Cis-(-)-4[(1(2)n-tetrazol-5-yl)methyl]-2-piperidinecarbonitrile acid and a pharmaceutical composition active antagonist of excitatory amino acid receptors

 

(57) Abstract:

Usage: as farmacevticheskogo of the drug in treating a number of disorders that are associated with excitatory amino acid receptors, including neurological disorders. Product: CIS-(-)-4-/(1(2)H-tetrazol-5-yl)methyl-2/-2-piperidinecarbonitrile acid. So pl. 162-167oC []D= -18,7. 2 S. and 1 C. p. F.-ly.

In the application Europatent N 89301337.5. reveals a number of 4-/(tetrazol-5-yl)alkyl/2-piperidinecarboxylic acids, which can block the excitatory amino acid receptors in mammals. It is shown that the disclosed compounds have varying degrees of activity. Now a new connection is created, related, but not proposed earlier patent application, and it has a higher activity compared with all previous connections.

The present invention provides a derivative of tetrazole, which is an antagonist of excitatory amino acid receptors. More specifically, the present invention relates to the compound CIS-(-)-4-/(1 (2)H-tetrazol-5-yl)methyl/-2-piperidinecarboxylic acid or its pharmaceutically acceptable salt.

The present invention also PCI-acceptable carriers, diluents or inert fillers.

Additional embodiments of the present invention include the use of compounds as a pharmaceutical preparation, especially for blocking one or more excitatory amino acid receptors, and methods of treating a number of disorders that are associated with excitatory amino acid receptors, including neurological disorders (e.g. epilepsy, stroke, anxiety, cerebral ischemia, muscular spasms and neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease.

As noted above, the present invention includes pharmaceutically acceptable salts of the compounds defined by formula 1. These salts may exist in combination with acidic or basic part of the molecule and can exist as acid additive, primary, secondary, tertiary or Quaternary ammonium salt or salt of an alkali metal or alkaline earth metal. Acids commonly used for the formation of such salts include inorganic acids such as hydrochloric, Hydrobromic, uudistoodetena, sulfuric and phosphoric acid, and organic Neorganicheskie and organic acids. Such applied pharmaceutical salts include the sulfate, persulfate, bisulfate, sulfite, bisulfite, phosphate, ammonium, monohydrogenphosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, lithium, bromide, iodide, acetate, magnesium propionate, Tetramethylammonium, decanoate, kaprilat, acrylate, formate, isobutyrate, capriate, heptanoate, potassium, propiolate, oxalate, trimethylammonio, malonate, succinate, suberate, sebacate, fumarate, maleate, Butin-1,4-diet, sodium, hexyne-1,6-diet, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylammonium, ecological, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, calcium, -hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 - sulfonate, naphthalene-2-sulfonate, mandelate and similar salts.

The connection offered by the present invention, a receiving method, which involves the interaction of alkyl CIS-(-)-4-cyanomethyl-N-vinyloxycarbonyl-2-piperidinecarboxylate with usedatabaseyou and hydrolysis of the obtained intermediate compound, and a salt formation, if the connection is required in the form of salt.

More concretel/-2-piperidinecarbonitrile acid.

A. Bromhead 4-hydroxy-2-pyridineboronic acid.

To a solution of 30.5 g (0.24 mol) of 4-methoxypyridine-N-oxide in 250 ml methylene chloride was added to 30.3 g (0.31 mol, 40,7 ml) trimethylsilylacetamide. After about five minutes 32,8 g (0.31 mol, of 28.0 ml) N, N-dimethylammoniumchloride add four 7 ml portions over one hour. The resulting mixture is stirred over night at room temperature. To the mixture carefully add 250 ml of a 10 mass% aqueous solution of potassium carbonate. After 15 min at room temperature the aqueous layer was extracted twice with methylene chloride and once simple diethyl ether, then the organic layer separated. The combined organic extracts are dried in the presence of anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is dissolved in 150 ml of 48% by weight aqueous solution of Hydrobromic acid. The resulting mixture was heated under reflux overnight and cooled to a temperature of 0oC. the Formed crystals are collected by filtration under vacuum, washed with simple diethyl ether and dried in the presence of a vacuum at a temperature of 50oC obtaining 45,5 g bromhidrosis 4-hydroxy-2-pyridineboronic acid.

Century Charger is bromhidrosis 4-hydroxy-2-pyridineboronic acid and 500 ml of ethanol, saturated hydrochloric acid. The mixture is heated under reflux overnight, cooled and concentrated in vacuo to 1/3 of its original volume. After cooling the mixture to a temperature of about 0oC the resulting crystals are collected by filtration under vacuum, washed with ethanol and simple diethyl ether and dried under vacuum to obtain 29.5 g of the hydrochloride of ethyl 4-hydroxy-2-pyridinecarboxylic.

C. Ethyl CIS-4-hydroxy-N-tert-butoxycarbonyl-2 - piperidinecarboxylate.

Hydrochloride ethyl 4-hydroxy-2-piperidinecarboxylate to 27.2 g, 0.13 mol) hydronaut in 200 ml of ethanol with 15.5 g of a 5% by weight rhodium on alumina at a temperature of 100oC and a pressure of 1000 pounds per square inch (70,3 kg/cm2within 10 hours the Mixture is cooled, filtered and concentrated under vacuum. To the residue was added 250 ml of methylene chloride, 50 ml of ethanol 25.2 g (0.20 mol, 34,0 ml), Hunig base, followed by adding dropwise 28.4 g (0.13 mol, and 29.9 ml) di-tributylphosphate within thirty minutes. After one hour the mixture is concentrated under vacuum and the residue is dissolved in methylene chloride and washed with twice 10% by weight aqueous solution of sodium bisulfate. The combined aqueous washings extracted once methylthio what about the sodium sulfate filter and concentrate under vacuum. Liquid chromatography high pressure relative to the remainder of the results of 21.3 g of ethyl CIS-4-hydroxy-N-tert-butoxycarbonyl-2-piperidinecarboxylate in the form of a colorless oil.

D. Ethyl 4-oxo-N-tert-butoxycarbonyl-2 - piperidinecarboxylate.

In a 1-liter round bottom flask was added 33.6 g (0,16 (mol) pyridinesulfonamide, 35 g of powdery molecular sieves 4A and 200 ml of methyl chloride. After stirring the mixture at room temperature for sixty minutes, add a solution of 21.3 g (0,078 mol) of ethyl CIS-4-hydroxy-N-tert-butoxycarbonyl-2-piperidinecarboxylate in 50 ml of methylene chloride. After stirring the mixture for sixty minutes at room temperature add 700 ml simple diethyl ether. The mixture is filtered through celite(brownmillerite) with a layer of 3/4 inch (1.9 cm), and a layer of silica gel size/ 3/4 inch (1.9 cm) (230-400 mesh mesh) in 650 ml funnel fused glass with an average porosity. Solid washed with 1 l of simple diethyl ether and the filtrate concentrated under vacuum. To the residue was added 200 ml of a simple diethyl ether and the mixture filtered through a layer of celite size 3/8 inch (about 1 cm) and a layer of silica gel is and then washed with 500 ml simple diethyl ether and the filtrate concentrated under vacuum. The residue is purified liquid chromatography high pressure to obtain 14.6 g of ethyl 4-oxo-N-tert-butoxycarbonyl-2-piperidinecarboxylate in the form of a colorless oil.

E. Ethyl 4-cyanopyridine-N-tert-butoxycarbonyl-2-piperidinecarboxylate.

To a suspension of 0.75 g (0.019 mol, 60% by weight in oil) of sodium hydride (washed three times with hexane) in 40 ml THF is added to 3.34 g (0.019 mol)citizen.metropolitan. After stirring the reaction mixture for thirty minutes PI room temperature was added a solution of 4.26 deaths g (to 0.016 mol) of ethyl 4-oxo-N-tert-butoxycarbonyl-2-piperidinecarboxylate in 10 ml of THF. The mixture is stirred for 30 min at room temperature m 90 minutes at a temperature of distillation of the reaction mixture is then cooled to room temperature and cooled water. The organic layer is separated and the aqueous layer was extracted two times simple diethyl ether. The organic extracts are combined, dried in the presence of anhydrous magnesium sulfate, filtered and concentrated under vacuum. Liquid chromatography high pressure relative to the remainder of the results 3.58 g of ethyl 4-cyanopyridine-N-tert-butoxycarbonyl-2-piperidinecarboxylate.

F. Ethyl CIS-4-cyanomethyl-N-tert-bout boxill (9.00 g, 0,031 mol) hydronaut in 140 ml of ethanol with the use of 0.90 g of a 5% by weight palladium charcoal at room temperature and a pressure of 60 psig (4.2 kg/cm2within 60 minutes the Mixture is filtered through a layer of zeolite and concentrate under vacuum. Liquid chromatography high pressure relative to the rest allows you to get to 8.20 g of ethyl CIS-4-cyanomethyl-N-tert-butoxycarbonyl-2-piperidinecarboxylate.

G. Ethyl CIS-()-4-cyanomethyl-N-allyl-2-piperidinecarboxylate.

To a solution of 19.9 g (67.2 per mmol) ethyl 4-cyanomethyl-N-tert-butoxycarbonyl-2-piperidinecarboxylate (obtained in accordance with stage (F) in 100 ml dichloromethane was added 50 ml triperoxonane acid (allocation of CO2). The mixture is stirred for three hours at room temperature and then concentrated under vacuum. To the residue add 100 ml of dichloromethane and the solution again concentrated under vacuum. The residue is dissolved in 200 ml of dichloromethane, was added 200 ml of saturated aqueous sodium bicarbonate solution and the mixture is stirred for 15 min at room temperature. The organic layer is separated and washed with 100 ml saturated aqueous sodium bicarbonate solution and the combined aqueous washing twice extra stricty dried in the presence of Na2SO4filter and concentrate to obtain 12.7 g (96%) of ethyl 4-cyanomethyl-2-piperidinecarboxylate. Gas chromatographic analysis shows a mixture of 85: 15 of CIS:TRANS isomers. To a solution of 11.6 g (59,1 mmol) of the product in 60 ml of dimethyl sulfoxide was added to 9.9 g (119,2 mmol) of sodium bicarbonate and 5.7 ml (7.9 g, 65,0 mmol) allylbromide. After one hour at room temperature add additional 1.1 ml of allylbromide, and after two hours at room temperature the mixture is poured into 100 ml water and 100 ml of saline solution, and perform extraction (five times) 50 ml (each time) of dichloromethane and once with 50 ml simple diethyl ether. The combined organic layers are washed with 100 ml water, then dried in the presence of Na2SO4filter and concentrate. The residue is purified preparative liquid chromatography high pressure to obtain 8.6 g (62%) of ethyl CIS () -4-cyanomethyl-N-allyl-2-piperidinecarboxylate and 1.2 g (9% ) of ethyl TRANS-()-4-cyanomethyl-N-allyl-2-piperidinecarboxylate, both of these compounds have more than 99.9% of one isomer in the analysis by gas chromatography.

H. di-p-Toluoyl-D - and L-tartrate(Sol) ethyl CIS- (+)-4-cyanomethyl-N-allyl-2-piperidinecarboxylate.

A mixture of 7.36 g (31,1 mmol) of the above result when heated. The solution is filtered and most of the ethyl acetate is removed to obtain a final volume equal to about 50 ml, the Mixture is cooled to room temperature and the formed crystals are collected and washed with ethyl acetate, simple diethyl ether and pentane and dried to obtain 13,0 g (67%) of product. The substance is recrystallized from ethyl acetate to obtain 6.4 g (33% ) of the desired (+) -salt, melting point 142 - 142,2oC []D= +108,9(C= 1, methanol) a Small part of (+)-salt is a free base and its1H NMR in d6-benzene with one equivalent of R- (-)-2; 2,2-Cryptor-1- (9-antrel)ethanol shows that less than 97% of one enantiomer.

1. Ethyl CIS-(+)-4-cyanomethyl-N-allyl-2-piperidinecarboxylate.

To the flask was added 6.0 g (9.7 mmol) of (+)-salt obtained above, 100 ml of dichloromethane and 100 ml of saturated aqueous sodium bicarbonate solution. The mixture is stirred for 10 min at room temperature, the organic layer is separated and the aqueous layer was extracted with three times 100 ml (each time) of dichloromethane and once with 75 ml simple diethyl ether. The combined organic extracts are dried in the presence of Na2SO4filter and concentrate. The residue is purified on 100 g of silica gel, AluI is B>= +72,3(c=1, dichloromethane).

J. Ethyl CIS -(-)-4-cyanomethyl-N-vinyloxycarbonyl-2-piperidinecarboxylate.

A solution of 2.0 g of the product of stage 1 above, 1.8 g (16.5 mmol) of vinylchloride and 3.5 g (16.5 mmol) of 1,8-bis-dimethylaminonaphthalene in 40 ml of dichloromethane is heated under reflux for 6 hours the mixture is Then cooled to ambient temperature and concentrate under vacuum. The residue is dissolved in simple diethyl ether and washed twice in 10% aqueous solution of acidic sodium sulfate and once with saturated aqueous sodium bicarbonate. The organic layer is dried in the presence of magnesium sulfate, filter and concentrate under vacuum. Preparative liquid chromatography high pressure allows to obtain 1.8 g (79%) of the desired intermediate compound, []D= -24,8(c=1, dichlorethane).

K. Cys-(-)-4-/1 (2) N-Tetrazol-5-yl)methyl/-2-piperidinecarbonitrile acid.

A mixture of 1.6 g (6.2 mmol) of the product from stage D above and 4.0 g (12.4 mmol) of usedatabaseyou heated at a temperature of 60oC for 44 hours the Mixture is cooled to ambient temperature. Add 50 ml of 6N. hydrochloric acid and the mixture is heated for 1.5 h at testim diethyl ether and the aqueous layer was concentrated under vacuum. The remainder lyophilized and purified by ion exchange chromatography. The purified solid is heated under reflux in acetone for one hour. The solid is washed with acetone and simple gialinovym ether and dried under vacuum at a temperature of 80oC to obtain 1.0 g of the desired product, []D= -18,7(c= 1, N HCl), melting point 162-167oC (foam)1H NMR (D2O) of 3.57 (DD, J=13,0, 3.1 Hz, 1H), 3,44 (Shir. d, J=11,1 Hz, 1H) 2,96 (m, 3H), of 2.21 (m, 2H), 1,82 (d, J=14,2 Hz, 1H), 1,40 (m, 2H).

As noted above, the compound of the present invention is an antagonist of excitatory amino acid receptors. Therefore, another variant of implementation of the present invention is the method of locking the one or more excitatory amino acid receptors in mammals, which provides for the introduction to a mammal in need of reduced excitatory amino acid neurotransmission, pharmaceutically effective amounts of compounds in accordance with the present invention.

The term "pharmaceutically effective amount", as used herein, means an amount of compound of the present invention, which is able blokirovati with the present invention, will, of course, determined by specific circumstances accompanying the case, including the type of connection, the route of administration, the particular condition to be treated, and similar considerations. The connection can be introduced in a variety of ways, including oral, rectal, transdermal (through the skin), subcutaneous, intravenous, intramuscular or intranasal routes of administration. A typical daily dose is from 0.01 to 20 mg/kg, approximately, the active compounds of the present invention. Preferred daily doses of 0.05-10 mg/kg, ideally, about 0.1-5 mg/kg

It is shown that a number of physiological functions influenced by the excessive stimulation of excitatory amino acid neurotransmission. The compound of the present invention, it is believed, has the ability to treat a variety of disorders in mammals associated with this condition, including neurological disorders, such as convulsive disorders, such as epilepsy, stroke, anxiety, cerebral ischemia, muscular spasms, and neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease. Therefore, the present invention also provides methods is now receptors in mammals.

The following experiment carried out in order to show a better ability of the compounds of the present invention to invigorate reaction due to the stimulatory effect of amino acid agonists (substances with a means to receptors). Typical receptor substance is characterized by N-methyl-D-aspartic acid (NMDA)

Male mice Charles river line CF1 contain in the laboratory at least three days, then put 12 on the cage bedding on sawdust in transparent plastic boxes with lids wire mesh. Animals provide free access to food and water before the test.

Unless specified otherwise, the compound prepared in dimethyl sulfoxide (DMSO) and diluted to 5% solution of DMSO/ sterile water/ volume. The start dosing with 160 mg/kg If there is any significant activity, the dose of the test drug are divided into half up until you cannot detect any activity. The test compound is administered using vnutribruchinnah injection (i.p) 0,01 cm3/,

Plastics cells selected five mice injected with the test compound, after which the animal is owned absorption mice injected intraperitoneally with 200 mg/kg NMDA. This dose of NMDA receptors leads to the death of more than 95% of the animals treated with the control product. Twenty minutes after administration of NMDA animals register with regard to dead or alive. Data are given as the minimum effective dose (MED) to block NMDA-induced lethality. Protection against mortality corresponds to survival, at least three of the five animals. These tests are presented below in table.1.

Table 1.

NMDA-induced lethality in vivo

N Example of the test compound dose rate (mg/kg body weight)

1 5

For comparison, EDR known racemic compounds, CIS(-4-/(1(2)H-tetrazol-5-yl)methyl/-2-piperidinecarboxylic acid is 10 mg/kg Thus, one can see a more significant effect proposed by the applicant for the connection.

Connection in accordance with the present invention are preferably before the introduction. Therefore, another embodiment of the present invention is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.

We offer pharmaceutical compositions have known techniques to IP the Oia active ingredient is usually mixed with a carrier, or diluted by a carrier, or enclosed in a carrier, which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it can be solid, semi-solid, or liquid material which acts as a carrier, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, pellets, sachets, starch those capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectively solutions and sterile powders in the package.

Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, Arabic gum, calcifolic, alginates, tragakant, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl - and propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulgirujushchie with the present invention may be so, to provide fast, long-term (prolonged or delayed release of the active ingredient after administration to the patient using techniques well known in this field of knowledge.

Compositions of the present invention are preferably in the form of a uniform (standard) doses, with each dose contains about 5 to 500 mg, more often, about 25 to 300 mg, of the active ingredient. The term "standardized dosage" refers to physically discrete units suitable as standard dosages for humans and other mammals, each unit contains a predetermined quantity of the active substance, calculated to provide the desired therapeutic effect, in combination with a suitable pharmaceutical carrier.

The following examples of the preparation of a medicinal product are only illustrative and are not intended to limit the scope of the present invention.

Composition 1.

Hard gelatin capsules is obtained using the following ingredients (mg/capsule):

Example 1 250

starch, dried 200

magnesium stearate 10

Total 460 mg

The above ingredients is obtained using the following components (mg/tablet):

Example 1 250

cellulose, microcrystalline 400

silicon dioxide, fumigated 10

stearic acid 5

Total 665 mg

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

Part 3.

Aerosol solution is obtained using the following components (wt.):

Example 1 0,25

ethanol 29,75

the gas propellant 22 (Chlorodifluoromethane) 70,00

Total 100,00

The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to a temperature of 30oC and transferred to a filling device. The required amount is then applied to the stainless steel container and diluted with the rest of the propellant. Then to the container fasten the valve elements.

Part 4.

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

Example 1 60 mg

starch 45 mg

microcrystalline cellulose 35 mg

polyvinylpyrrolidone (as 10% solution in water) 4 mg

natrocarbonatite-starch 4.5 mg

magnesium stearate 0.5 mg

talc 1.0 mg

A total of 150 mg

The active ingredient, starch and cellulose are passed through a sieve with the CTE is Scam, which then pass through a sieve with holes N 14 U.S. standard. Thus obtained granules are dried at a temperature of 50oC and pass through a sieve with holes N 18 U.S. standard. Natrocarbonatite-starch, magnesium stearate and talc, previously passed through a sieve with holes N 60 U.S. standard, then added to the granules, and the resulting material after mixing compressed on a tablet machine to obtain tablets each weighing 150 mg

Part 5.

Capsules, each containing 80 mg medicines get the following:

Example 1 80 mg

starch 59 mg

microcrystalline cellulose 59 mg

magnesium stearate 2 mg

A total of 200 mg

The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a sieve with holes N 4 U.S. standard and fill them hard gelatin capsules in 200 mg

Part 6.

Suppositories, each containing 225 mg of active ingredient, can be obtained as follows:

Example 1 225 mg

saturated fatty acid glycerides 2,000 mg

Total 2225 mg.

The active ingredient is passed through a sieve with holes N 60 mill the material necessary heat. The mixture is then poured into a mold to manufacture suppositories having a nominal capacity of 2 g, and leave to cool.

Part 7.

Suspensions, each containing 50 mg of the drug per dose of 5 ml, was prepared as follows:

Example 1 50 mg

the sodium carboxymethyl cellulose 50 mg

syrup 1.25 ml

a solution of benzoic acid 0.10 ml

corrigent (flavouring substance) as you need

coloring matter how much you will need

purified water to volume, 5 ml

The drug is passed through a sieve with holes N 45 U.S. standard and mixed with the sodium carboxymethyl cellulose and syrup with the formation of a smooth paste. A solution of benzoic acid, corrigent and dye diluted with some water and add the paste with stirring. Then add water in an amount sufficient for the formation of the desired final volume.

Part 8.

Composition for internal injections can be obtained on the basis of the following components:

Example 1 100 mg

isotonic saline 1000 ml

The solution of the above ingredients is injected with an intensity of 1 ml per minute to a patient, kotoryy> 2. The pharmaceutical composition active antagonist of excitatory amino acid receptors, including the active ingredient and pharmaceutically acceptable carrier, characterized in that it contains as active ingredient the compound under item 1 in an amount of 5 to 500 mg per dose.

3. Connection on p. 1, showing the property antagonist of excitatory amino acid receptors.

 

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