Intermediate products and method for producing salts naphthyridinone acid

 

(57) Abstract:

Describes how to obtain salts naphthyridinone acid of the formula I, where R1N denotes a pharmaceutically acceptable acid selected from the group comprising R4SO3H, R4PO3H and YH, where R4selected from (C1- C6)alkyl and optionally substituted phenyl or naphthyl, where the Deputy is (C1- C6)alkyl, and Y is selected from Cl, NO3, characterized in that the compound of formula II, where R2is (C1- C6)alkyl, aryl (C1- C6)alkyl or hydrogen and R3indicates NO2, is subjected to the interaction with the regenerating agent, optionally in the presence of the compounds of formula R1H, where R1defined above, followed, if necessary, by processing the compounds obtained compound of the formula R1H, which may be the same or different from R1H at the stage of recovery. Describes also the intermediate products of the compounds exhibiting antibacterial activity. The technical result is simplification. 4 C. and 30 C.p. f-crystals.

< / BR>

The invention relates to new methods and intermediate products for poika[3,1,0]Gex - 3-yl)-1-(2,4-differenl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

< / BR>
where R1H denotes a pharmaceutically acceptable acid selected from the group comprising R4SO3H, R4PO3H and YH, where R4selected from (C1-C6)alkyl and optionally substituted phenyl or naphthyl, where the Deputy is (C1-C6)alkyl; and Y is selected from Cl, SO4, HSO4, NO3, HPO3H or PO4.

Antibacterial activity of the above afterinvoke antibiotic described in U.S. Pat. USA 5164402 and 5229396 issued 17.11.92 and 20.07.93, respectively, and described them fully included in this description by reference. This application is a continuation of the above patents.

Description of the invention

In the first implementation of the present invention relates to a method for obtaining compounds of formula

< / BR>
where R1H denotes a pharmaceutically acceptable acid selected from the group comprising R4SO3H and R4PO3H and YH, where R4selected from (C1-C6)alkyl and optionally substituted phenyl or naphthyl, where the Deputy is (C1-C6)alkyl; and Y is selected from Cl, SO4, HSO4, NO3, HPO3H or PO4that includes handling the connection forms of the>indicates NO2or NH2;

a) when R3is the NH2then the compound of the formula R1H, above;

b) when R3is NO2then the reducing agent in the presence of the compounds of formula R1H, where R1H defined above.

The invention also relates to a method for obtaining compounds of formula II, where R3denotes NH2and R2defined above, by treating the compounds of formula II, where R3indicates NO2, a reducing agent in the presence of the compounds of formula R1H, where R1H defined above.

In another execution of the present invention relates to a method for obtaining compounds of formula II, where R3indicates NO2that includes the interaction of the compounds of formula

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with the compound of the formula

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where R2defined above and J is a suitable leaving group.

In accordance with another implementation of the invention the compound of formula IV is obtained by processing the N-dealkylase agent compounds of the formula

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where R is selected from (C1-C6)alkyl or (C6-C10)aryl, where this aryl group may be substituted, optionally, one or more Deputy who but or trifloromethyl. Preferably, R represents a phenyl or hydrogen. The compound of formula V can be obtained by treatment with a reducing agent compounds of the formula

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where R is defined above. The compound of formula VI is produced by interaction of the compounds of formula

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where R is defined above, with a compound of the formula X-XH2-NO2where X is a suitable leaving group, in the presence of a base. Preferred is 1,2-dimethyl-1,4,5,6-tetrahydropyrimidin.

Another implementation of the invention relates to a method for obtaining compounds of formula I, comprising the stage of:

a) interaction of the compounds of formula VII with the compound of the formula X-CH2-NO2where X is a leaving group, in the presence of a base to form compounds of formula VI, which is then treated with a reducing agent to form compounds of formula V;

b) processing the compounds of formula V dealkylase agent with the formation of the compounds of formula IV;

in the interaction between the compounds of formula IV, a compound of formula

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where R2defined above and J is a suitable leaving group, with formation of compounds of formula II, where R - NO2;

g) processing the compounds of formula II, Etalon and acid of the formula R1H above, with the formation of:

I) the compounds of formula I, when the hydrogenation is carried out with hydrogen in the presence of acid, R1H above, or when R1H is a compound of formula YH or R4SO3H, where Y and R4specified above; or

II) compounds of formula II, where R3represents NH2with further processing of the compounds of the formula R1H, which may be the same or different from R1H from the stage of recovery, or a compound of the formula R4CO2H, where R4defined above, to form compounds of formula I.

In another implementation of the invention relates to a compound of the formula

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Another implementation of the invention relates to the compound of the formula

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where R2defined above.

Another implementation of the invention relates to the compound of the formula

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where R2defined above.

Used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine, as appropriate.

Used herein, the term "alkyl" includes straight, and when it contains more than two carbon atoms, a branched hydrocarbon chain and a hydrocarbon cycles, and the combination of direct the Oia

The methods of the present invention and obtaining the compounds of the present invention is illustrated by the following reaction scheme. In the reaction scheme and the following discussion, the substituents R, R1H, R2, R3and X previously defined unless otherwise specified.

< / BR>
The above reaction scheme illustrates obtaining salts afterinvoke antibiotic of formula I, new intermediates used in these syntheses, and methods for producing these intermediates.

According to the scheme given above, the interaction of compound 1 with the compound of the formula X-CH2-NO2where X represents a suitable leaving group, such as chlorine and bromine, in the presence of a base leads to the corresponding connection 2. Typically this reaction is carried out in an inert polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) or dimethylacetamide (DMAA), in the ether solvent such as diethyl ether, glyme, diglyme, dioxane or tetrahydrofuran (THF), or in an aromatic solvent such as optional chlorinated benzene or toluene. It is preferable to use toluene. A suitable reaction temperature is in the field is to add the base of the latter. Examples of suitable bases include carbonate base, such as sodium carbonate or potassium, phosphoramidite bases, such as 2-tert-Butylimino-2-diethylamino-1,3-dimethylpyridine-1,3,2-datafactory, and amine bases such as triethylamine, guanidine, diisopropylethylamine, tetramethylguanidine, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), 1,5-deathcycle-[4,3,0]non-5-ene (DBN) and 1,2-dimethyl-1,4,5,6-tetrahydropyrimidin. Mainly used amine base. Preferred is 1,2-dimethyl-1,4,5,6-tetrahydropyrimidin.

The recovery of the compounds of formula 2 in an inert ethereal solvent gives the corresponding connection 3. Suitable reducing agents include borane, sodium borohydride and boron TRIFLUORIDE, epirate complexes. Used for recovering the inert volatile solvents include glyme, diglyme, diisopropyl ether, dimethyl sulfide, DMSO, diethyl ether and THF. The preferred reducing agent is a borane, and the preferred solvent is THF or diethyl ether. Usually the recovery is carried out at a temperature in the range from about 25oC to about 90oC. it is Preferable to restore at a temperature in the range from about 25oto OK the San in U.S. Pat. USA 5256791 included in this invention as a reference.

Compound 3, where R is a (C1-C5)alkyl or (C6-C10)aryl, converted into compound 4 by treating compound 3:

a) when R is a (C6-C10)aryl, hydrogen or (-chloroethyl)chloroformate; or

b) when R is a (C1-C6)alkyl, (-chloroethyl)Glorieta.

When R is a (C6-C10)aryl, deleting the hydrogenation RCH2group of compound 3 is usually carried out by reacting the compounds with gaseous hydrogen at a pressure of from about 10 to about 2000 psi, preferably from about 14 to about 60 psi in the presence of a catalyst of a noble metal such as palladium, platinum or rhodium, or their salts. Preferred is palladium, or palladium hydroxide on charcoal grill. The temperature can vary from about 20oC to about 80oC, the preferred temperature is about 25oC. the Solvent is usually (C1-C6)alkilany alcohol, preferably methanol.

Compound 4 is converted into compound 5 by reacting with the compound of the formula

< / BR>
where R2defined above, and J is podle preferred leaving group is chlorine.

The reaction can be conducted in a solvent or without it. If used, the solvent must be inert under the reaction conditions. Suitable solvents are acetonitrile, tetrahydrofuran, ethanol, chloroform, dimethylsulfoxide, dimethylformamide, pyridine, water or mixtures thereof.

The reaction temperature usually varies from about 20oC to about 150oC.

Convenient may be carrying out the reaction in the presence of an acid binding agent such as an inorganic or organic base, for example, a carbonate or bicarbonate of alkali or alkaline earth metal, tertiary amine, e.g. triethylamine, pyridine or picoline.

Compound 5 is converted into compound 6 by treatment with a metal and acid of the formula R1H, where R1H defined above in the presence of aqueous aprotic solvent, such as acetonitrile or DMF. The preferred metal is zinc. Suitable acids include inorganic acids such as hydrochloric and sulphuric acids, and organic acids such as sulfonic acid, e.g. methane, triptorelin - and p-toluensulfonate acid. Methansulfonate or hydrochloric acid are PR is Nol, 1-propanol and 2-propanol, preferably ethanol, at a temperature of from about 0oC to about 80opreferably, at a temperature of approximately 25oC.

Alternatively, compound 5 can be converted to 6 by reacting with hydrogen in the presence of Raney Nickel or noble metal catalyst. The Raney Nickel is the preferred catalyst.

The hydrogenation is usually carried out in a mixed aqueous solvent. Suitable solvents include (C1-C6)alkalemia alcohols, such as ethanol, methanol, 1-propanol and 2-propanol, and miscible with water, aprotic solvents such as DMF, THF, dimethylacetamide, dioxane, and (C1-C6)alkalemia esters. Used the hydrogen pressure is in the range from about 14 to about 100 psi, preferably in the range from about 40 to about 60 psi, and the temperature is in the range from about 15oC to about 80oC, preferably from about 20oC to about 30oC.

Compound 6 is converted into compound 7 by reacting with the compound of the formula R1H, as defined above, in the aquatic environment.

Alternatively, compound 5 can be directly converted to compound 7 treatment metalia zinc, and the preferred acid is methansulfonate.

Pharmaceutically acceptable salts of addition of the acid, which acid is a compound of formula R4CO2H, or R1H, where R4and R1H defined above, receive the usual way by treatment of a solution or suspension of compound 1 in free base form approximately one chemical equivalent of a pharmaceutically acceptable acid. To highlight the salts used conventional methods of concentration and recrystallization. Examples of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, methanesulfonate, p-toluensulfonate, cinnamic, fumaric, phosphonic, hydrochloric, Hydrobromic, itestosterone, sulfamic and sulfonic acid.

Antibacterial compounds of formula I and related antibiotics - derived azabicycloalkanes acid that can be synthesized using methods and intermediate products of this invention are used for treating bacterial infections in animals and humans. They are applied to a wide range of bacterial is yourself at any time, but usually introduced in a mixture with a pharmaceutical carrier selected with regard to the intended route of administration and conventional pharmaceutical practices. For example, they may be administered orally or in the form of tablets containing such additives, such as starch or lactose, or in capsules either alone or in a mixture with additives, or in the form of elixirs or suspensions containing flavouring agents and colouring agents. In the case of animals, it is convenient to include them in animal feed or in drinking water at concentrations of from about 5 to about 5000 parts per million, preferably from about 25 to about 500 parts per million. They can be entered parentale, for example, intramuscularly, intravenously or subcutaneously. For parentline introduction it is best to use a connection in the form of a sterile aqueous solution which may contain other solvents, for example sufficient to give isotonicity of the number of solutions of salts and glucose. In the case of animals, the compounds of formula I can be administered intramuscularly or subcutaneously at a dose level of from about 0.1 to about 50 mg/kg/day, mostly from about 0.2 to about 10 mg/kg/day as single daily dose or up to 3 separate doses.

The invention also relates to pharmaceutical compositions of the second solvent or carrier.

Compounds according to the invention can be administered for treatment of bacterial infections in humans orally or parentally ways, and can be administered orally at the dose level of from about 0.1 to about 500 mg/kg/day, the easy way, of 0.5-50 mg/kg/day as a single dose or up to 3 separate doses. For intramuscular or intravenous dosage levels are from about 0.1 - 200 mg/kg/day, the easy way, of 0.5-50 mg/kg/day. If intramuscular injection can be performed as a single injection, and up to 3 separate doses, intravenous administration can include using a dropper. Depending on the weight and condition of the patient being treated, and the selected route of administration, will be held changes, as is clear to a person skilled in the art.

Antibacterial activity of the compounds according to the invention is shown by research in accordance with replicating methodology Stirs, which is the standard bacterial in vitro study described E. Steers et al. , Antibiotocs and Chemotherapy, 9, 307 (1959).

The following examples illustrate the methods and compounds of the present invention. Note, however, that the invention is not limited to Xan

22-liter vessel equipped with a top stirrer, thermometer, dropping funnel, and cooling bath, direct dial refrigerator, bubbler and the input of nitrogen, rinsed with nitrogen. In a nitrogen purged vessel load N-benzylmaleimide (500 g, to 2.67 mol), toluene (12 l), bromonitromethane (751, 90% of 4.83 mol) and powdered molecular sieves (2020) and stirred at from about 10 to about 15oC. Suspension for 3 hours handle, adding dropwise 1,2-dimethyl-1,4,5,6-tetrahydropyrimidin (DTGP) (616,, 5,49 mol). Addition TGP leads to the formation of large amounts of resin collected molecular sieves. The reaction mixture is heated to about 25oC and stirred for 60-90 minutes. Molecular sieve is collected on a large Buchner funnel and washed twice with 2 l of toluene. The filtrate is washed three times with 750 ml of 2 M HCl. In a 22-liter vessel equipped with a reflux condenser, download the filtrate and Darco (trade mark) SSC (50 g). The mixture is heated at 60-70oC and stirred for 1 hour. The mixture is then cooled to about 25oC, filtered through covered with Celite (trade mark) filter Buchner funnel, and the precipitate washed with toluene twice with 500 ml. Treated with charcoal, the filtrate is evaporated under vacuum in a 12-liter round bottom flask, equipped with top m the Evaporation in vacuum is considered complete, when remains from about 2 to about 3 liters of concentrate. The concentrated solution was slowly treated with 4 liters of 2-propanol. Azeotropic distillation (25oC) continue until, until you remove all of toluene (which is reflected in the rise of the boiling point of 10oC). Yellow-orange solid is collected on a filter funnel, washed with twice 500 ml of 2-propanol and dried in vacuum at 40oC. Output 175,38 g (26.7 percent), so pl. 108-112oC. the Purity was determined by WGH compared to the pure sample (89-96%).1H NMR (CDCl3) , and 7.3 (s, 5H), 4,55 (s, 2H), 4,45 (s, 1H), 3,36 (s, 2H).

Example 2

Hydrochloride (1a,5a,6a)-6-nitro-3-azabicyclo[3,1,0]hexane

In a 250-ml 3-necked round bottom flask, equipped with direct-refrigerator, top stirrer and addition funnel, load 1,2-dichloroethane (115 ml), (1a,5a,6a)-3-benzyl-6-nitro-3-azabicyclo-[3,1,0]-hexane (obtained from the connection specified in the header of the example 1 by the method according to example 2 of U.S. patent 5256791 (included here as a reference in this description) (25.1 g, 115 mmol). The solution is cooled to from about 0 to about 5oC for 20 minutes, added dropwise chloroethylphosphonic (OEHF) (25,3 g , 172 mmol). The reaction mixture is heated to from about 50 to about AHAHH distilled off on a rotary evaporator. Received a black residue is dissolved in methanol (100 ml) and heated to from about 55 to about 60oC for 3 hours. The obtained suspension is cooled to room temperature and granularit for 18 hours. The suspension is then treated with concentrated hydrochloric acid (10 ml, 115 mmol) and stirred for 1.5 hours. Product highlight on the filter with suction. The cake on the filter is washed with chloroform (25 ml) and dried in vacuum. Output: 9,99 g, 60 mmol (53%), so pl. 170-180oC (decomp.).1H NMR (DMSO-d6) 9,8 (user. s, 2H), 4,9 (s, 1H), 3,5 (m, 4H), 2,9 (s, 2H).

Example 3

Ethyl ester of 7-([1a, 5a, 6a]-6-nitro-3-azabicyclo[3,1,0]Gex-3-yl)-6 - fluoro-1-(2,4-differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

In a 500-ml 3-necked round bottom flask, equipped with a top stirrer, direct refrigerator and thermometer, load acetonitrile (190 ml), ethyl ester of 7-chloro-6-fluoro-1-(2,4-differenl)-1,4-dihydro - 4-oxo-1,8-naphthyridinone acid (19,07 g, 50 mmol) of the compound indicated in the heading of example 2 (9.88 g, 60 mmol), triethylamine (15.3 g, 151 mmol). The mixture is heated to boiling (82oC), stirred for 6.5 hours and check the completeness of the reaction by TLC (ethyl acetate: hexane 3:2, UV). The obtained suspension is cooled the P>C for 1 hour. The product is collected on a funnel for filtration as a white solid and washed with CH3CN:water 1:1 (50 ml). The product is dried in vacuum at 40oC. Output: 21,17 g and 44.6 mmol (89,2%), so pl. 245-250oC. 1H NMR (CDCl3) a 8.4 (s, 1H) and 8.1 (d, 1H), and 7.4 (m, 2H), 7,05 (m, 1H), 4,35 (kV, 2H), 4,1 (s, 1H), 3,95 (m, 2H), 3,65 (m, 2H), 2,75 (m, 2H), of 1.35 (t, 3H).

Example 4

Ethyl ester of 7-([1a, 5a, 6a]-6-amino-3-azabicyclo[3,1,0]Gex-3-yl)-6 - fluoro-1-(2,4-differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

A. 250-Millerovo 3-necked round bottom flask, equipped with direct-fridge, a thermometer and overhead stirrer, download the connection specified in the header of example 3 (10.0 g, 21.1 mmol), acetonitrile (50 ml), water (50 ml) and zinc dust (6,9 g is 105.6 mmol). The grey suspension is treated methanesulfonic acid (70%, of 25.5 ml, 241 mmol), causing the temperature rises to 40oC. Orange-yellow reaction mixture is heated to 50-55oC and incubated for 3 hours (the end of the reaction by WGH). The mixture is cooled to room temperature, treated with water (100 ml) and Celite (trade mark) (1 g) and stirred for 15 minutes. The suspension is filtered through covered with Celite funnel, getting dark amber solution. The solution is alkalinized 50% aqueous NaOH to CI. The organic layer is evaporated to dryness, to obtain the crude product (to 2.57 g, 27.4 per cent). A sample of the crude product (0.55 g) chromatographic on a column of silica gel. Elute seven times 50 ml of ethyl acetate and thirteen times 50 ml of methanol. The last five fractions are combined and concentrated to obtain pure indicated in the title compound (0.14 g, 27,2% extraction rate with columns). Total yield 5,73%. The product is characterized comparative VGH (in comparison with a pure sample) and FAB MS [M+H]+= 445. 1H NMR (CDCl3) 8,35 (s, 1H), and 7.8 (d, 1H), 7,35 (m, 1H), 7,05 (m, 2H), 4,35 (kV, 2H), 3,6 (user. s, 2H), 3,5 (user. s, 2H), 2.05 is (s, 1H), 1.57 in (s, 2H) and 1.51 (s, 2H), 1.39 in (t, 3H).

B. 600-ml Parr apparatus (trade mark) with a gas flow meter Preteric Ltd. Pressflow (trade mark) Gas Controller (Model 1502), load the connection specified in the header of example 3 (2,04 g, 4.3 mmol), Raney-Nickel [A-4000, Activated Metals and Chemicals Inc., Seviorille, TN] (1.44 g, wet weight) N,N-dimethylformamide (70 ml) and water (20 ml). The device is sealed, double-rinsed with nitrogen (35 psi), filled with hydrogen (50 psi) and heated for 45 minutes to from about 40 to about 45oC. the Pressure is then raised to about to about 57 psi and incubated for 24 hours. The reaction mixture is cooled to room temperature, rinsed with nitrogen and province for filtering, covered with Celite, and washed with water (25 ml). To the filtrate was added water (40 ml) and extracted three times with 100 ml of ethyl acetate. An ethyl acetate layer is then concentrated to 100 ml and extracted with water (100 ml) to remove residual DMF. An ethyl acetate layer is evaporated to dryness on a rotary evaporator. Crude yield: 1,36 g (71,1%). Analysis VGH purity (76,5%). The yield of pure substance (54%). The product was characterized VGH (in comparison with a pure sample). Data1H NMR similar to those obtained for the product in section a above.

Century Way section B repeat loading, including the connection specified in the header of example 3 (10.0 g, 21.1 mmol), 4.3 g of the Raney-Nickel (4.3 g wet), tetrahydrofuran (THF) (180 ml) and water (40 ml). The device is sealed and double-rinsed with nitrogen (35 psi). The device is then filled with hydrogen (50 psi) and stirred at 25 to 29oC 2.5 hours (until hydrogen absorption). The reactor is rinsed with nitrogen and check the completeness of the reaction by TLC (89 CHCl3: 10 methanol : 1 NH4OH.

The catalyst is filtered off through covered with Celite funnel. The cake on the filter is washed twice THF (20 ml). THF is distilled off on a rotary evaporator, receiving light yellow suspension. To a suspension add ethanol (25 ml), then suspended pellet, the analysis VGH purity (97,1%). The yield of pure (78,3%). The product is characterized VGH (in comparison with a pure sample). Data1H NMR correspond obtained for the product in section A. was collected second portion (yield by weight to 7.5%), but the purity of it below, as shown 1H NMR.

Example 5

Methanesulfonate 7-([1a, 5a, 6a]-6-amino-3-azabicyclo[3,1,0]Gex-3-yl)-6 - fluoro-1-(2,4-differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

A. 200-ml 3-necked round bottom flask, equipped with direct-fridge, a thermometer and overhead stirrer, download the connection specified in the header of example 4 (1.54 g, 3.46 mmol), and water (25 ml). The white suspension is treated with 70% aqueous methanesulfonic acid (5,25 g, 38.4 mmol) and heated to from about 45 to about 50oC. the Original product slowly goes into solution. The mixture is stirred for 18 hours (completion of the reaction according to TLC). The mixture is cooled to room temperature and the product produce by filtering with suction. Yield: 1.48 g (83.5 per cent). VGH % purity (compared to pure sample) 96,1%.1H NMR (DMSO-d6) cent to 8.85 (s, 1H), 8,17 (user. m, 2H), 8,11 (d, 1H), 7,83 (m, 1H), 7.62mm (m, 1H), 7,37 (m, 1H), 3,67 (user. s, 3H), of 2.45 (s, 1H), 2,37 (s, 4H), 2,08 (s, 2H).

B. 100-ml 3-necked round bottom flask, equipped with the example 3, 1.01 g (2,13 mmol), zinc (0,70 g of 10.7 mmol), acetonitrile (20 ml) and water (20 ml). The grey suspension is heated to about 50oC and treated with 5 ml of 70% aqueous methanesulfonic acid (3.3 g, 24 mmol). The course of the reaction is periodically controlled by WGH to complete (23 hours). The reaction mixture is heated to from about 80 to about 85oC, then treated with an additional amount of 70% water methanesulfonic acid (2.6 g, 19 mmol) to complete the hydrolysis of the ester (VGH). The reaction mixture is cooled to room temperature and treated with water (250 ml) to give a yellow-brown suspension. The suspension is filtered, the filtrate was added to 500 ml of water. The resulting solution was evaporated on a rotary evaporator to remove acetonitrile. To the concentrate is added 2-propanol (50 ml), then evaporated to dryness. The residue is treated with water (50 ml) and acetone (50 ml) to give a brown suspension. The suspension was filtered to separate the insoluble particles. The filtrate is cooled to 0-5oC for crystallization. Get listed in the title compound as yellow crystals (105 mg, yield of 10.5%). VGH (20% CH3CN : 80% pH2, 50 mm H3PO4; 270 nm of 1.00 ml/min; Bond (brand) RX C185 MK 4.6 mm x 15 cm) in comparison with the standard is specified in the connection header shows the product in this example is the connection specified in the header. Data1H NMR of the product are the same as for the product of section a above.

1. The method of obtaining the salts naphthyridin-carboxylic acid of the formula I

< / BR>
where R1H denotes a pharmaceutically acceptable acid selected from the group comprising R4SO3H, R4PO3H and YH, where R4selected from (C1-C6)alkyl and optionally substituted phenyl or naphthyl, where the Deputy is (C1-C6)alkyl, and Y is selected from Cl, NO3,

characterized in that the compound of formula II

< / BR>
where R2is (C1-C6)alkyl, aryl(C1-C6)alkyl or hydrogen;

R3indicates NO2,

subjected to interaction with the regenerating agent, optionally in the presence of the compounds of formula R1H, where R1defined above, followed, if necessary, by processing the compounds obtained compound of the formula R1H, which may be the same or different from R1H at the stage of recovery.

2. The method according to p. 1, characterized in that the interaction with the regenerating agent is carried out in the presence of the compounds of formula R1
< / BR>
where R2matter specified in paragraph 1,

and then handle the connection specified by the connection of the formula R1H, which may be the same or different from R1H at the stage of recovery.

4. The method according to p. 1 or 3, characterized in that the regenerating agent is hydrogen gas.

5. The method according to p. 2, characterized in that the regenerating agent is a mixture of metal and acid of the formula R1H, where R1defined above.

6. The method according to p. 5, wherein the metal is zinc and acid selected from HCl and methanesulfonic acid.

7. The method according to p. 6, wherein the acid is methansulfonate acid.

8. The method according to p. 2, characterized in that the compound of formula II, where R3is NO2get the interaction of the compounds of formula IV

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with the compound of the formula

< / BR>
where R2defined above and J is a leaving group.

9. The method according to p. 8, wherein J is selected from chlorine and bromine.

10. The method according to p. 9, wherein J represents chlorine.

11. The method according to p. 8, characterized in that the interaction is of the formula IV is obtained by processing the N-dealkylase agent compounds of formula V

< / BR>
where R is selected from (C1-C6)alkyl or (C6-C10)aryl, where specified, the aryl may be optionally substituted by one or more substituents, independently selected from halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, amino and trifloromethyl.

13. The method according to p. 12, characterized in that R represents benzyl.

14. The method according to p. 12, characterized in that R represents methyl.

15. The method according to p. 12, characterized in that dealkylase agent is chloroethylphosphonic, when R represents a benzyl or (C1-C6)alkyl, or hydrogen, when R is benzyl.

16. The method according to p. 15, wherein R is benzyl and dealkylase agent is chloroethylphosphonic.

17. The method according to p. 12, characterized in that the compound of formula V is produced by processing regenerating agent compounds of formula VI

< / BR>
where R has the above significance.

18. The method according to p. 12, characterized in that the compound of formula VI is produced by interaction of the compounds of formula VII

< / BR>
where R has the above significance,

with the compound of the formula

X-CH2-NO2,

where X denoted the causesa fact, that R is benzyl.

20. The method according to p. 18, wherein R denotes methyl.

21. The method according to p. 18, wherein X denotes chlorine or bromine.

22. The method according to p. 21, wherein X is bromine.

23. The method according to p. 18, characterized in that the interaction is carried out at a temperature from about -78oC to about 80oC.

24. The method according to p. 18, characterized in that the interaction is carried out in a solvent selected from benzene, toluene, dimethylformamide or tetrahydrofuran.

25. The method according to p. 24, characterized in that said solvent is toluene.

26. The method of obtaining salts naphthyridinone acid of General formula I

< / BR>
where R1H denotes a pharmaceutically acceptable acid selected from sulfonic acid R4SO3H, R4PO3H and YH, where R4selected from (C1-C6)alkyl and optionally substituted phenyl or naphthyl, where the Deputy is (C1-C6)alkyl;

Y is selected from Cl, NO3, characterized in that it comprises the stages of: a) interaction of the compounds of formula VII

< / BR>
where R is selected from (C1-C6)alkyl or (C6-C10)aryl, where ukazaniya, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, amino and trifloromethyl,

with the compound of the formula X-CH2-NO2where X is a leaving group, preferably chlorine or bromine, in the presence of a base to form compounds of formula VI

< / BR>
in which R has the above meanings, preferably benzyl or methyl,

and processing the obtained compounds of formula VII regenerating agent with obtaining the compounds of formula V

< / BR>
where R has the above meanings, preferably benzyl or methyl;

b) processing the compounds of formula V dealkylase agent with the formation of [1A,5A,6A]-6-nitro-3-azabicyclo[3, 1, 0]-hexane of the formula IV

< / BR>
c) interaction of the compounds of formula IV with the compound of the formula

< / BR>
where R2is (C1-C6)alkyl, aryl(C1-C6)alkyl or hydrogen, and V is a suitable leaving group such as chlorine or bromine,

in the presence of a base to obtain the compounds of formula IIIB

< / BR>
in which R2have the above values,

and (d) (I) processing the obtained compounds of formula IIIB regenerating agent is a metal and acid of the formula R1H, as defined above, in the presence of wall with obtaining the compounds of formula IIIA

< / BR>
which is then converted into a compound of formula I by interaction with an acid of formula R1H, as defined above, in the aquatic environment,

II) or, alternatively, the compound of formula IIIB is directly converted into a compound of formula I by treatment with a metal and an acid of the formula R1H, as defined above.

27. The method according to p. 26, characterized in that said base at the stage a) is 1,2-dimethyl-1,4,5,6-tetrahydropyrimidin.

28. The method according to p. 26, characterized in that said dealkylase agent at the stage b) is chloroethylphosphonic, when R in the compound of formula V represents a benzyl or (C1-C6)alkyl, or hydrogen, when R is benzyl.

29. The method according to p. 26, characterized in that said regenerating agent at the stage d) II is metal and the acid of formula R1H or hydrogen over Raney Nickel.

30. The method according to p. 26, characterized in that the acid in stage (d) is a (C1-C6)alkanesulphonic acid.

31. The method according to p. 30, characterized in that the acid is methansulfonate acid.

32. The method according to p. 31, characterized in that said metal is zinc.


< / BR>
III B

where R2is (C1-C6)alkyl, aryl(C1-C6)alkyl or hydrogen.

 

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FIELD: organic chemistry, medicine, psychiatry, pharmacy.

SUBSTANCE: invention relates to medicinal agents used for prophylaxis and treatment of schizophrenia by inhibition or suppression of neurodegenerative disease caused by hypofunction of glutamic acid receptors. As an active component agents comprise derivative of 5-substituted 3-oxadiazolyl-1,6-naphthiridine-2(1H)-one of the formula (I):

wherein Het represents oxadiazolyl group; R1 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, trifluoromethyl group, lower alkenyl group, lower alkynyl group, lower alkoxyl group, lower alkoxy-(lower)-alkyl group, lower hydroxyalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; R2 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, lower cycloalkylmethyl group, lower alkenyl group, lower cycloalkenyl group, lower alkynyl group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group wherein indicated groups represent phenyl or naphthyl and indicated heteroaryl groups represents furyl, thienyl or pyridyl, or their physiologically acceptable acid-additive salts.

EFFECT: valuable medicinal properties of agents.

10 cl, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

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EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

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EFFECT: valuable medicinal and pharmaceutical properties of composition.

3 cl, 9 tbl

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

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

7 cl, 2 sch, 2 tbl, 5 ex

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

6 cl, 2 tbl, 83 ex

FIELD: medicine, pharmacy.

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EFFECT: improved preparing and using method, valuable medicinal properties of agent.

7 cl, 1 dwg, 19 ex

FIELD: organic chemistry, pharmacy.

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EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 216 ex

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