compound (0.8 g) as a colourless solid. Yield 43%, so pl. 176-178oC.

Examples 7-54. By analogy with the above-described example 6 receive connection examples 7-54 presented in table 3.

Example 55. Getting 6-benzyl-3-(5-cyclopropyl-1,3.4-oxadiazol-2-yl)-5,6,7.8-tetrahydro-1,6 - naphthiridine-2(1H)-it.

1). A solution of the hydrochloride of 6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-carboxylic acid (1.5 g, 4.7 mmol) and N, N' - carbonyldiimidazole (1,14 g, 7 mmol) in dimethylformamide /30 ml/ heated under stirring at 70oC for 3 hours. To the solution add cyclo is operating the solution is concentrated to dryness under reduced pressure and forming a residue add isopropanol and triethylamine. Deposited crystals are filtered off and recrystallized from methanol to obtain cyclopropanecarbonyl-6-benzyl-5,6,7,8-tetrahydro-2-(1H)-oxo-1,6-navigatin - 3-carbohydrazide (1.2 g) as a colourless solid.

The output of 66.1%, so pl. 256-258oC.

2) To a solution of the above product (1.1 g, 2.9 mmol), triphenylphosphine (1,62 g, 6.2 mmol) and triethylamine (1,05 g, 10 mmol) in anhydrous tetrahydrofuran (75 ml) is added dropwise with stirring a solution of diethylazodicarboxylate (1,05 g, 6 mmol) in anhydrous THF (5 ml) under cooling with ice. The mixture is heated with stirring to 60oC for 2 hours, then add a small amount of water and concentrate to dryness. The residue is treated with an average pressure on the chromatographic column with Diona CHP-20P, elwira acetonitrile and water (concentration gradient). After recrystallization from acetonitrile receive a colourless solid (0.31 g).

The yield of 44.5%, so pl. 212-214oC.

Examples 56-110. By analogy with example 55 receive connections presented in table 4.

Example 111. Getting 6-benzyl-3-(5-isopropyl-1,3,4-oxadiazol-2-yl)- 5,6,7,8-tetrahydro-1,6-naphthiridine-2(1H)-it:

1) To a solution of 6-benzyl-5.6.7,8-t is akriloilkhlorida (0,57 g, 5.5 mmol) under ice cooling. The mixture is heated to room temperature and stirred for 2 hours, then concentrated to dryness under reduced pressure. To the resulting residue, add 10% aqueous potassium carbonate solution and the mixture extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure to remove solvent. To the residue add isopropanol and the precipitated crystals are filtered out. After recrystallization from methanol to obtain N'-methacryloyl-6-benzyl-5,6.7.8-tetrahydro-2(1H)-oxo 1,6-naphthiridine-3-carbohydrates (1,21 g) as colorless solids. Yield 66%, so pl. 245-248oC.

2) To a solution of the above product (0,92 g, 2.5 mmol), triphenylphosphine (1.35 g, mmol) and triethylamine (0.87 g, 8.6 mmol) in anhydrous tetrahydrofuran (50 ml) is added dropwise with stirring a solution of Diethylazodicarboxylate (0.87 g, 5 mmol) in anhydrous THF (5 ml) under ice cooling. The mixture is heated under stirring at 60oC for 2 hours and add a small amount of water, then concentrated to dryness under reduced pressure. To the resulting residue add isopropanol and precipitated crystals otherthrow theoC.

Examples of wing 112-116. By analogy with example 111 receive connections presented in table 5.

Example 117. Getting 6-benzyl-3-(5-methylthio-1,3,4-oxadiazol-2-yl)-5,6,7,8-tragida-1,6 - naphthiridine-2(IH)-it.

1). To a solution of 6-benzyl-5,6,7,8-tragida-2(IH)oxo-1,6-naphthiridine-3-carbohydrazide (1,49 g, 5 mmol) in ethanol (20 ml) add a solution of potassium hydroxide (0.29 grams) in water (1 ml) and stirred while adding with perodically (0,46 g, 6 mmol) under ice cooling. The mixture is then refluxed for 7 hours. After cooling, the precipitated crystals are filtered out. Get potassium salt of 2-(6-benzyl-5,6,7,8-tetrahydro-2(IH)-oxo-1,6-naphthiridine-3-yl)-1,3,4 - oxadiazol-5-thiol (1,88), as colourless solid. Exit 98%.

2) To a solution of the above product (1,14 g, 3 mmol) in methanol (500 ml) add methyliodide (0.51 g, 3.6 mmol) and the mixture stirred at room temperature for 3 hours. The reaction solution is concentrated to dryness under reduced pressure, to the resulting residue add isopropanol. Deposited crystals are filtered off and recrystallized from ethanol to give the desired compound (0,59 g) as colorless solids. The output one-3-carbonyl.

1). A solution of 1-benzyl-4-piperidone (26,8 g, 0.14 mmol) and pyrrolidone (20 g, 0.28 mmol) in toluene (300 ml) is refluxed for 4 hours with distillation of water. The reaction solution is concentrated to dryness under reduced pressure and to the resulting residue add anhydrous dioxane (300 ml). To the mixture is added gradually dropwise with stirring a solution of ethoxymethylenemalononitrile (19 g, 0.16 mol in anhydrous dioxane (40 ml) under ice cooling. The mixture is heated to room temperature and stirred for 1 hour. To the mixture is added ammonium acetate (22 g, 0.29 mol) and stirred overnight at 70oC. the mixture is Then concentrated to dryness under reduced pressure. To the resulting residue add isopropanol precipitated crystals are filtered off, washed with water and dried. Get 2-amino-6-benzyl-5,6,7,8-tetrahydro-1,6-naphthiridine-3-carbonitrile (18,3, yield 49%), which is used in subsequent reactions without purification.

2). To a solution of the above product (15 g, of 56.7 mmol) in 10% aqueous solution of sulfuric acid (150 ml) is added dropwise with stirring sodium nitrite (7,88 g, 113 mmol) under ice cooling, after which the mixture is stirred for 2 hours. With stirring and ice cooling gap is irout chloroform, and the extract is dried over anhydrous sodium sulfate and evaporated under reduced pressure to remove solvent. The residue is diluted with isopropanol precipitated crystals are filtered off and recrystallized from acetonitrile. Get the desired compound (10 g) as a colorless solid product. Yield 66%, so pl. 230-233oC.

Example 119. Getting 6-benzil-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-2(IH)-it.

1). To a solution of 6-benzyl-5,6,7,8-tetrahydro-2(IH)-oxo-1,6 - naphthiridine-3-carbonitrile (1.6 g, 6 mmol) in ethanol (30 ml) is added hydroxylamine hydrochloride (0.52 g, 7.5 mmol) and sodium carbonate (0.8 g 7.5 mmol) and the mixture refluxed overnight. The reaction solution is concentrated to dryness under reduced pressure and to the resulting residue water is added. Deposited crystals are filtered off, washed with isopropanol and dried. Get amidoxime (1.4 g) as a colourless solid, which is used in subsequent reactions without purification.

2). To a suspension of the above product (1.19 g, 4 mmol) and potassium carbonate (0.66 g, 4.2 mmol) in methyl ethyl ketone (50 ml) is added dropwise with stirring a solution of cyclopropanecarbonyl and stirred for 2 hours. The reaction solution is boiled to dryness under reduced pressure and to the resulting residue water is added. Deposited crystals are filtered off and successively washed with water and isopropanol. The resulting mixture of crystals and toluene (50 ml) is boiled for 24 hours under reflux and concentrated to dryness under reduced pressure. The residue is treated through column chromatography with silica gel, elwira a mixture of chloroform:methanol = 100:3, and precrystallizer from acetonitrile. Get the desired compound (0,93 g) as a colorless solid product. The output of 66.7%, so pl. 187-190oC.

Examples of 120-140. By analogy with the above example 119 receive connections presented in table 6.

Examples 126 -140. Using appropriate starting compound by analogy with example 119 receive connections presented in table 7.

Example 141. Getting 6-benzyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5,6,7,8-tetrahydro-1,6 - naphthiridine-2(IH)-it.

1). To a suspension of the hydrochloride of 6-benzyl-5,6,7,8-tetrahydro-2(IH)-oxo-1,6-naphthiridine-3-karbonovoi acid (1.6 g, 5 mmol) and triethylamine (0.56 g, 5.5 mmol) in 1,2-dichloroethane (50 ml) is added N,N'-carbonyldiimidazole (1.22 g, 7.5 mmol) and the mixture is heated p is benzamidoxime (0,82 g, 6 mmol), after which the mixture is stirred for 2 hours. The reaction solution is concentrated to dryness under reduced pressure and the residue diluted with isopropanol. Deposited crystals are filtered off, receiving a colorless solid product (1.4 g, yield 70%), which is used in subsequent reactions without purification.

2) Solution of the above product (1.4 g) in toluene (50 ml) is refluxed overnight. The reaction solution is concentrated to dryness under reduced pressure and the residue is treated on a chromatographic column with silica gel, elwira a mixture of chloroform: methanol 100:3, and recrystallized from a mixture of chloroform/methanol, obtaining a desired compound (0,91 g) as a colorless solid product. Yield 68%, so pl. 231-233oC.

Example 142-167. Using the appropriate starting compound. IN analogy to example 141 receive connections presented in table 8.

Example 163. Getting 6-benzyl-3-(5-methoxy-1,2,4-oxadiazol-3-yl)-5,6,7,8-tetrahydro-1,6 - naphthiridine-2(1H)-it.

1). To a mixture of 0-methoxycarbonyl-6-benzyl-5,6,7,8-tetrahydro-2(1H) oxo-2(H)-oxo-1,6-naphthiridine-3-oidoxie (3.8 g, 10 mmol) and dichloromethane (40 ml) is added dropwise with stirring Ute in the fridge overnight and concentrated to dryness under reduced pressure. The obtained crystals are used in subsequent reactions without purification.

2). The above product is dissolved in anhydrous toluene (40 ml) and the mixture is refluxed for 15 hours. The reaction solution is concentrated to dryness under reduced pressure and the residue diluted with isopropanol. Deposited crystals are filtered off and precrystallizer from methanol to give the desired compound as a colourless solid.

When using the corresponding starting compounds in analogy to example 163 receive the following compounds shown in the examples 164 - 165.

Example 164. 6-benzyl-3-(5-ethoxy-1,2,4-oxadiazol-3-yl)-5,6,7,8-tetrahydro-1,6 - naphthiridine-2(1H)-he.

Example 165. 6-benzyl-3-(5-isopropoxy-1,2,4-oxadiazol-3-yl)-5,6,7,8-tetrahydro-1,6 - naphthiridine-2(1H)-he.

Example 166. Getting 6-benzyl-3-(3-methoxy-1,2,4-oxadiazol-5-yl)-5,6,7,8-tetrahydro-1,6 - naphthiridine-2(1H)-it.

A suspension of N-methoxydibenzoyl-6-benzyl-5,6,7,8-tetrahydro - -2(1H)-oxo-1,6-naphthiridine-3-carboxamide (3.6 g, 10 mmol) and hydroxylamine-hydrochloride (1.4 g, 20 mmol) in pyridine (20 ml) is refluxed overnight. The reaction solution is concentrated to dryness under p is crystallizers from methanol, receiving a colorless solid product.

When using the corresponding starting compounds in analogy to example 166 to obtain the following compounds of examples 167 - 168.

Example 167. 6-benzyl-3-(3-ethoxy-1,2,4-oxadiazol-5-yl)-5,6,7,8-tetrahydro-1,6 - naphthiridine-2(1H)-he.

Example 168. 6-benzyl-3-(3-isopropoxy-1,2,4-oxadiazol-5-yl)-5,6,7,8-tetrahydro - 1,6-naphthiridine-2(1H)-it.

The control example 1. Getting 6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-carbohydrazide.

A solution of ethyl-6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-carboxylate (5.6 g, 18 mmol) and hydrazine monohydrate (2.7 g, 54 mmol) in ethanol (300 ml) is refluxed for 3 hours. After cooling, the deposited crystals are filtered and precrystallizer from ethanol to obtain colorless solid product (5.2 g). Output 96,8%, so pl. 218 - 220oC.

Control example 2. Obtain 1-methyl-1-cyclopropanecarbonitrile.

A mixture of ethyl-1-methyl-1-cyclopropanecarboxylate (10 g, 7.8 mmol) and hydrazine monohydrate (5,! g, 0.1 mol) is heated with stirring at 100oC for 4 hours. To the reaction solution was added toluene (50 ml) and the mixture is refluxed 3 hours the om. Get the desired connection (8, 9 g) as colorless crystals. A yield of 99%, so pl. 85 - 87oC.

Control example 3. Getting 6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-methanol.

A mixture of ethyl-6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-carboxylate (20 g, 64 mmol), tetramethylpiperidine (25 g, 97 mmol) and 1,2-dichloroethane (200 ml) is refluxed for 4 hours. The reaction solution is concentrated to dryness under reduced pressure. By forming the residue water is added, after which the mixture is refluxed overnight and cooled with ice. Deposited crystals are filtered and dried. Get the desired connection.

Reference example 4. Getting 6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-carbaldehyde.

To a solution of 6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-methanol (2.7 g, 10 mmol) in chloroform (100 ml) was added active manganese dioxide (13.5 g) and the mixture is refluxed for 5 hours. After cooling, the insoluble matter is filtered off and the filtrate is concentrated to dryness under reduced pressure. The residue is treated on chromatographic colace at an average pressure diyana CHP-20P,made example 5. Getting 6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-aldoxime.

A solution of 6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-carbaldehyde (5.4 g, 20 mmol) and hydroxylamine-hydrochloride (2.8 g, 40 mmol) in ethanol (50 ml) is refluxed for 3 hours. After cooling, the precipitated crystals are filtered and dried, obtaining the desired connection.

Reference example 6. Getting 6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-hydroxykynurenine.

To a solution of 6-benzyl-5,6,7,8-tetrahydro-2(1H)-2(1H)-oxo-1,6-naphthiridine-3-aldoxime (2.8 g, 10 mmol) in dimethylformamide (30 ml) is added N-chlorosuccinimide (1.4 g, 10 mmol) in portions at room temperature and the resulting mixture is stirred for 5 hours. The reaction solution was poured into ice water and the precipitated crystals are filtered and dried, obtaining the desired connection.

Reference example 7. Getting 6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-easidock.

A mixture of 6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3 - hydroxykynurenine (3.2 g, 10 mmol), sodium azide (0.65 g, 10 mmol) and dimethylformamide (30 ml) was stirred at room temperature for 6 hours. The reaction RA.

Reference example 8. Getting 0-methoxycarbonyl-6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine - 3-oidoxie.

To a solution of 6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-oidoxie (3.2 g, 10 mmol) and triethylamine (1.1 g, 10 mmol) in dichloromethane (60 ml) is added dropwise with stirring a solution of methylcarbamate (1.0 g, 10 mmol) in dichloromethane (5 ml) under cooling with ice. The mixture is heated to room temperature and stirred for 3 hours. The reaction solution is concentrated to dryness under reduced pressure, the residue diluted with water. Deposited crystals are filtered and dried, obtaining the desired connection.

Reference example 9. Getting 6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-carbonization.

1). To a solution of the hydrochloride of 6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-carboxylic acid (3.2 g, 10 mmol) and triethylamine (3.1 g, 30 mmol) in dichloromethane (50 ml) is added dropwise with stirring, a solution of thionyl chloride (1.3 g, 10 mmol) in dichloromethane (5 ml) under cooling with ice. Once added, the mixture is heated to room temperature and stirred for one hour, then concentrated under reduced pressure, obtaining the acid chloride in the form of oily is sodium (25 ml) add potassium thiocyanate and the mixture is stirred at room temperature for 20 hours. The mixture is extracted with chloroform and the extract is dried over anhydrous acid and concentrated to dryness under reduced pressure.

The residue is purified by chromatography on a column of silica gel, elwira a mixture of chloroform-methanol 5:1 to give the desired compound as a colorless solid product.

Reference example 10.

Obtaining N-methoxydibenzoyl-6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine - 3-carboxamide.

To a solution of 6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-carbonization (3.3 g, 10 mmol) in absolute methanol (30 ml) is added sodium methoxide (1.1 g, 20 mmol) and the mixture refluxed for 20 hours. The reaction solution is concentrated under reduced pressure, and forming the remainder add the ethanol. Deposited crystals are filtered and dried, obtaining the desired connection.

Composition 1. Capsules, g:

6-Benzyl-3-(3-methoxy-1,3,4-oxadiazol-5-yl-5,6,7,8-tetrahydro - 1,6-naphthiridine-2(1H)-one - 5

Corn starch - 57

Lactose - 10

Crystalline cellulose - 25

Hydroxypropylcellulose - 2

Lightweight silicon dioxide - 0,5

Magnesium stearate 0.5 in.

The above compounds are mixed obeznalichivanie composition (100 mg each).

Part 2. Tablets, g:

6-Benzyl-3-(3-methoxy-1,3,4-oxadiazol-5-yl)-5,6,7,8-tetrahydro - 1,6-naphthiridine-2(1H)-one - 5

Corn starch - 20

Lactose - 30

Hydroxypropylcellulose - 5

Nizkozameshhennoj hydroxypropylcellulose - 10

The above compounds (components) are mixed in the usual way and carefully knead, adding to them a light silicon dioxide and magnesium stearate, and then the mixture is pressed into tablets containing 10 mg of active ingredient per tablet.

Part 3. Powders, g:

6-Benzyl-3-(3-methoxy-1,3,4-oxadiazol-5-yl)-5,6,7,8-tetrahydro - 1,6-naphthiridine-2(1H)-one - 5

Corn starch - 173

Lactose - 300

Hydroxypropylcellulose - 20

These components are mixed in the usual way and carefully knead, converting into powder, then add to them a light silicon dioxide, receiving 50-powdered composition.

1. The derived 3-oxadiazolyl-5,6,7,8-tetrahydro-1,6-naphthiridine formula

< / BR>
where Het - oxadiazole ring;

R1- lower alkyl group, or a group of the formula

< / BR>
where cyclonite-alkyl-, lower Alchemilla group, benzyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, the substituents of phenylenecarbonyl, low alkoxygroup and nitro, heteroaromatic group containing 5 to 6 members in the ring, from 1 to 2 atoms are heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by 1 to 3 substituents selected from halogen, lower alkyl groups, lower alkoxygroup and trifloromethyl;

R2- lower alkyl, cyclessa alkyl group, a lower Alchemilla group, lower Alchemilla group, phenyl, substituted phenyl, naphthyl, substituted naphthyl, the substituents of phenyl and naftilos groups are 1 to 3 substituent selected from a halogen, a lower alkyl group, trifloromethyl, low alkoxygroup and nitro, heteroaromatic group containing 5 to 6 members in the ring, from 1 to 2 atoms are heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by 1 to 3 substituents selected from a halogen, a lower alkyl group, low alkoxygroup and trifloromethyl, gorodnitsa accelgroup, lower alkoxylate altergroup lowest alkoxygroup lowest alkenylacyl, fenoxaprop or lower allylthiourea,

or its pharmaceutically acceptable additive salt of the acid.

2. Connection on p. 1, characterized in that cheela, selected from halogen, lower alkyl group, trifloromethyl, low alkoxygroup and nitro, 5-membered heteroaromatic group containing 1 to 2 heteroatoms from the group nitrogen, oxygen and sulfur;

R2- lower alkyl, cyclonite alkyl, lower alkenyl, phenyl, substituted phenyl, whereby phenyl may contain 1 to 3 substituent selected from a halogen, a lower alkyl group, trifloromethyl, low alkoxygroup and nitro, 5-membered heteroaromatic group containing 1 to 2 heteroatoms from the group nitrogen, oxygen and sulphur, lower alkoxy,

or their pharmaceutically acceptable additive salts of acids.

3. Connection under item 1 or 2, wherein R2- C1- C3is an alkyl group, cyclopropyl or1- C3group, or its pharmaceutically acceptable additive salt of the acid.

4. The compound according to any one of paragraphs. 1 to 3, characterized in that Het is 1,3,4-oxadiazole ring, or its pharmaceutically acceptable additive salt of the acid.

5. Connection PP.1, 2 or 3, characterized in that Het is 1,2,4-oxadiazole ring, or its pharmaceutically acceptable additive salt of the acid.

6. Connection on p. 1, representing a 6-benzyl-3-(5-methoxy-1,3,4 - OK is ahydro-1,6-naphthiridine-2(1H)-he,

6-(4-Chlorobenzyl)-3-(5-methoxy-1,3,4-oxadiazol-2-yl)- 5,6,7,8-tetrahydro-1,6-naphthiridine-2(1H)-he,

6-(2-bromobenzyl)-3-(5-methoxy - 1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-2(1H)-he,

6-(2-chloro-5-terbisil)-3-(5-methoxy-1,3,4-oxadiazole 2-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-2(1H)-he,

6-(2-bromo-5-terbisil)-3-(5-methoxy-1,3,4-oxadiazol-2 - yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-2(1H)-he,

6-benzyl-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5,6,7,8 - tetrahydro-1,6-naphthiridine-2(1H)-he,

6-benzyl-3-(5-ethyl-1,3,4 - oxadiazol-2-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-2(1H)-he,

6-benzyl-3-(5-isopropyl-1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-1,6 - naphthiridine-2(1H)-he,

6-benzyl-3-(5-cyclopropyl - 1,2,4-oxadiazol-3-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-2-(1H)-he,

6-benzyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-2-(1H)-he,

6-benzyl-3-(5-ethyl-1,2,4-oxadiazol-3-yl)-5,6,7,8 - tetrahydro-1,6-naphthiridine-2-(1H)-he,

6-benzyl-3-(5-methyl-1,2,4 - oxadiazol-5-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-2(1H)-he,

or pharmaceutically acceptable additive acid salt compounds.

7. Connection on p. 1, representing a 6-benzyl-3-(5-methoxy - 1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-1,6-naphthiridine-2(1H)-he, or its pharmaceutically additive salt of the acid.

8. Poorly

< / BR>
where cyclessa alkyl, lower Alchemilla, benzyl, phenyl, substituted phenyl, naftalina, substituted naftalina groups, while the substituents of phenyl and naftilos groups are 1 to 3 substituent selected from a halogen, a lower alkyl group, trifloromethyl, low alkoxygroup and nitro-group, heteroaromatic group containing 5 to 6 members in the ring, from 1 to 2 atoms are heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by 1 to 3 substituents selected from halogen, lower alkyl groups, lower alkoxygroup and trifloromethyl;< / BR>
X is carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl or nitrile group, provided that R1is not the stands,

or its salt.

9. Connection on p. 8, which represents ethyl-6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6 - naphthiridine-3-carboxylate, 6-benzyl-5,6,7,8-tetrahydro-2(1H) oxo-1,6-naphthiridine-3-carboxylic acid, ethyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine-3-carboxylate or

6-benzyl-5,6,7,8-tetrahydro-2(1H)-oxo-1,6-naphthiridine - 3-carbonitrile, or salt of any of the specified connection.

Priority signs:

02.09.92 when Het is 1,3,4-oxadiazol-2-yl,
X is a nitrile group.

 

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< / BR>
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