Derivatives decahydroquinoline or their pharmaceutically acceptable salts

 

(57) Abstract:

Usage: in the pharmaceutical industry. Essence: derivatives decahydroquinoline or their pharmaceutically acceptable salts total f-ly I, where X is COOH , RHO3(R)2or R' - substituted 5-tetrazolyl, one PE Y or Z is COOH or COR", and the other of Y and Z is H, R'- (C1-C4)alkyl or H, R ' - (C1-C6)alkoxy or N. The compounds have activity to block excitatory amino acid receptors. Connection structure of f-crystals of I are given in the description. 3 C. p. F.-ly, 1 table.

The present invention provides compounds that are antagonists of excitatory amino acid receptors.

It was shown that a number of physiological functions influenced by the excessive stimulation of excitatory amino acid neurotransmission. Compounds that have the ability to block excitatory amino acid receptors, can treat a number of disorders in mammals, which include neurological disorders, such as convulsive disorders such as epilepsy, stroke, anxiety, cerebral ischemia, muscular spasms, and neurodegenerative disorders, such as disease Alzheimer is:

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one of Y and Z represents

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and the other of Y and Z is hydrogen, each R3independently is C1-C16alkoxy, phenylselenenyl1-C4alkoxy or a group forming an oral ester, each R4independently is hydrogen, C1-C16the alkyl, phenyl substituted WITH1-C4the alkyl or phenyl, or their pharmaceutically acceptable salts.

In the above formula, the term "C1-C16alkyl" represents a straight or branched alkyl chain having from 1 to 16 carbon atoms. Typical C1-C16alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, 2-methylpentyl, n-octyl, decyl, undecyl, hexadecyl and others. The term " C1- C16alkyl" and "C1-C4alkyl". The term "C111-C16alkoxy" can be represented (WITH1-C16alkyl)-0 - and includes in the term "C1-C4alkoxy".

The term "phenyl substituted WITH1-C4alkyl" represents a C1-C4alkyl group bearing a phenyl group, such as benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4 - phenylbutyl, 2-m is followed by a session, represented by the Deputy, which, when joining the group, carboxylic acid forms a complex function of the ether, are suitable for the introduction of mammals, which need treatment. Examples of such groups, forming oral ester are1-C4alkoxy, benzyloxy, benzyloxy substituted in the phenyl ring by halogen, C1-C4the alkyl or C1-C4alkoxy, C1-C5alkanoyloxy, or C1-C5alkanoyloxy substituted in oxomethane1-C4the alkyl or C4-C7cycloalkyl.

Although all of the compounds of the present compounds are antagonists of excitatory amino acid receptors, there are certain compounds according to the invention, which are preferred for such use. Preferably the connection in ring-CIS, Y means COON, Z denotes hydrogen, and X means the PINES, 5-tetrazolyl or phosphonyl, i.e. the compounds of formula I, where X is COOH, 5-tetrazolyl or phosphonyl.

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Other preferred aspects of the present invention will be described below. Compounds of the present invention have four asymmetric carbon atom represented substituted stikovymi carbon atoms. As such, the compounds can exist as diastereoisomers, each of which can exist as a racemic mixture of such isomers or as individual optical isomer. Accordingly, the compounds of the present invention will include not only the racemates, but also their corresponding optical active isomers.

As indicated above, the present invention includes pharmaceutically acceptable salts of the compounds defined by formula I. These salts may exist in combination with acidic or basic part of the molecule and can exist in the form of additive salts of acids, primary, secondary, tertiary or Quaternary ammonium, or alkali metal or alkaline-earth metal salts. Acid, which is used usually for the formation of such salts include inorganic acids such as hydrochloric, Hydrobromic, itestosterone, sulfuric and phosphoric acid and organic acids such as paratoluenesulfonyl acid, metasolv acid, oxigenobaroterapia acid, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Thus, such a pharmaceutical acceptable is ly phosphate, dihydrophosphate, metaphosphates, pyrophosphates, chlorides, literality, iodides, acetates, salts of magnesium, propionate, salts of Tetramethylammonium, decanoate, caprylate, acrylates, formats, isobutyrate, caprate, peptonate, potassium salts, propiolate, oxalates, trimethylammonium salt, malonate, succinate, suberate, sebacate, fumarate, maleate, butene-1,4-dioate, salts of sodium, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalates, sulfonates, salts of methylamine, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, the citrates, lactates, calcium salts, In-hydroxybutyrate, glycolate, maleate, tatrate, methansulfonate, propanesulfonate, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelate and other salts.

Compounds of the present invention can contain one or two tetrazole rings. Tetrazol known to exist in tautomeric structures. Tetrazol having the double bond of the nitrogen atom in position I and R Deputy N-2-nitrogen atom is properly called 2H-tetrazol and represented by the following structure:

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This connection has a corresponding tautomeric form, where R is the Deputy is at N-1 with a double bond at the nitrogen atom in the floor>BR>
A mixture of two tautomers are referred to hereinafter as 1(2)N-tetrazole. The present invention includes both the individual tautomeric forms, and combinations of two tautomers.

In the present invention it is also proposed a method of obtaining compounds of formula I.

Compounds of the present invention can be obtained by well-known specialists in the field of technology ways. Preferably, hydroxy substituted 3-carbalkoxy-1, 2,3,4-tetrahydroisoquinoline block of nitrogen, in the ring, standard blocking reagent and reduced to the corresponding system with fully saturated bicyclic ring or hydroxy substituted 1-carbalkoxy-1,2,3,4-tetrahydroisoquinoline reduced to the corresponding system with fully saturated bicyclic ring, then block the nitrogen in the ring is standard blocking reagent. Blocked hydroxy compound are oxidized to the ketone, which is then subjected to interaction with the reagent Witting for introduction of the group ring predecessor. Restore this functionality and further transformation leads to compounds of the formula I. This reaction can be represented using the following scheme, Kotikov substituted carboxylic acid tetrahydroquinoline II (R5=R6= hydrogen) is transferred to the corresponding derivative of ester II (R5=C1-C4alkyl, R6= H) in accordance with the standards of the condition of esterification. These intermediate compounds are then protects a blocking group, preferably C1-C6alkoxycarbonyl group, obtaining doubly protected intermediate compound (II), where R5means1-C4alkyl, and R6means COO (C1-C6alkyl). This material gidrogenit in the presence of a catalyst such as platinum oxide or rhodium on aluminum oxide and a suitable solvent. Suitable solvents include alcohols, such as ethanol and especially methanol. The reaction is finished after about 1-24 hours, if it is conducted at a temperature in the range from about 20oC to about 100oC. the resulting product III (R7means1-C4alkyl) it is easy to distinguish by filtering the reaction mixture through diatomaceous earth and concentration of the filtrate under vacuum. The obtained residue may be further purified, if necessary, but preferably is used directly in the next reaction.

Hydroxy intermediate compound III obtained in this way, C is the God of many oxidizing agents, such as chlorproma pyridinium, pyridinium dichromate or oxalicacid and dimethylsulfoxide. It should be noted that the oxidizing agent and the conditions that apply, should be sufficient for translation of the secondary alcohol to the ketone without oxidation of other functional groups in the system with a bicyclic ring.

The intermediate compound IV is then subjected to interaction with the Wittig reagent of General formula (CH3CH2O)2ROCH2X1where X1means R7Joint VENTURE or RO(OR4)2.

This reaction is usually carried out by treating the appropriate diethylphosphonate strong base such as sodium hydride, to obtain the sodium salt of phosphonate, which then interacts in a non-reactive solvent such as dry tetrahydrofuran, with a compound IV with getting methylene derivative of formula V. This reaction is usually carried out between ABOUToWith the temperature and reflux distilled reaction mixture. When using a slight excess of the phosphonate anion, the reaction is usually completed after heating for about 6 hours at the temperature of reflux distilled mixture. Intermediate compound V then restore with obtaining the appropriate Naydenova, preferably in the presence of a catalyst such as palladium on charcoal, and an inert solvent, such as ethanol.

The obtained intermediate compound VI can then be converted into the compound according to the invention by a release as acid and nitrogen functionalities, as well as by transformation of the functional groups X1in the functional group X. One multifunctional intermediate connection is cyano derivative (X1=-CN), which can be used for many other compounds of the present invention.

For example, the cyano derivative VI (X1=-SP) can be transformed into tetrazole intermediate connection and then the connection according to the invention in accordance with the following method. The original cyanide compound interacts with azide anti /also known as azido tributylstannyl/. This reaction is carried out at a temperature of from about 50 to 120oC, preferably at about 80oC for from about 12 to 120 hours. The product can be selected, but preferably it directly to hydrolyze the compound according to the invention using standard acidic or basic hydrolysis. The reaction is carried out n the Product can then be cleaned using standard methods, such as crystallization with a simple solvent such as water, acetone or ethanol, or by chromatography over solid substrates such as silica gel, ionoobmennye resin or standard absorbents. Using this reaction, if you use the subsequent acid treatment, it is possible not only to effectively transform nitrile intermediate compound in the desired tetrazole, but it is also effective to remove the blocking group R6and R7.

On the other hand the corresponding acid of the present invention /pack, X-PINES/ can be obtained from the same nitrile intermediate compounds simply by heating the nitrile c acid, preferably at a temperature of heating under reflux of the solution. Again this treatment effectively hydrolyzes not only the nitrile to the acid, but also releases the group R6and R7to obtain the final compounds of the present invention.

Compounds of the present invention, where X, Y or Z have values other than the Deputy of the free carboxylic acid is obtained using methods well known to the person skilled in the art. Compounds where X, Y or Z have a value With/=0/R3and R3means C1-With3H in the presence of hydrochloric gas. Compounds where X, Y or Z have values of-C/=0/R3and R3is a group forming oral ester, is obtained using standard alkylation or acylation. Compounds where X, Y or Z have values of-C/=0/NHC/=O/R3, obtained by reaction of a derivative of the free carboxylic acid intermediate compounds that blocked R6as described above, and /or selected as a product of partial hydrolysis conversion of VI to VII or VII, which is converted into N R6blocked intermediate compound in the same manner as described above with an appropriate substituted amine NH/R4/2, sulfonamide NH2S02R4or acylamino NH2C/=0/R3in the presence of reagent combinations and common organic solvent.

Suitable agents of the combination-C/= 0/0-/phenyl/- C/=0/N/R4/2, -C/=0/NS O2R4or include carbodiimide such, an NN'- dicyclohexylcarbodiimide, and NN" diisopropylcarbodiimide or NN'-diethylcarbamazine, imidazoles such as carbonyldiimidazole; as well as reagents such as N-ethoxy-carbonyl-2-ethoxy,2-dihydroquinoline /DQ/. The compound obtained then this will release from the groups is also obtained by hydrolysis of CYANOGEN intermediate compounds, obtained as described above, into the corresponding carboxylic acid derivative, which is then treated with ammonia in the presence of the agent combinations as described above to obtain the corresponding primary carboxamide. Carboxamid dehydration to the appropriate carbonitrile after treatment with phenylphosphonothioic or triphenylphosphonium in the presence triticale amine such as triethylamine or pyridine. The compound obtained was transferred to tetrazole intermediate connection using azide presence of TBT in the conditions described above. The desired compound is then processed as described previously.

Compounds of the present invention, where R4Deputy tetrazolium ring is other than hydrogen, can be obtained by known methods, or methods-analogues. Typically, the alkylation of unsubstituted starting material with a suitable halide reagent R4-CL, R4-Br, or R4-l, get a connection according to the invention or an intermediate compound, which can be modified in the connection according to the invention, as described here. If alkylation reaction used the base, attaching first on tetrazolium kolainu connection at the nitrogen atom of the piperidine. Any free nitrogen atom can also block before the reaction and then be released in accordance with standard conditions using standard blocking reagents. Of course, di - and tizamidine the same Deputy requires simply use the desired molar excess of reagent for each Deputy of the end connections. Specialists in the field of organic synthesis will be clear that a certain type of substitution in the case when X and/or Y or Z are both tetrazolo, can be adjusted by the use of blocking agents or by the introduction functionalization of one tetrazolyl group, before you can enter another tetrazolyl group.

The preceding description of the synthesis of compounds of the present invention provides the ability to get the preferred isomers with CIS-bond in the ring. The diastereomers can be readily separated from the mixture by using standard chromatography, for example using the adsorbents are silica gel or aluminum oxide or fractional crystallization. Selected diastereoisomer can be transformed into the other diastereoisomer by treatment with base such as tertiary amine or alkali metal alkoxide in the corresponding alcohol. Although the division or a debate or make out with a blocked ketone derivative as described above.

Isomers with TRANS structure rings can be obtained as follows. The connection 11 is locked at the phenolic hydroxy in the form of methyl ester by treatment such as sodium carbonate or potassium, and methyliodide in a solvent such as acetone or DMF ester and then hydrolyzing a base such as sodium hydroxide or potassium hydroxide in water and/or ethanol to obtain the acid VIII. After processing acid lithium, sodium or potassium in liquid ammonia with or without added solvent such as ethanol, butanol, ether or tetrahydrofuran followed by treatment of the aqueous acid to obtain the acid IX. Restoration IX as well as for VIII will ketone XI with ternstroemia rings. The division and the inter-conversion of axial and equitorial isomers of ester should be as for IV. Conversion of the ketone XI in the corresponding products VII, with the TRANS-compound in the ring, should be carried out as described for the conversion of IV to VII.

Pharmaceutically acceptable salts according to the invention is produced by the interaction of the compounds of the present invention with an equimolar amount or an excess of salt-forming reagent. The reagents will normally be collected in a common solvent, such as diatrofi the days, and it can be identified by filtering.

Replacement of intermediate compounds corresponding to formula 11 used as starting materials in the synthesis of compounds of the present invention, are known and can be obtained by the method well-known to specialists in this field of technology.

The following examples further illustrate the compounds of the present invention and methods for their synthesis. The examples are not limiting the scope of claims of the present invention.

Example 1

Decahydro-6-/1/2/N-tetrazol-5-ylmethyl/-3-izohinolinove acid.

A. Obtain hydrochloride of 6-hydroxy-1,2,3,4-tetrahydro-Z-ethinlestradiol acid.

To a mixture of 100.0 r 3-hydroxyphenylglycine in 820 ml of 5% hydrochloric acid add 78 ml of formaldehyde /37% in water/. The reaction mixture is heated at 90-95oWith / external bath temperature/ within 45 minutes. The mixture is cooled and concentrated in vacuo. Add 500 ml of ethanol and the mixture is again concentrated in vacuo, to obtain 115 g of intermediate compound indicated in the title in the form of a white solid which is used without purification in the next stage.

C. Obtain hydrochloride of ethyl 6-hydroxy-1,2,3,4-tet bubbles of hydrogen chloride for 10 minutes. The gas stopped and the mixture is heated under reflux during the night. The mixture is cooled and concentrated under vacuum to obtain 130 g of the desired intermediate compound indicated in the subtitle, which is used without further purification.

C. Obtaining ethyl-6-hydroxy-1,2,3,4-tetrahydro-2-methoxy-carbonyl-C-ethanolinduced.

130 g of ester from example 1B above are suspended in 850 ml of methylene chloride. To this mixture add 192 ml diisopropylethylamine. The solution is cooled to 0oC using an ice bath and added dropwise 42,6 ml of methylchloroform. After 30 minutes stirring at 0oWith add 60 ml of diisopropylethylamine and the mixture is stirred for another 30 minutes. Add one liter of 30% aqueous acidic sodium sulfate. The layers are separated and the aqueous layer was extracted twice with methylene chloride and once with diethyl ether. All organic layers were combined together and washed once with a saturated solution of sodium chloride. The organic solution is dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by means of preparative Ehud getting oil. After trituration with ether get 86,2 g of the desired intermediate soedinenie purified material with a melting point 124-127oC.

D. Obtaining ethyl, decahydro-6-hydroxy-2-methoxycarbonyl-3-ethanolinduced.

The mixture 85,8 g tetrahydroisoquinoline of example 1C above in 900 ml of absolute ethanol gidrogenit under 100oC overnight in the presence of 22 g of 5% rhodium on aluminium oxide at 2000 lb/in2. The reaction mixture was filtered through Celite /Celite/ and concentrate under vacuum. Add ether and the mixture filtered through Celite, then concentrated under vacuum, obtaining 87,9 g of the desired intermediate compound indicated in the subtitle, which is used without purification.

E. Obtaining ethyl, decahydro-6-oxo-2-methoxycarbonyl-3-ethanolinduced.

The mixture 146,1 g Harrogate pyridinium, 146,1 g sieves in powder form 4 and 1000 ml of methylene chloride is stirred for one hour at room temperature. The solution to 87.9 g of ethyl decahydro-6-hydroxy-2-methoxycarbonyl-3-ethanolinduced in 30 ml of methylene chloride is added dropwise in 200 ml of dichloromethane and reactional the mixture is stirred for 3 hours at room temperature. To the mixture is added diethyl ether (1400 ml) and the mixture is then filtered through the gasket from Celite and silicagel. The filtrate is concentrated under vacuum, re-dissolved in diethyl the product, mentioned in the title in the form of 28:72 mixture equatorially/ axial isomers of ester. The residue is dissolved in 600 ml of ethanol and add to 1.11 g of sodium hydride dissolved in 60 ml of ethanol and the mixture is heated at 80oC for 2.25 hours. The mixture is cooled and concentrated under vacuum. To the residue add 700 ml of 1:1 dichloromethane/ether and the solution washed with 300 ml of 10% aqueous sodium bisulfate. The organic layer is separated and the aqueous layer was extracted three times with diethyl ether. The combined organic layers are dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is filtered through silica gel with 40% ethyl acetate in hexane and the filtrate concentrated under vacuum to obtain oil. After crystallization from a mixture of ether/hexane receive and 32.3 g of the desired intermediate compound indicated in the subtitle, so pl. 79 - 80oWith, this compound was identified using gas chromatography. Using1H NMR and x-ray crystallography this ketone was identified as ethyl 1A-R*-3-R*-4A-R*-DECA hydro-6-oxo-2-methoxy-carbonyl-3-ethanolammonium. Consider that the stereochemistry of the leads to each of the final products.

Getting ethyl, decahydro-6-cyano-stands three times with hexane and suspended in 45 ml of dry tetrahydrofuran. Under stirring is added dropwise to 10.0 g of diethyl cyanomethylphosphonate and the mixture is stirred under nitrogen atmosphere for 30 minutes. To phosphonate anion type of 11.5 g of ethyl decahydro-6-oxo-2-methoxycarbonyl-3-ethanolinduced in 60 ml of dry tetrahydrofuran. The mixture is heated under reflux for 0.5 hours, then cooled to room temperature and 50 ml of water and 50 ml of diethyl ether is added. The layers are separated and the aqueous layer was extracted two times with diethyl ether. The combined organic layers are dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by means of preparative DVD to obtain 12.1 g of the intermediate as specified in the subtitle.

G. Obtaining ethyl, decahydro-6-cyano-methyl-2-methoxycarbonylaminophenyl.

A mixture of 12.1 g of the intermediate from example 1F above and 85 ml of absolute ethanol hydrogeneous over night at room temperature in the presence of 2.5 g of 5% palladium on coal. The reaction mixture was filtered and concentrated under vacuum. The residue is collected in diethyl ether and filtered through Celite and the Celite washed twice with dichloromethane and then concentrated under vacuum. The residue is purified by POM-ylmethyl-/-3-ethinlestradiol acid.

A mixture of 9.6 g of the nitrile intermediate compound from example 1G above is dissolved in 20.7 g azide presence of TBT and the mixture is heated at 80oC in nitrogen atmosphere. After 3 days of heating additionally add 2 g of azide presence of TBT and heating continued for one day. The mixture is cooled, dissolved in 200 ml of ether and then pass the Hcl gas bubbles in the solution for 10 minutes. The mixture is concentrated under vacuum, dissolved in 250 ml of acetonitrile and extracted five times with 200 ml each of hexane. Acetonitrile layer is concentrated under vacuum, then add 500 ml of 6 N. hydrochloric acid and the mixture is heated under reflux during the night. The mixture is cooled extracted three times with 100 ml each of ether, then the aqueous layer was concentrated under vacuum. The compound is dissolved in a minimum amount of water and placed in a column with resin Dowex 50X8-100, elwira water and 10% pyridine/water. The desired fractions are collected and concentrated under vacuum. The residue is suspended in acetone, heated under reflux for one hour, filtered and the solid is washed with acetone and diethyl ether. After drying overnight at 60oWith under vacuum, obtain 7.0 g of the desired product as specified in the nae is the analysis for C12H19N5O20,25 H2About 0.2 acetone /S3H6O/:

Calc. WITH 52,28; N 7,52; N 24,19

Found: 52,09; N. OF 7.55; N 24,20

Example 2

3 carboxylicacid-6-ethanolicus acid hydrochloride.

The mixture 3,02 g nitrile intermediate compound from example 1G above and 100 ml of 6 N. hydrochloric acid is heated under reflux in a nitrogen atmosphere over night. The reaction is cooled to room temperature and the mixture is concentrated under vacuum. Acetone is added and the solution concentrated under vacuum. The obtained solid is suspended in diethyl ether, filtered and the solid is washed with acetone and diethyl ether obtaining of 2.51 g of the desired product mentioned in the title, so pl. 263-267oC. the product was carried out elemental analysis with 1.2 mol of ammonium chloride.

Analysis for C12H19N04l1,2 NH4CL: Calc. With 42,15; N 7,31; N 9,01; CL 22,81

Found: 42,20; N 7,46; N 9,14; Cl One-22.67.

Example 3 Decahydro-6-/phosphonomethyl/-3-izohinolinove acid

A. Obtaining ethyl, decahydro-6-/diethyl-phosphonomethyl/- -2-methoxycarbonyl-3-ethanolammonium.

To a suspension of 2.4 g of 60% sodium hydride in oil, prewashed with hexane is. After stirring for 15 minutes added 12.0 g of the ketone from example 1E above in the form of a solution in 35 ml of tetrahydrofuran. The reaction mixture is heated under reflux for 6 hours. After cooling, to the reaction mixture is added 200 ml of diethyl ether and the organic solution is washed twice with water. The combined aqueous layers washed with diethyl ether. All organic layers are combined, washed with a saturated solution of sodium chloride, dried and filtered. After concentration under vacuum, the residue is purified by means of liquid chromatography high pressure over silica gel. After combining and concentrating the desired fractions gain of 14.4 g of the desired intermediate compound indicated in the subtitle.

C. Obtaining ethyl, decahydro-6-/diethyl-phosphonomethyl/- -2-methoxycarbonyl-C-ethanolammonium.

14.4 g of the intermediate from example 3A above gidrogenit, following the method of example 1G c obtain 11.3 g mentioned in the title intermediate as a clear colorless oil.

C. Obtaining decahydro-6-/phosphonomethyl/-3-ethinlestradiol acid.

11.3 g of the intermediate from example 3B above is heated with reverse holovid add acetone and removed under reduced pressure. The residue is dissolved in about 5 ml of water and treated with approximately 3.8 ml of propylene oxide at 50oC for 30 minutes. After concentration under vacuum, ethanol is added and the mixture heated under reflux. Formed white solid, which after cooling are filtered. The residue is washed with ethanol, acetone and diethyl ether. The solid is triturated with acetone, filtered, washed with acetone and ether and dried to obtain 7.2 g specified in the product name, so pl. 208-211oC. Elemental analysis corresponded to the product, which had a 1/2 mole of water and 1/4 mole of acetone.

Analysis for C11H20N05P0,5 H2O0,25 C3H6O:

Calculated: 46,92; N rate of 7.54; N 4,66

Found: 46,84; H Of 7.36; N 4,39.

Example 4

The hydrochloride hemihydrate, decahydro-6-/phosphonomethyl/-1-izohinolinove acid.

A. Obtaining ethyl-6-hydroxy-1,2,3,4-tetrahydro-2-t-butoxycarbonyl-1 ethanolinduced.

A mixture of 36.5 g 3-/2-amino-ethyl /fragilaria and 23.1 g of Glyoxylic acid hydrate in 500 ml of 5% hydrochloric acid is stirred for 6.5 hours at 80oC. the Solution is concentrated under vacuum and the residue is dissolved in 1.2 l of ethanol, which is then h and concentrated under vacuum. The obtained solid is dissolved in 400 ml of methylene chloride and 29 ml of base Janiga followed by the addition of four 7.5 ml portions of di-t-butyl-dicarbonate within one hour. After about 46 minutes, add an additional 6 ml of the base of Haviva. The mixture was washed with 500 ml of 10% solution of sodium bisulfate. The layers are separated and the aqueous layer was extracted once with methylene chloride and once with diethyl ether. The organic layers collected, dried, filtered and concentrated under vacuum to obtain a red oil. After liquid chromatography high-pressure balance gain of 33.6 g of the intermediate as specified in the subtitle, which is used without further purification.

C. Obtain hydrochloride of ethyl 6-hydroxy-1,2,3,4 - tetrahydro-1-ethanolinduced. of 33.5 g of the intermediate from example 4A above dissolved in a mixture of 200 ml of methylene chloride and 200 ml triperoxonane acid. The solution was stirred at room temperature for two hours and then concentrated under vacuum. The residue is dissolved in about 300 ml of ethanol, which is pre-saturated with hydrochloric gas. After concentration under vacuum, the material is suspended in diethyl ether and filtered. Received TBE is the subtitle, so pl. 216-218oC.

C. Obtaining hydrochloride ethyl, decahydro-6-hydroxy-1-ethanolinduced.

The intermediate compound from example 4B above /21,7 g/ gidrogenit in 370 ml of 6:1 ethanol/acetic acid at 60oWith 10.8 g of 5% radium in coal. After about 16 hours add an additional 10.8 g of catalyst and gidrogenizirovanii continue for another 21 hours. The reaction mixture is filtered and then the filtrate concentrated under vacuum. The residue is again gidrogenit under the same conditions in the presence of 21.6 g of catalyst. After 4 days the reaction mixture was filtered and concentrated under vacuum obtaining of 13.0 g of the desired intermediate compound indicated in the subtitle, which is used in the next stage without purification.

D. Obtaining ethyl, decahydro-6-hydroxy-2-butoxycarbonyl-1-isoquinoline of the carboxylate. 13,0 g of the amine hydrochloride from example 4C above are suspended in 150 ml of methylene chloride. Add base Janiga /12,68 g/ followed by the addition of 12.7 g of di-t-butyl dicarbonate. After stirring for 60 minutes, the mixture washed with 10% solution of sodium bisulfate. The layers are separated and the aqueous layer was extracted twice with methylene chloride and once with diethyl ether. The organic layer unite the connection, specified in the subtitle.

C. Obtaining ethyl, decahydro-6-oxo-2-t-butoxycarbonyl-ethanolinduced.

Following the procedure of example 1E above, the alcohol from example 4 is treated with 23.7 g Harrogate pyridinium obtaining after preparative DVD 5,4 desired intermediate compounds specified in the subtitle. The material is dissolved in 130 ml of ethanol and treated with 1.65 ml of a solution of 600 mg of 60% sodium hydride in 15 ml of ethanol /for axial adjustment and equitirely isomers of ester/. After one hour at reflux the mixture is concentrated under vacuum, dissolved in 200 ml of dichloromethane and washed with 100 ml of 10% aqueous sodium bisulfate. The aqueous layer was extracted with 100 ml of ether, then the combined organic extracts are washed with 100 ml saturated aqueous sodium bicarbonate, dried over MgSO4filter and concentrate under vacuum. After chromatography over silica gel get 2.5 g specified in the product name in the form Equatoriale isomer.

F. Obtaining ethyl, decahydro-6-/diethylphosphoramidite/ -2-t-butoxycarbonyl-1 ethanolinduced.

Following the technique of example 3A above, 2.0 g ethyl, decahydro-6-oxo-2-t-butoxycarbonyl-1-athinaikos intermediate compounds, specified in the subtitle.

G. Obtaining ethyl, decahydro-6-/diethyl-phosphonomethyl/-2-butoxy carbonyl-1-ethanolinduced.

Methylene derivative of example 4F above /at 2.36 g/ gidrogenit following the procedure of example 1G and obtaining of 2.13 g of intermediate compound indicated in the title.

H. Obtaining hydrochloride hemihydrate decahydro-/phosphono-methyl/-1-ethinlestradiol acid.

Specified in the title of the product is obtained with a 76% yield of 1.8 g of ester intermediate from example 4G, following the method of example 3C, so pl. 231-232oC.

Analysis for C11H20NO5P0,85 SN2O:

Calculated: 40,50; N 7,06; N 4,29; CL 9,24

Found: 40,61; N 7,02; 4,45 N; CL 9,23

Example 5. Decahydro-6-/tetrazol-5-ylmethyl/-1-izohinolinove acid.

Specified in the title of the product is obtained with 55% of total output, since 2,47 g of ethyl decahydro-6-oxo-2-t-butoxycarbonyl-1 ethanolinduced, following the procedure of examples 1F,1G, and 1H.

Analysis for C12N19N5O20,75 H2O0,10 (C3H60/acetone/:

Calculated: WITH better than anticipated at 51.90; H 7,47; N 24,60

Found: 51,99; N. Of 7.35; N 24,64.

Example 6. Ethyl ester of decahydro-6-/phosphonomethyl/-3-itinerante Soldatov, suspended in 250 ml of ethanol. The solution is saturated with hydrochloric groove. After about 10 minutes the solution is heated under reflux during the night. After cooling and concentration under vacuum, the residue is dissolved in 15 ml of water and add 2 ml of propylene oxide. After one hour at 50oWith material concentrated under vacuum, then dissolved in water and purified on a column with resin Demeksa 50X8-100 as in example 1H to obtain foam. The foam is suspended in acetone and heated under reflux for 30 minutes, then cooled and filtered. The residue is washed with acetone and ether and then dried under vacuum at 60oC with the receipt of 1.95 g of the desired product mentioned in the title, so pl. 184-185oC.

Analysis for C13H24NO5P0,4 H2O:

Calculated: 49,96; 8,00; N 4,48

Found: 49,98; H 7,84, with 4.64 N

Example 7. Butyl ether of decahydro-6-/(phosphonomethyl)-3-isoquinoline carboxylic acid.

Listed in title product is obtained with 95% yield, following the procedure of example 6 from 1.06 g of the same starting material. amino acid and butanol, T. pl. 161-169oC.

Analysis for C15H28NO5P0,7 C3H7l0 (chloropropanol):

Calculated: 49,83; N 8,39; N 3,40

N is th acid.

Specified in the title of the product is obtained by following the method of example 6 from 1,25 g of amino acids from example 3 in 250 ml of Hcl-saturated geksanalem. The product are dissolved in about 50 ml of ethanol and adding ethyl acetate to precipitate the product. The obtained solid is filtered and suspended in acetone and heated under reflux for one hour, then cooled and filtered, washed with acetone and ether to obtain 0.28 g of the specified names of the product, so pl. 149-155oC.

Analysis for C17H32NO5P1,0 C3H7Cl0 (chloropropanol):

Calculated: 52,68; N TO 8.62; N 3,07

Found: 52,39; N. OF 8.37; N 3,40

Example 9. 3S, 4R, 6S, 8aR-6-(phosphonomethyl)-decahydroquinoline-3 - carboxylic acid.

A. Obtaining ethyl 3SR: 4aRS, 8RS-6-oxo-2-methoxycarbonylaminophenyl-3-carboxylate.

The solution 158,9 g (or 0.57 mole) of tetrahydroisoquinoline of the above 1C frozen in 1760 ml of absolute ethanol was subjected to hydrogenation at 2000 pounds per square inch (140,62 kg/cm2) at a temperature of 180oIn the presence of 80 g of 5% Ru/Al2ABOUT3for 16 hours. The mixture was cooled, filtered through Celite and concentrated in vacuum. The resulting oil was dissolved in EtOAc fiml CH2CL2and was added dropwise to a suspension of 260,5 g (1,21 mole) RCC and 260,5 g of powdery Zaletov 4 angstroms in 1400 ml of CH2CL2(which was stirred for one hour before adding the above alcohol). After the reaction is deemed complete by thin layer chromatography (50% EtOAc /hexane), was diluted simple ether and filtered through a layer consisting of Celite and silica gel, in the funnel of sintered glass, the solid was well washed with a simple ether, and then the filtrate was concentrated in vacuo.

The resulting oil was dissolved in simple ether, again filtered through Celite and silica gel and the filtrate was concentrated in vacuum to obtain to 128.8 g (83% ) of a mixture of target compound and epimerase connection-3 (ratio of 22: 78 by gas chromatography). This mixture was dissolved in 1000 ml of ethanol and treated with 1,82 g ( 45.5 mmol) Pan in 100 ml of ethanol, and the mixture was heated to boiling under reflux for 1.5 hours, at this time, gas chromatography (GC) shows a mixture of 87:13 target connection epimerase connection-H. the Mixture was cooled, concentrated in vacuo, was dissolved in 800 ml of CH2CL2/ simple ether /1:1/, and washed with 600 ml of 10% n is adicheskie extracts were dried (MgSO4), filtered and concentrated in vacuum. The residue was purified by chromatography on silica gel to WATERS PPEP 500 LC (elution gradient of hexane to 25 ethyl acetate/hexane) to obtain 106,9 g (66%) of a mixture of target compound and epimerase connection With-C (ratio of 87:13, by GC). After recrystallization from a simple broadcast received 67,0 g ( 41%) of target compound, so pl. 78-79oC.

Analysis for C14H21NO5:

Calculated: 59,35; N 7,47; N 4,94

Found: 59,62; N TO 7.61, N equal to 4.97

B. Obtaining (-) and (+) salts-methylbenzylamine-6-oxo-2-methoxycarbonyl-decahydroquinoline-3-carboxylic acid.

A solution of 20.0 g (70.6 mmol) of ester from example 9A and 77,7 ml of 1N NaOH in 185 ml of absolute ethanol was stirred overnight at room temperature, then concentrated in vacuo. The residue was divided into portions between tOAc and 10 aqueous NaHSO4200 ml of each aqueous layer was separated and was extracted twice, each time with 100 ml of EtOAc and once with 100 ml of CH1CL2. Together organic matter was dried (Na2SO4), filtered and concentrated in vacuo to obtain of 13.6 g (100%) of the acid used without purification. To this acid in 550 ml of EtOAc was added 9,11 mordue substance was filtered and washed with EtOAc to obtain 10.8 g of the crude salt ( +) ( ratio of 96:4 diastereomers, that was determined by conversion into amide and GC analysis. Recrystallization from tetrahydrofuran gave of 3.45 g (13%) salt (+). / //D/ + 55,0 (1 H20).

Analysis for C20H28N2O5:

Calculated: WITH 63.81; H 7,50; N 7,44

Found: 63,57; N 7,42; N 7,55

Royal solutions from the initial crystallization and subsequent recrystallization gathered together, concentrated in vacuo, then was divided between 300 ml of CH2Cl2and 300 ml of 1N Hcl. After stirring for 0.5 hours at room temperature the organic layer was separated and the aqueous layer was extracted 3 times with 50 ml of CH2CL2each and every time. Together organic matter was dried (Na2SO4), filtered and concentrated in vacuum to obtain 7.2 g (28.3 mmol) of 40% acid. This acid was dissolved in 280 ml of EtOAc and treated with the help of 3.65 ml (3,49 g, 28.3 mmol) R-methylbenzylamine. Processing, as for salt (+), gave 7,71 g (29%) salt (-).

///D/ -57,0 (c=1, H2)

Analysis for C20H28NO5:

Calculated: WITH 63.81; H 7,50; N 7,44

Received: FROM 63,87; N 7,33; N 7,33

C. Obtaining ethyl-(-)-6-oxo-2-methoxycarbonyl-decapitation-3 - carboxylate.

A mixture of 5.1 g (13.6 mmol) of the salt of (-) from VA was heated at 60oWith all night. The mixture was cooled and divided between 150 ml of CH2Cl and 150 ml of 10% aqueous NaHSO4. The aqueous layer was separated and was extracted twice with 100 ml of CH2Cl2and once with 100 ml of a simple ester. Collected together dried ( Na2SO4), filtered and concentrated in vacuum. The residue was chromatographically on 200 g silica was suirable with 50% EtOAc /hexane to obtain 3,36 g (88%) of the desired ketone. //D51,3 (c=1, CH2CL2).

Analysis14H21NO5:

Calculated: 59,35; H 7,47; N 4,94

Found: 59,11; N 7,20; N 4,90

Was Getting ethyl 3S, 4aR, 8R-6-(diethylphosphonate)-2-methoxycarbonylamino hydroisoquinoline-3-carboxylate.

Tetraethyl methylenediphosphonate with (58.2 g, 202 mmol) was added dropwise to a suspension of sodium hydride (8,1 g, 202 mmol, 60 weight. in oil ) in 155 ml of tetrahydrofuran, and the solution was stirred for 30 minutes at room temperature. To light the solution was added (-) of the ketone from example 9B (40,8 g, 144 mmol) in 140 ml of tetrahydrofuran, and the mixture was treated with water, and the resulting mixture was extracted with simple ether (4 times). Combined ether extracts were dried over MgSO4. Was filtered and concentrated in vacuum. The residue was purified Pat) to obtain 50,8 g (85%) of the target intermediate substance.

D. Receipt of 3S, 4aR, 8aR-6-(phosphonomethyl)-decahydroquinoline-3-CT boom acid.

A solution of 45.8 g (110 mmol) of the intermediate substances in the above example 9G and 135 ml of aqueous 1N sodium hydroxide in 465 ml of ethanol was stirred overnight at room temperature, then concentrated in vacuo. The residue was treated with 10% aqueous sodium bisulfate and extracted with ethyl acetate (4 times). The organic extracts were collected together, dried over MgSO4, filtered and concentrated in vacuum. This residue was dissolved in 420 ml of chloroform and 146,1 g (730 mmol) of idolisation was added dropwise within 20 minutes. The solution was heated to boiling under reflux for three hours, cooled and concentrated in vacuum. The residue was treated with 300 ml of water and the resulting mixture was concentrated in vacuum. The material was purified by ion exchange chromatography on BiO-Rad AGIX-8 (form hydroxide, column 7 x 22 cm), elwira using aqueous acetic acid for 3H receipt of 33.5 g (100%) of target compound.

E. Receipt of 3S, 4aR, 6S, 8aR-6-(phosphonomethyl) -decahydroquinoline-3-carboxylic acid.

A solution of 33.5 g (122 mmol) of the acid from example 9D in twii 17.0 g of 5% palladium on carbon. The mixture was filtered through Celitepand concentrated in vacuum. Son-in-law filter catalyst was heated under reflux in 1000 ml of water for 2 hours, filtered through Celitepwhile hot, the filtrate was added to the above material, directly selected from hydrogenation, and concentrated in vacuum. This residue was dissolved in 75 ml of water at pH 12, was filtered through CeliteppH was adjusted to 7 and was purified using ion-exchange chromatography on Dowex X-8 (500 g resin, column 7 x 22 ), elwira c using acetic acid 3H. Collected six fractions of 500 ml Fractions 2-5 were collected together and concentrated in vacuo to obtain a solid substance. The solid is suspended in 500 ml of acetone and heated to boiling under reflux for one hour, cooled, filtered, washed with acetone and simple ether, then dried in vacuum at 60oFor obtaining of 27.2 g (81%) of target compound, so pl. 278-279oC.

//D-32,0 (c=1 1N Hcl).

Analysis for C11H20NO5P0,1 p2H402(acetic acid):

Calculated: 47,49; N. OF 7.25; N 4,94

Received: FROM 47,36, N 7,17, N 4,85

As noted above, the compounds of this image the shadow is a way to block one or more excitatory amino acid receptors in mammals, the mammal that requires a reduction in excitatory amino acid neurotransmission, enter pharmaceutically effective amount of the compounds according to the invention.

The term "pharmaceutically effective amount", as used here, represents the number of compounds that can block one or more excitatory amino acid receptors. A certain dose of a compound, introduced in accordance with the present invention, will be determined by special circumstances of the disease, including an input connection, method of introduction, certain symptoms that should be treated, and other considerations.

Connections can be entered in various ways, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or through the nose. A typical daily dose will contain from about 0.01 mg/kg to about 20 mg/kg of active compound of the present invention. The preferred daily dosage is about 0.05 to 10 mg /kg, ideally about 0.1 to 5 mg/kg

It has been proven that a number of physiological functions influenced by excessive stimulation of excitatory amino xilitol neurotransmission. As such, the compounds of the us is / establishment, which includes neurological disorders, such as convulsive disorders, such as epilepsy, stroke, anxiety, cerebral ischemia, muscular spasms, and neurodegenerative disorders such as Huntington's disease. Therefore, the present invention also provides methods of treatment for these disorders at doses above for excitatory amino acid receptors in mammals.

Experiments were carried out to demonstrate the suppressive activity of the compounds of the present invention with N-methyl-D-aspartate /NMDA/ subtype of excitatory amino acid receptor in rats in vivo.

Males or females newborn /7 to 8 days of age/ rats, sprag-Shares were extracted from the uterus and placed in a plastic camera for surveillance, which maintained at a temperature of 30-32oC. All test drugs were dissolved in normal saline. Activation of NMDA receptors in these rats resulted in easily detectable gross motor seizure is characterized by increased motor activity followed clinically-tonic movements of the front and rear legs, and long-term loss of orientation. These attacks are not blocked by the introduction of non-selective antagonist to NMDA, but easily blokir g body weight/ and observed for 30 minutes for the activity attack /potential agonist/. Then they were introduced NDA at the dose of 20 mg/kg of body weight within the abdominal testing the activity of the antagonist. The control rats /entered normal saline solution/ this dose NDA leads to attack more than 95% of the animals. Rats were observed attack for an additional 30 minutes after administration of NMDA. Animals are classified into positive and negative terms-definition demonstration tonic-planning activity attack with loss of orientation. Observations of attacks, caused by one test connection /activity agonist/ or blockade of attacks, caused by NMDA, the test connection /activity antagonist/ were taken into account separately. For each dose of compound is usually used five animals. The full range and intervals used doses are 200, 100 50, 20, 10,5, 2 and 1 mg/kg In the dose range is reduced in steps up until at least 3 out of 5 animals do not demonstrate attacks.

The minimum effective dose /MED/ is the lowest tested dose that prevented the attacks, called NMDA, at least 3 of the 5 animals as shown in the table.

For illustration of the advantages of the claimed compounds were carried out comparative tests ant the private shock.

In the case of this test system compound under test was administered to each of the ten white mice (standard line of Coke (SOH), male, 18-24 g) with dose explored. At fixed time intervals after the introduction in connection mice were subjected to electric shock ( 0.1 s 50mA), feeding the current through corneal electrodes. Animals were examined and evaluated immediately after the shock in the presence of clonic, flexor, tonic or tonic extensor convulsions, or death; the value of the ED50was determined for each connection in the form of dose, with the introduction which eliminates the manifestation of tonic extensor seizures in half of the animals immediately after the shock. For example, the current 18 mA usually been sufficient for the appearance of tonic extensor seizures in approximately half of the control animals, at a current of 50 mA almost all control animals (receiving only filler) was killed.

When exposed to electric shocks through 120 min after oral administration of doses (entered via a probe in the form of a suspension in the Arabian gum) it was found that the interpolated value of the ED50for known anticonvulsive phenytoin Rav is the lake of the corresponding compounds for 5 min prior to the impact of the shock value of the ED50of phenytoin and the compound of example 3, respectively, were 9.6 and 1.9 mg/kg

Compounds of the present invention is preferably prepared in the form of drugs before the introduction. Therefore, the present invention offers yet another aspect of the pharmaceutical composition containing the compound according to the invention and a pharmaceutically acceptable carrier; diluent or excipient.

These pharmaceutical compositions get by known methods, using a well-known and became available ingredients. Upon receipt of the compositions of the present invention the active ingredient is usually mixed with a carrier, or diluted by a carrier or cover carrier, which may be in the form of a capsule, sachet, paper or other container.

When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a carrier, excipient or medium for the active ingredient. Thus the composition can be in the form of tablets, powders, pellets, sachets, capsules, Alexiou, suspensions, emulsions, solutions, syrups, aerosols /solids or liquid environment/, ointments containing for example up to 10% weight. active ingredientami.

Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starch, resin acacia, calcium phosphate, alginates, tragakant, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl - and propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The composition can additionally include lubricating agents, wetting agents, emulsifiers and suspendresume agents, preserving agents, sweetening agents and flavouring agents. The composition of the invention can be prepared in such a way as to provide rapid, continuous or delayed release of the active ingredient after administration to the patient, using techniques well known in the field of technology.

The composition is preferably prepared in the form of single doses, each dose should contain from about 5 to about 500 mg, typically from about 25 to about 300 mg of the active ingredient. The term "unit dosage" refers to physically discrete units to be applied as a single dose for humans and other mammals, each unit contains will precede the reaction, in combination with a suitable pharmaceutical carrier.

The following examples of the preparation of compositions illustrative only and are not restrictive of the scope of the invention.

Preparative form 1.

Get hard gelatin capsules, using the following ingredients quantity (mg/capsule:

Decahydro-6-//2/N-tetrazol-5-yl-methyl/-3-izohinolinove acid 250

Dry starch 200

Magnesium stearate 10

Total 460 mg

These ingredients are mixed and filled into hard gelatin capsule in the amount of 460 mg.

Preparative form 2.

Get a tablet, using the following ingredients: quantity (mg/tablet:

3 Carboxylicacid-6-ethanolicus acid 250

Microcrystalline cellulose 400

Silicon dioxide, a pair of 10

Stearic acid 5

Total 655 mg

The components are mixed and pressed to form tablets, each weighing 665 mg

Preparative form 3.

Get a spray solution containing the following components, in weight.

Decahydro-6-/phosphonomethyl/-3-izohinolinove acid 0,25

Ethanol 29,75

Propellant 22 /Chlorodifluoromethane/ laidout to -30oWith and transferred to a filling device. The desired number then injected into a stainless steel container and diluted with the remainder of propellant. Then attached to the container valve.

Preparationa form 4.

Tablets, each containing 60 mg of active ingredient, was prepared as follows:

3 Carboxylicacid-6-ethanolicus acid vinylsulfonate 60 mg

Starch 45 mg

Microcrystalline pulp 35 mg

Polyvinylpyrrolidone /in the form of a 10% solution in water/ 4 mg

Natrocarbonatite starch 4.5 mg

Magnesium stearate 0.5 mg

Talc 1 mg

A total of 150 mg

The active ingredient, starch and cellulose are passed through sieve No. 45 mesh U.S. and mix thoroughly. The solution polyvinylpyrrolidone mixed with the obtained powders which are then passed through sieve No. 14 mesh U.S. dollars. Thus obtained granules are dried at 50oWith and pass through a sieve No. 18 mesh U.S. dollars. Natrocarbonatite starch, magnesium stearate and talc, previously passed through sieve # 60 mesh U.S. then added to the granules which, after mixing is pressed on the machine to obtain tablets with obtain tablets each weighing 150 mg

Preparative form 5.
Starch 59 mg

Microcrystalline cellulose 59 mg

Magnesium stearate 2 mg

A total of 200 mg

Active ingredient, cellulose, starch and magnesium stearate are mixed, passed through a sieve N 45 USA and filled into hard gelatin capsule 200 mg

Preparative form 6.

Candles, each containing 225 mg of active ingredient, can be obtained in the following way:

5-/Decahydro-6-/1/2-/N-tetrazol-6-yl/-methyl/3-from the quinoline-3-yl/-1-/2-/N-tetrazol 225 g

Glycerides of saturated fatty acid 2000 mg

Total 2225 mg

The active ingredient is sifted through sieve # 60 mesh U.S. and suspended in the glycerides of saturated fatty acids, previously melted using the minimum required amount of heat. The mixture is then poured into the form of a candle, with a capacity of nominally 2 g and cool.

Preparative form 7.

Suspensions, each containing 96 mg of the drug per 5 ml dose, receive the following way:

2.2-Dimethylpropanolamine decahydro-6-phosphonomethyl-3-ethanolammonium 50 mg

The sodium carboxymethyl cellulose 50 mg

Syrup 1.25 ml

A solution of benzoic acid 0.10 ml

Flavouring substance, O.

Dye, O. t with sodium carboxymethyl cellulose and syrup with the formation of a soft paste. A solution of benzoic acid, flavoring substance and the dye is diluted with some water and add. Then add enough water to get the desired volume.

Preparative form 8.

Intravenous preparative form is received as follows:

Methylsulfonate decahydro-6-phosphonomethyl-3-ethinlestradiol acid 100 mg

Isotonic solution of 1000 mg

The solution of the above ingredients is injected at a speed of 1 ml per minute to a subject in need of treatment.

1. Derivatives decahydroquinoline General formula

< / BR>
where X PINES, -PO3(R)2or

< / BR>
one of Y and Z is COOH or-fulfills I TS cor2;

and the other of Y and Z is hydrogen;

R1WITH1WITH4is alkyl or hydrogen;

R2WITH1WITH6-alkoxy,

or its pharmaceutically acceptable salt.

2. Connection on p. 1, representing decahydro-6-[1(2)N-tetrazol - 5-yl-methyl]-3-ethanolammonium acid or its pharmaceutically acceptable salt.

3. Connection on p. 1, representing decahydro-6-(phosphonomethyl)-3-ethanolammonium acid or its pharmaceutically acceptable salt.

4. Connection p. the Cesky acceptable salt.

 

Same patents:

The invention relates to organic synthesis and relates to new quinoline derivatives and method of production thereof

The invention relates to new biologically active compounds derived pyrimidine-4-or their pharmaceutically acceptable salts with serotoninergicheskoi, dopaminergically, antihistaminic activity, and compositions on their basis

The invention relates to new biologically active chemical compounds, namely, to derive a cyclic amide of the formula I

R1-(CH2)n-Z,

where R1group cyclic amide, such as 2H-3,4-dihydro-1,3-benzoxazin-2-she, 2H-3,4-dihydro-1,3-benzoxazin-2,4-dione, and 1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1,2,3,4-tetrahydroquinazolin-2-it, 1,2,3,4-tetrahydropyrido(3,2-d)-pyrimidine-2,4 - dione, and 1,2,3,4-tetrahydropyrido(3,2-d)pyrimidine-2-it, 1,2,3,4-tetrahydropyrimidine-2,4-dione, pyrrolidin-2-it, 1,2,3,4 - tetrahydropyridine-2-it, 5H-6,7,8,9-tetrahydropyrido(3,2-b)azepin-6-she N-5,6,7,8-tetrahydropyrido(2,3-b)azepin - 8-she, 2H-3,4-dihydropyrido(2,3-e)-1, 3-oxazin-2-thione or 2-she pyrrolidine (3,4-b)-pyrazin-5-she 1H-2,3,4,5-tetrahydrothieno(2,3-b)indol-2-it, 8H-4,5,6,7-tetrahydrothieno(2,3-b)thiophene-7-she 4H-pyrazolo(5,4-f)benzazepin-9-it, isoindoline-1,3-dione, benzoxazolyl-2-it, unsubstituted or substituted lower alkyl, lower alkoxy, halogen, the nitro-group, carboxy, benzoyl or benzyl, n is zero or an integer from 1 to 6, Z is a group of formula (A) or (B):

N-(CH2)mR2(A) or -(CH2)p, dioxolane, furan, tetrahydrofuran, methylfuran or thiophene, m is an integer from 1 to 3; R3is lower alkyl; R4is phenyl or a radical of dioxolane, furan or thiophene, p = 1, provided that when R1radical 1,2,3,4-tetrahydrobenzo-2-or 1,2,3,4-tetrahydroquinazoline-2,4-dione, R2and R4are not phenyl or substituted by a halogen phenyl, or their pharmacologically acceptable salts with antiacetylcholinesterase activity
The invention relates to medicine, namely to dermatology

The invention relates to a new one with pharmacological properties dihydroisoquinoline derivative, processes for their preparation, pharmaceutical compositions containing these derivatives, and their use as medicines

The invention relates to medicine and can be used for inhibiting the activity of human immunodeficiency virus HJV in vivo experiment by introducing antimalarials - primaquine

The invention relates to new heterocyclic compounds, more specifically to new heterocyclic compounds, which are inhibitors of the enzyme 5-lipoxygenase (hereinafter referred to as 5-LO)
The invention relates to medicine, in particular to pharmacology and Psychoneurology

The invention relates to new derivatives of benzimidazole, possessing valuable pharmacological properties, in particular a derivative of benzimidazole of General formula I

< / BR>
(I) where R1in position 4 means fluorine atom, chlorine or bromine, alkyl with 1-4 carbon atoms, cycloalkyl, vermeil, deformity or trifluoromethyl;

R2alkoxyl with 3-5 carbon atoms, substituted imidazolium in position 3, 4 or 5, alkoxyl with 2-5 carbon atoms, a substituted benzimidazole or tetrahydroimidazo in position 2, 3, 4 or 5, 2-(imidazol-1-yl)-ethoxyl provided that R4means 1H-tetrazolyl, alkylsulfonate with 1-4 carbon atoms, benzosulfimide or generalconclusions, unsubstituted or substituted at the nitrogen atom by alkyl with 1-6 carbon atoms, phenyl, cycloalkyl, phenylalkyl, cycloalkylation, bicyclohexyl or the biphenyl alluminare, in which the acyl radical is alkanoyl with 1-7 carbon atoms, alkoxycarbonyl with a total of 2-4 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, benzoyl, benzazolyl, generalkonsulin, naphthalenesulfonyl, cycloalkylcarbonyl, phenylalkanoic or Central electoral commissions substituents from the group includes fluorine atom, chlorine or bromine, methyl, methoxy, phthalimido, hemophthalmia, 2-carboxymethylamino or 2-carboxymethylamino, and one carbonyl group in phthalimidopropyl replaced by methylene, alkylamino or dialkylamino, one methylene group in hoofdlijnen may be substituted by one or two alkyl groups, and the phenyl nucleus may be optionally mono - or tizamidine the alkyl or alkoxyl, and the substituents may be the same or different and are wholly or partially gidrirovanny, unsubstituted or substituted by one or two alkyl groups or one tetramethylenebis or pentamethylene group 5-, 6 - or 7-membered, alkylamino or alkenylamine in which one methylene group may be replaced by a carbonyl or sulfonyl, imides bicycloalkyl-2,3-dicarboxylic acid and imine bicycloalkyl-2,3-dicarboxylic acid, where bicycloalkanes and bicycloalkanes part can contain 9 or 10 carbon atoms can be substituted by 1, 2 or 3 methyl groups, and endometrioma group may be replaced by oxygen atom, amidinopropane, unsubstituted or substituted by one or two alkyl groups is whether the two alkyl groups or tetramethylene or pentamethylene, maleinimide, unsubstituted or mono - or disubstituted by identical or different substituents from among alkyl and phenyl, linked through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup, oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and mentioned heteroaromatic rings in the carbon skeleton may be substituted by alkyl with 1-6 carbon atoms or phenylalkyl to 5-membered and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methylene group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom of the formed pyridine ring with the sulfur atom, or formed anilinophenol phenyl ring by one or two methyl groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroalkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene bridge, and available if needed in the imidazole ring NH group may be substituted by an alkyl group with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl, imidazolidinedione group, unsubstituted or substituted alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene, pyridazin-3-one and dihydropyridin-3-one, which is in position 2 can be substituted and,

the group R7-NR6CO NR5where R5a hydrogen atom, alkyl with 1-8 carbon atoms, cycloalkyl with 5-7 carbon atoms or phenylalkyl;

R6a hydrogen atom, alkyl with 1-8 carbon atoms, alkenyl with 3-5 carbon atoms, phenyl, phenylalkyl or cycloalkyl with 5-7 carbon atoms,

R7a hydrogen atom or alkyl with 1-6 carbon atoms,

one of the radicals R5, R6or R7may mean bicyclohexyl or diphenylol, R6and R7together with the enclosed nitrogen atoms means the unbranched alkalinising with 4-6 carbon atoms, or R5and R6ashamed mean alkylen with 2-4 carbon atoms, 1H, 3H-hinzelin-2,4-Dion-3-yl, pentamethylene-oxazoline-2-yl, or R1a hydrogen atom or is in position 5, 6 or 7 atoms fluorine, chlorine or bromine, an alkyl group with 1-4 carbon atoms, vermeil, deformity or trifluoromethyl; R2bound through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup and the oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and said heteroaromatics and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom, or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methine group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom formed piperidino ring sulfur atom, or formed anilinophenol phenyl ring, one or two methine groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroaromatic rings in the carbon skeleton may additionally be monogamist fluorine atom, chlorine or bromine, the alkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene my with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl,

R3a hydrogen atom, an alkyl group with 1-5 carbon atoms in which one methylene group may be replaced by oxygen atom or sulfur, or cycloalkyl with 3-5 carbon atoms,

R4carboxyl, cyano, 1H-tetrazolyl, 1-triphenyl-methyl-tetrazolyl, alkoxycarbonyl with the total number of carbon atoms 2-5, alkanesulfonyl, arylsulfonamides, triftormetilfullerenov, and if nothing else is specified, then the above alcoolica, alkyl and CNS part can contain 1-3 carbon atoms, and cycloalkyl part of 3-7 carbon atoms, and moreover, if (a) R1a hydrogen atom, R3N-propyl and R4carboxyl, R2in position 6 does not mean 3-methylimidazo[4,5-b]pyridine-2-yl or 3-n-hexyl-imidazo[4,5-b]pyridine-2-yl, or if (b) R1a hydrogen atom, R3n-propyl or n-butyl and R41H-tetraza the sawdust and R4carboxyl, R2in position 5 or 6 does not mean 1-methylbenzimidazole-2-yl or 6 position 1H-butylbenzothiazole-2-yl, 1,5-dimethylbenzimidazole-2-yl or 1-methyl-5-trifluoromethyl-benzimidazole-2-yl, or if g) R1a hydrogen atom, R3n-butyl and R4carboxy or 1H-tetrazolyl, R2in position 6 does not mean 1-methylbenzimidazole-2-yl, or if d) R1a hydrogen atom, R3n-butyl and R4carboxyl, R2in position 6 does not mean benzimidazole-2-yl, mixtures of them 1-, 3-isomers or individual isomers and hydrates and salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases which are used, for example, as antagonists of angiotensin II, the method of obtaining derivatives of benzimidazole containing the substances, medicinal product and method of its production

The invention relates to medicine and relates to means for the prevention and treatment of diabetic complications, angiopathy, neuropathy, katakey

The invention relates to new 7-azabicyclo-substituted hinolan carboxylic acids, pharmaceutical composition containing such compounds, and methods of treatment using such compounds

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

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

13 cl, 3 tbl, 35 ex

FIELD: medicine, oncohematology.

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

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides antibacterial drug in the form of enveloped tablet with its nucleus containing ofloxacin as active substance and auxiliary ingredients: silica powder, calcium stearate, collidone, sodium carboxymethylcellulose, milk sugar, talc, and microcrystalline cellulose. Envelop of tablet contains collidone, hydroxypropylcellulose, talc, and titanium dioxide. Manufacture of tablet comprises mixing ofloxacin, silica powder, milk sugar, and microcrystalline cellulose; moistening resulting mixture with collidone solution; wet granulation; drying; dry granulation; and powdering of granules with mixture of calcium stearate and sodium carboxymethylcellulose. Afterward, granules are enveloped.

EFFECT: increased storage stability.

2 cl

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I): with the crystalline modification A and a drug eliciting effect against pathogenic microorganisms. The prepared crystalline modification shows stability and doesn't transform to another crystalline modification or amorphous form being even at prolonged storage.

EFFECT: improved and valuable properties of compound.

4 cl, 4 dwg, 6 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides composite therapeutical agent exhibiting antituberculous effect and made in the form of solid dosage form containing as active principle combination of lomefloxacin, isoniazid, pyrazinamide, ethambutol hydrochloride, and pyridoxine hydrochloride plus auxiliaries.

EFFECT: increased assortment of antituberculous drugs.

4 cl, 1 tbl, 4 ex

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