Derivative chromone, the method of production thereof and pharmaceutical composition

 

(57) Abstract:

The invention relates to new derivatives of chromone General formula 1, in which ring a is unsubstituted or one-deputizing halogen, and where the ring is unsubstituted or substituted by one to four substituents selected from the group consisting of lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio or halogen, and their salts, also describes a method of production thereof and pharmaceutical composition based on compounds of the formula I, which has antagonistic activity against neirokinina 1. 9 C. and 3 h.p. f-crystals.

The invention relates to compounds of formula I,

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where ring A is unsubstituted or substituted, and ring B is unsubstituted or substituted. These compounds find valuable pharmacological properties and are the most effective, in particular as antagonists of neirokinina 1 or antagonists of substance P.

In particular the invention relates to compounds of formula I where ring A is unsubstituted or one-deputizing lower alkyl, lower alkoxyl, halogen, the nitro-group or trifluoromethyl, and where the ring B is unsubstituted or substituted by 1-4 for the IO, halogen, nitro, ceanography or trifloromethyl, and their salts, process for the preparation of these compounds, to pharmaceutical preparations containing these compounds, the use of these compounds for therapeutic treatment of humans or animals or for the preparation of pharmaceutical preparations.

Because of the claimed compounds have at least two optically active carbon atom, they can be represented, respectively, in the form of stereoisomers, mixtures of stereoisomers, as well as (mostly) pure geometric isomers of the compounds of the ethylene series. The proposed invention also includes the corresponding stereoisomer. The preferred way of compounds of formula I are presented in the form of geometric isomers of the compounds of the ethylene series, as reflected in the formula Ia:

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Hereinafter used General concepts, in order to avoid discrepancies, have the following meanings:

The term "lower" indicates that the corresponding groups and compounds contain from 1 to 7 and 7, preferably from 1 to 4 and 4 carbon atoms.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl or tx2">

Lowest arcoxia is, for example, methoxyl, ethoxyl, n-propyloxy, isopropoxy, n-butyloctyl, isobutoxy, secondary butyloctyl, tertiary butyloctyl or appropriate pentyloxy, hexyloxy or heptyloxy balance. Preferred is C1-C4-alkoxyl.

Halogen is, for example, fluorine, chlorine or bromine, however this may be, and iodine. Preferred is chlorine.

The compounds of formula I can be represented as salts, in particular salts used in pharmacology. Using the main centre piperidino rings can form acid salt of accession. As acid components are considered, for example, inorganic acids such as mineral acids, for example sulfuric acid, phosphoric acid, for example phosphoric acid, halogenation acid, for example hydrochloric acid, or strong organic carboxylic acids, as optionally substituted, for example, halogen lower alcancarao acid, for example acetic acid or triperoxonane acid, optionally unsaturated dibasic carboxylic acids, for example oxalic, malonic, succinic, the, Nikolaeva, lactic, malic, tartaric or citric acid, amino acids, for example aspartic or glutamic acid, or benzoic acid, or organic sulfonic acids, as optionally substituted, for example, halogen lower alcamovia sulfonic acids, for example methane acid, or optionally substituted, for example, lower alkyl akrilovye sulfonic acids, for example p-toluensulfonate. Also included are salts, not suitable for use in therapy, which can be used, for example, for the isolation or purification of free compounds of the formula I or their salts used in pharmacology. For therapeutic use are only those salts that are used in pharmacology, i.e., non-toxic salts, which is why they are most preferred.

The compounds of formula I, including their salts, are used in pharmacology and referred to hereinafter possess valuable pharmacological properties. They, in particular, act as antagonists neirokinina 1 (NK 1-antagonists) and therefore able to keep the painful symptoms that come among other things because of the release of substance P.

The respiratory tract is equipped with sensitive nerves, sometimesare sensitive nerves causes local release of neuropeptides in the lung. Released primarily substance P and neurokinin A, which causes an acute inflammatory reaction, called "neurogenic inflammation". This inflammatory response is accompanied mainly by the activation of NK receptor 1 and characterized, in particular, the expansion of blood vessels, the appearance of holes in microvessels, the formation of inflammatory leukocytes and excessive mucus discharge. This effect is caused by the expulsion of substance P, is a typical sign of asthma.

Pharmacological action of the compounds of the formula I is based, in particular, on antagonization NK receptor 1. The compounds of formula I are able, therefore, to suppress "neurogenic inflammation", as well as the compression of the bronchi caused by the action tachykinin.

Beneficial effects of the compounds of the formula I is confirmed by various tests conducted in the laboratory and in living organisms. Thus, they are effective, for example, in experiments investigating the bronchospasm Guinea pigs, using NK 1 with the parameter ED-50 from about 0.03 mg/kg oral, and substances used in the experiment, are given for 2, 4 or 24 hours before intravenous injection of 3.0 mg/kg [Sar9, Met(02)11]-substance P[= SarSP] . Due to delivery SarSP good efficiency for oral use, and unusually long duration.

As antagonists of receptors of NK 1 the compounds of formula I are useful in therapy in preventive therapy, treatment or diagnosis of a number of diseases, for example diseases of the upper and lower respiratory tract, such as bronchial asthma, allergic asthma, non-allergic asthma, allergic hypersensitivity and hypersecretion condition, such as chronic bronchitis and cystic fibrosis; pulmonary fibrosis resulting from various causes; diseases of the pulmonary and bronchial cycle, such as high blood pressure in the lung, angiogenesis, metastasis, diseases of the gastrointestinal tract as Crohn's disease, a disease hirshprung, diarrhea, a condition caused by malabsorption, inflammation; affective, traumatic or inflammatory disorders of the Central or peripheral nervous system such as depression, fear, migraine and other forms of headache, stroke, vomiting; diseases of the blood vessels, particularly vessels of the brain; diseases associated with microcirculation in various tissues, such as skin and eye diseases immunogen disease, in which the action of neurokinin, tachykinins and other substances in the pathogenesis, pathology and etiology.

Substance P is a non-Decapeptide natural origin of the family of tachykinins. It is produced in mammals and is valid from the pharmacological point of view as neuropeptide. Substance P plays a significant role in various diseases, such as States of pain, migraines and some Central nervous system disorders, such as fear, vomiting, schizophrenia and depression, as well as in inflammatory diseases such as rheumatoid arthritis, inflammation of the iris and conjunctivitis, also with certain disorders of the locomotor system as Parkinson's disease, diseases of the respiratory tract like asthma and chronic bronchitis, diseases of the gastrointestinal tract, such as ulcerative colitis and Crohn's disease, and hypertension.

The purpose of repeated efforts is the further development in the study area antagonists of substance P, for example, find the suitable antagonists of substance P with a broader spectrum of activity, which would have increased the asset and the ability to crystallization.

Extensive pharmacological studies have shown that the claimed compounds and their salts in the most preferred amounts are antagonists of substance P and thus suitable, in particular, for the treatment of diseases caused by substance P.

The effect of inhibition of the activity of substance P can confirm, for example as described below with the aid of testing techniques known to the expert. Such effects found in research both in laboratory conditions and in vivo. Thus, compounds of formula I are unexpectedly strongly suppressed, for example, communication3H-substance P in the retina of cattle in radioreceptor experience H. Bittiger, Ciba Foundatios Symposium 91 (1982) 196 to 199, with the parameter IC50from about 5 nM.

Furthermore, in experiments in vivo is hampered, for example, induced substance P education phosphoinositol in human cell astrocytomas. This gives the value of the IC50from about 1 nM. As a test model to prove this deceleration is suitable, for example, test method C. M. Lee and others, as described in the journal of Neurochem. 59 (1992) 406-414.

In the in their behavior. This effect may be hindered as a result of making a living body compounds of formula I for oral administration. As the test methodology used method Vassout, A. and others , presented at the Congress "Substance P and connectivity with peptides: cellular and molecular physiology", held in Worcester in 1990, there were obtained the values of the ED50from about 0.1 mg/kg p. O. Judging from these data, the compounds of formula I are very suitable for the treatment of diseases of the Central nervous system.

In contrast to the known prior to the present time of the NK antagonists 1 or substance P claimed compounds have clearly higher activity, in addition they reveal a significantly higher chemical stability, for example in the case of oxygen, improved ability to crystallizability, and improved biological possibility of oral administration.

Declared cooked antagonists of substance P in the formula I are suitable in accordance with this mainly for therapeutic treatment of these pathological phenomena.

In particular, the invention relates to compounds of formula I where ring A is unsubstituted or one-deputizing ", consisting of lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio, halogen, nitro and ceanography, and their salts, used in pharmacology.

Primarily the invention relates to compounds of formula I where ring A is unsubstituted or one-deputizing chlorine and where the ring B is unsubstituted or substituted by one or two substituents selected from the group consisting of hydroxyl, lower alkoxyl, chlorine and bromine, and their salts, used in pharmacology.

Primarily the invention relates to compounds of formula I where ring A is unsubstituted or one-deputizing chlorine and where the ring B is unsubstituted or one-deputizing chlorine or fluorine, and their salts, which have found their use in pharmacology.

As a sub-group of compounds of formula I are: (a) the compounds of formula I where ring A is unsubstituted or substituted in the 4 position by chlorine; (b) the compounds of formula I in which ring A is a 4-position substituted with chlorine; (c) the compounds of formula I in which ring B is a one-deputizing chlorine or fluorine; (d) the compounds of formula I in which ring B is unsubstituted.

The invention relates primarily to pre"ptx2">

The compounds of formula I can be obtained in a known manner, according to which, for example,

a) a compound of formula IIa,

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in which rings A and B have data in the formula I value, replace the compound of formula IIb,

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where Q1denote optionally esterified with the formation of a simple ester of the hydroxyl as hydroxyl, lower alkoxy or optionally substituted phenoxy, or capable of responding esterified with the formation of ester hydroxyl as halogen, in particular chlorine, or a residue of the formula,

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or its salt; or

b) the compound of the formula IIIa,

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in which ring A is given in formula I is the value substituted compound of formula IIIb,

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in which ring B is given in the formula I is, and Q1denotes optionally esterified with the formation of a simple ester of the hydroxyl as hydroxyl, lower alkoxy or optionally substituted phenoxy, or capable of responding esterified with the formation of ester hydroxyl as halogen, in particular chlorine, or a residue of the formula,

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or its salt;

and, optionally, a compound of the formula I is converted into another compound of formula I, is obtained free compound of formula I with salt-forming properties is converted into salt, and/or, if desired, the mixture of stereoisomers and geometric isomers of compounds of the ethylene series is divided into individual stereoisomers and geometric isomers of compounds of the ethylene series.

Salts of starting materials, having at least one basic centre are, for example of the formula IIa or IIIa, are the corresponding acid salts of accession, while the salt of the source substances having an acid group, for example of the formula IIb or IIIb presented as salts with bases.

In the following, more detailed description of how the rings A and B have data in the formula I values if not given anything else.

Substitution shown in the embodiments hereinafter, are carried out in a known manner, for example without or usually in the presence of a suitable solvent or diluent or a mixture thereof, and, if required, with cooling, at room temperature or while heating, for example in a temperature range from approximately -80oC to the boiling temperature of the environment in which the reaction occurs, preferably from about -10oC to +200oC, and, if necessary, in a closed vessel, under pressure, in an atmosphere of inert gas and/or under anhydrous conditions.

The condensation can be carried out in the presence of a conventional condensing means. To the usual condensing means include, for example, diimide carbonic acid, for example diethyl-, dipropyl-, N-ethyl-N'-(3-dimethylaminopropyl)-imide of carbonic acid and, in particular, dicyclohexylamine carbonic acid, also suitable carbonyl compounds, for example carbonyldiimidazole, the compounds 1,2-oxazole, such as 3'-sulfonate-2-ethyl-5-phenyl-1,2-oxazole and perchlorate 2-critic. -butyl-5-methylisoxazole or a suitable acylamino connection, for example 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline also active derivatives of phosphoric acid, for example diphenylphosphoryl, diethylphosphoramidite, phenyl-N-phenylphosphonothioic, chloride bis-(2-oxo-3-oxazolidinyl)-phosphinic acid or hexaphosphate 1 benzothiazolinone-Tris-(dimethylamino)-phosphonium.

Optionally add an organic base, such as tri-lower alkylamine with bulky residues such as ethyl is but N-methyl-morpholine.

Condensation galodamadruga carboxylic acids, for example with an appropriate amine, can also be performed in the presence of a suitable base without adding suitable koulimousi components.

The condensation is carried out mainly in an inert, polar, apothecom, preferably anhydrous solvent or mixture of solvents, for example in amide carboxylic acids, for example formamide or dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, a cyclic simple ether, for example tetrahydrofuran, complex ether such as ethyl ether, acetic acid, or a nitrile, for example acetonitrile, or in mixtures, optionally at reduced or elevated temperature, for example in a temperature range from approximately -40 to +100oC, preferably from approximately -10 to +50oC, and, if necessary, in the atmosphere of inert gas, such as nitrogen atmosphere.

Capable of reacting derivatives of the acids can also be formed at the right place.

Starting materials of formula IIb and IIIb are known and can be obtained in a known manner.

The compounds of formula II means, for example, lower alkyl or lower alkyl substituted by phenyl. Its N-alkylate, for example, by the reaction of the currency with the lower alkoxy-halogen-methane, as ethoxy-harmatan, in the presence of a base. Thus obtained compound of the formula (IIId),

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where Q4means, for example, lower alkyl, process nitrile, for example acetonitrile, in the presence of a strong acid such as chlorosulfonic acid. In the thus obtained compound of formula IIIe

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cleaved group-C(=O)-OO3as a result of processing a strong acid, such as Hydrobromic acid.

For connection with the pure enantiomers in the thus obtained compound of formula IIIf

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acelerou secondary amino group of the optically active compound as the corresponding O-acylated-hydroxycarbonate acid or able to respond derived, for example, dichlorohydrin O-acetyl-(+)almond acid, and so available mixture of geometric isomers of the compounds of the ethylene series split in a known manner, for example by chromatography. After removal of both N-atilovykh groups, for example by the method of acid hydrolysis, nab the formula IIIg temporarily secured in a known manner, for example, by exchange reaction with benzaldehyde. After that enter the group, 3,5-bistrifluormethylbenzene, for example, as described for the variant of method (a), by copulation with a compound of formula IIb, and the protective group 4-amino otscheplaut, for example, by treatment with acid, such as hydrochloric acid, and thus receive the corresponding compound of formula IIIa.

The compounds of formula IIa can be obtained in a known manner. For example, are based on the compound of formula IIIg and copolyol it, for example, as described for the variant of method (b), with the compound of the formula IIIb in the presence of an appropriate reagent and injected thus appropriate Alloway group. So obtain the corresponding compound of formula IIa.

The salts can be converted in a known manner into the free compounds, for example, by treatment with base, such as alkali metal hydroxide, metal carbonate or metal bicarbonate, or ammonia, or other above-mentioned salt-forming base or acid, such as mineral acid, for example hydrogen chloride, or other above-mentioned salt-forming acid.

The salts may be converted to known the such as sodium salt, barium or silver, another acid in a suitable solvent in which the resulting inorganic salt is insoluble and thus falls from the reaction equilibrium, and basic salts result in the release of the free acid and the new salt deposits.

The compounds of formula I, including their salts, can also be obtained in the form of hydrates or include used for crystallization solvent.

Because of the close relationships between the new compounds in free form and in the form of their salts, the free compounds and their salts according to the meaning and appropriate should be understood optionally also the corresponding salts or free compounds.

The mixture of geometric isomers of the compounds of the ethylene series and mixtures of racemates can be split in a known manner by reason of the physicochemical differences of the components in pure geometric isomers of the compounds of the ethylene series, or the racemates, for example by chromatographic methods and/or method of fractional crystallization.

Resulting racemates can, in addition, known methods of decomposing optical isomers, for example by using method precrystallization isomers of the compounds of the ethylene series, or the racemate on optically active auxiliary compound, for example respectively contained in the compounds of the formula I acid groups, groups with the main character or functionally changing groups on optically active acid, base or an optically active alcohol, a mixture of geometrically isomeric ethylene-number of salts or functional derivatives such as esters, separating them on the geometric isomers of the compounds of the ethylene series, from which you can select the desired enantiomer in the usual way. Suitable for these purposes, bases, acids or alcohols are, for example, optically active alkaloid bases, such as strychnine, cinchonine or brucine, or D - or L-(1-phenyl)ethylamine, 3-pipecolic, ephedrine, amphetamine and similar available for artificial by the Foundation, optically active carboxylic acids or sulfonic acids, such as Hinn acid or D - or L-tartaric acid, D - or L-di-o-toluylene acid, D - or L-malic acid, D - or L-mandelic acid or D - or L-sulfokamforna acid, or optically active alcohols, as borneol or D - or L-(1-phenyl)ethanol.

The invention relates also to those forms of the process, according to which we take as a basis the connection poluchennogo substance in the form of a salt or receive, in particular, under the reaction conditions.

New original substances, specially selected to obtain the claimed compounds, in particular the choice of the starting substances, leading to the formation of compounds of formula I above as the most preferred methods for their preparation and their use as intermediates is the subject of the invention.

The new compounds of formula I can be used, for example, in the form of pharmaceutical preparations containing an effective therapeutic amount of the active substance, optionally in combination with inorganic or organic, solid or liquid, used in pharmaceutical carriers suitable for intestinal, for example oral, or parenteral administration. Thus, the use of tablets or gelatin capsules containing a biologically active substance in combination with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or lubricating substances, such as silicon dioxide, talc, stearic acid or its salts, such as magnesium stearate or calcium, and/or polyethylene glycol. Tablets may also contain binders, for example silicate minicells, carboxymethylcellulose sodium and/or polyvinylpyrrolidone, and, if desired, bursting substances, for example starches, agar, alginic acid or its salt, for example sodium alginate, and/or effervescent mixtures, or absorbing substances, colorants, flavorings and sweeteners. In addition, the new compounds of formula I can be used as drugs parenteral administration or in the form of tinctures. Such solutions are mainly isotonic aqueous solutions or suspensions, and they can be prepared directly before use, for example if we are talking about lyophilizate containing biologically active substance alone or in combination with a carrier, for example mannitol. The pharmaceutical preparations may be sterile and/or contain auxiliary substances such as preservatives, stabilizers, wetting agents and/or emulsifiers, solutionsee agents, salts, regulating the osmotic pressure, and/or buffer solutions. The proposed pharmaceutical preparations containing, if desired, other pharmacologically effective substances, get in a known manner, for example by using traditional methods of mixing, granulating, drazhirovanija, dissolve the s to approximately 100% active substance.

The invention relates also to the use of compounds of the formula I, preferably in the form of pharmaceutical preparations. The dosage may depend on various factors such as route of administration, species, age and/or individual condition. Daily dose in oral introduction is to warm-blooded from about 0.25 to 10 mg/kg for body weight of about 70 kg, preferably from about 20 to 500 mg.

The following examples serve as illustrations of the invention: temperature given in degrees Celsius, the pressure in mbar. FD-MS=mass spectroscopy field desorption ("Field Desorption Spectroscopy".

Example 1: (2R, 4S)-N-[1-(3,5-bistritei-benzoyl)-2-(4 - chlorbenzyl)-piperidine-4-yl]-4-oxo-4H-1-benzopyran-2-carboxamide

To the solution prepared from 4,36 g (2R,4S)-4-amino-1-(3,5-bistritei-benzoyl)-2-(4-chlorbenzyl)- piperidine and 200 ml of methylene chloride, add 3.77 ml of triethylamine and 2.35 g of acid chloride of 4-oxo-4H-1-benzopyran-2-carboxylic acid (obtained from the corresponding carboxylic acid, for example, the company Sigma, the exchange reaction with chloride tiomila) and stirred for 4 hours at a temperature of 20o. The reaction mixture was washed with aqueous solution of 1N hydrochloric kilot critic. simple butyl methyl ether/hexane/methylene chloride. Get the target compound in the form of colorless crystals with so pl. 211-212o.

[]2D0= 3,7 2,6 (c=0,382 methanol).

The original connection can be obtained as follows:

a) methyl ester of N-[1-(4-chloro-benzyl)-but-3-enyl]-N-ethoxymethyl-carbamino acid

A suspension of 10.0 g of sodium hydride (80% in mineral oil, 333 mmol) in dry tetrahydrofuran (THF) in an argon atmosphere boiled with reverse flow. Within hours added dropwise a solution prepared from of 60.5 g (238 mmol) of a compound methyl ester [1-(4-chloro-benzyl)-but-3-enyl]-carbamino acid (McCarty FJ et al., J. Med. Chem. 1968, 11(3), 534) and 50 ml of dry THF. After that, the mixture is boiled with reverse flow for a further 2 hours and leave until gas evolution. The mixture is cooled to 0oC and added dropwise simple chloromethylation ether, so that the reaction temperature did not exceed 5oC. then slowly heated to 25oC and stirred for 12 hours. Excess sodium hydride is carefully removed by adding 1 ml of water before you add it to a larger number. The phases are separated, and the aqueous phase extracted with simple critic. butylmethylamine is placed, the product is distilled under a pressure of 0.1 mbar and it has a boiling point of 120-125oC. DC: ethyl ester of acetic acid/hexane (1:6) Rf= 0,34, FD-MS:M+=311 (313).

b) methyl ester (2Rx4Sx)-4-acetylamino-2-(4-chlorbenzyl)-piperidine-1-carboxylic acid

of 20.6 ml (308 mmol) of chlorosulfonic acid is placed at a temperature of 40oC in 500 ml of acetonitrile. Added dropwise a solution prepared from 48,0 g (154 mmole) of a compound methyl ester N-[1-(4-chloro-benzyl)-but-3-enyl] -N-ethoxymethyl-carbamino acid and 50 ml of acetonitrile, so that the temperature of the reaction did not rise above -10oC. and Then stirred for 20 minutes at a temperature of -15oC before adding 370 ml of 2N sodium hydroxide solution and 100 ml of 10% aqueous solution of sodium bicarbonate. The phases are separated, and the aqueous phase is extracted twice more with toluene. The combined organic phases are dried with sodium sulfate. The crude product is crystallized from toluene and obtain the target compound in the form of white crystals with so pl. 169-170oC. DC: methylene chloride/methanol/conc. ammonia (90:9:1) Rf= 0,42, FD-MS:M+= 325.

c) (2Rx4SxN-[2-(4-chloro-benzyl)-piperidine-4-yl]- ndimethylacetamide:

To 30.0 g (92.3 mmol) of a compound methyl ester (2Rx4Sx)-4-acetylamino-is. After 16 hours the mixture was added 200 ml of water and washed twice with toluene. The aqueous phase add alkaline and extracted twice with ethyl ether, acetic acid. The organic phase is dried with potassium carbonate and evaporated in a rotary evaporator. The target compound crystallized as the hydrochloride from ethanol/ethyl acetate. So pl. 288-289oC. DC: methylene chloride/methanol/Koh. ammonia (90:9:1) Rf=0,17, FD-MS:(M+1)+= 267.

d) complex of 2-[4-acetylamino-2-(4-chloro-benzyl)-piperidine-1-yl]-2 - oxo-1-phenyl-ethyl ester (2'S,2R,4S)-acetic acid

Racemic N-[2-(4-chloro-benzyl)-piperidine-4-yl]-ndimethylacetamide hydrochloride (20.5 g, 67.6 mmol) was placed under intensive stirring at 0oC in 34 ml of 2N sodium hydroxide solution, 150 ml of 10% aqueous solution of sodium bicarbonate and 50 ml of methylene chloride. Within 1 hour added dropwise 14.9 g (70 mmol) of the chloride of S(+)-O-acetyl-almond acid (Pracejus G, Ann., 1959, 622, 10). Thereafter stirred for one hour at a temperature of +4oC. the Phases are separated, the organic phase is dried with sodium sulfate and evaporated in a rotary evaporator. The target compound is isolated in the form of pure geometric isomer of the ethylene series after two crystallization of CR (9:1) Rf= 0,65, FD-MS:M+=443. [alpha]D=+77,5o(c=1, methylene chloride).

Royal solutions contain mainly non-crystalline geometric isomer of the compounds of the ethylene series (2'S, 2S, 4R)[2-(4-chloro-benzyl)-1-(acetoxy-phenyl-acetyl)-piperidine-4-yl] - ndimethylacetamide, DC: methylene chloride/isopropanol (9:1) Rf= 0,70.

e) (2R,4S)-4-amino-1-(3,5-bistritei-benzoyl)-2-(4-chlorbenzyl)- piperidine:

with 37.4 g (84.5 mmol) of complex 2-[4-acetylamino-2-(4-chloro-benzyl)- piperidine-1-yl] -2-oxo-1-phenyl-ethyl ester (2'S,2R,4S)-acetic acid is boiled for 2 days with reverse flow in 370 ml of 6N hydrochloric acid. After cooling, the mixture give alkaline by adding solid sodium hydroxide, and extracted with methylene chloride. The combined organic phases are dried with potassium carbonate and evaporated in a rotary evaporator. To the residue, representing almost pure (2R,4S)-2-(4-chloro-benzyl)-piperidine-4-amine (19,0 , 84.5 mmol, 100%), was added to 8.5 ml (84.5 mmol) of benzaldehyde and double-concentrated in a rotary evaporator with 150 ml of toluene. The oily residue is placed in 180 ml of methylene chloride and 15.3 ml (110 mmol) of triethylamine and cooled to 10oC. for 15 minutes and added dropwise to 25.7 g (92.9 mmol) bestreviews 250 ml of 1N hydrochloric acid, and the methylene chloride is removed in a rotary evaporator under reduced pressure. Add hexane and ethanol until then, until the formation of two homogeneous phases. After separation of the organic phase washed with water until you remove all of the benzaldehyde. The mixture give alkaline by adding solid sodium hydroxide and re-extracted with methylene chloride. The organic phase is dried with sodium sulfate and concentrated in a rotary evaporator. Crystallization from simple critic. butyl methyl ether/ hexane gives the target compound in the form of white crystals. So pl. 79-81oC. DC: methylene chloride/methanol/conc. ammonia (90:9: 1) Rf=0,21, FD-MS: (M+1)+= 465.

[alpha]D= -127o(c=1, methylene chloride).

In a similar manner as described in example 1 can also be obtained the following compounds. The receipt for this purpose the corresponding starting compound, (2R, 4S)-4-amino-1-(3,5-bistritei-benzoyl)-2-benzyl-piperidine described in EP-A-532456, example 38.

Example 1/1: (2R, 4S)-N-[1-(3,5-bistritei-benzoyl)-2-benzyl-piperidine-4-yl] -4-oxo-4H-1 - benzopyran-2-carboxamide, so pl. 107-108o, []20D/= 18,3 2,6 (c=0,388, methanol).

Example 1/2: (2R,4S)-N-[1-(3,5-UB>D0=21,5 to 2.5 (c=0,40, methanol).

Example 1/3: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2 - benzyl-piperidine-4-yl] -7-methoxy-4-oxo-4H-1-benzopyran-2-carboxamide, so pl. 190-192o, []2D0=25,7 2,3 (c=0,44, methanol).

Example 1/4: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-benzyl - piperidine-4-yl]-7-methylthio-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 1/5: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-benzyl - piperidine-4-yl]-6-methoxy-4-oxo-4H-1-benzopyran-2-carboxamide,

Example 1/6: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-benzyl - piperidine-4-yl]-6-chloro-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 1/7: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-benzyl - piperidine-4-yl]-6-bromo-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 1/8: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-benzyl - piperidine-4-yl]-6-fluoro-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 1/9: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-benzyl - piperidine-4-yl]-6-methyl-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 1/10: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-benzyl - piperidine-4-yl]-6-cyano-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 1/11: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-benzyl - piperidine-4-yl]-6-nitro-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 1/13: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-benzyl - piperidine-4-yl]-7-bromo-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 1/14: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-benzyl - piperidine-4-yl]-7-methyl-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 1/15: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-benzyl - piperidine-4-yl]-7-nitro-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 1/16: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-benzyl - piperidine-4-yl]-6,7-dimethoxy-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 2: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-benzyl - piperidine-4-yl]-7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxamide.

To the solution prepared from a to 0.127 g of (2R,4S)-4-amino-1-(3,5 - bistritei-benzoyl)-2-benzyl-piperidine and 3.1 ml of methylene chloride, add 0,038 g of 4-dimethylaminopyridine, 0,059 g of the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethyl-diimide carbonic acid and 0,064 g of 7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid in 2 ml of methylene chloride/ dimethylformamide (1: 1) and stirred for 24 hours at a temperature of 20oC. the Reaction mixture is evaporated and the residue is separated with silica gel using methylene chloride/methanol (19:1). Thereby obtaining the target compound in the form of powder swelcom, as described in example 2, we can obtain the following connection:

Example 2/1: (2R, 4S)-N-[1-(3,5-bistritei-benzoyl)-2-benzyl-piperidine-4-yl] -6-bromo-7 - hydroxy-4-oxo-4H-1-benzopyran-2-carboxamide. So pl. 173-174o.

Example 3: in a Similar manner as described in example 1 from (2R, 4S)-4-amino-(3,5-bistritei-benzoyl)-2-(4-Chlorobenzyl)-piperidine (example 1e), we can obtain the following connections:

Example 3/1: (2R, 4S)-N-[1-(3,5-bistritei-benzoyl)-2-(4 - chlorbenzyl)-piperidine-4-yl] -7-chloro-4-oxo-4H-1-benzopyran-2-carboxamide. So pl. 218-220o, []2D0=31,5 2,0 (c=0,50, methanol).

Example 3/1: (2R, 4S)-N-[1-(3,5-bistritei-benzoyl)-2-(4 - chlorbenzyl)-piperidine-4-yl] -7-methoxy-4-oxo-4H-1-benzopyran-2 - carboxamide. So pl. 198-200o, []2D0= 29,72,2 (c = 0.45, and methanol).

Example 3/3: (2R, 4S)-N-[1-(3,5-bistritei-benzoyl)-2-(4 - chlorbenzyl)-piperidine-4-yl]-7-methylthio-4-oxo-4H-1-benzopyran-2 - carboxamide. So pl. 137-140oC []2D0=20,8 of 2.8 (c=0,355, methanol).

Example 3/4: (2R,4S)-N-[3,5-bistritei-benzoyl)-2-(4-chlorbenzyl - piperidine-4-yl]-6-methoxy-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 3/5: (2R, 4S)-N-[1-(3,5-bistritei-benzoyl)-2-(4 - chlorbenzyl)-piperidine-4-yl]-6-chloro-4-oxo-4h-4-yl]-6-bromo-4H-1-benzopyran-2-carboxamide.

Example 3/7: (2R, 4S)-N-[1-(3,5-bistritei-benzoyl)-2-(4 - chlorbenzyl)-piperidine-4-yl] -6-fluoro-4-oxo-4H-1-benzopyran-2-carboxamide. So pl. 215-218o, Rf(ethyl ester of acetic acid/hexane 4:1) = 0,58. Required for use as a starting material, the acid chloride of the acid, acid chloride 6-fluoro-4-oxo-4H-1 - benzopyran-2-carboxylic acid, is described, for example, in chemical abstracts: 96: 52132w or 88:106066w and has CASper. N 65843-87-0.

Example 3/8: (2R, 4S)-N-[1-(3,5-bistritei-benzoyl)-2-(4 - chlorbenzyl)-piperidine-4-yl] -6-methyl-4-oxo-4H-1-benzopyran-2-carboxamide. So pl. 240-241o, Rf(ethyl ester of acetic acid/hexane 4:1) = 0,65.

Example 3/9: (2R, 4S)-N-[1-(3,5-bistritei-benzoyl)-2-(4 - chlorbenzyl)-piperidine-4-yl]-6-cyano-4-oxo-4H-1-benzopyran-2 - carboxamide.

Example 3/10: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-(4 - chlorbenzyl)-piperidine-4-yl]-6-nitro-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 3/11: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-(4 - chlorbenzyl)-piperidine-4-yl]-7-fluoro-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 3/12: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-(4 - chlorbenzyl)-piperidine-4-yl]-7-bromo-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 3/13: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-(4 - chlorin-benzoyl)-2-(4 - chlorbenzyl)-piperidine-4-yl]-7-nitro-4-oxo-4H-1-benzopyran-2-carboxamide.

Example 3/15: (2R,4S)-N-[1-(3,5-bistritei-benzoyl)-2-(4 - chlorbenzyl)-piperidine-4-yl]-6,7-dimethoxy-4-oxo-4H-1-benzopyran-2 - carboxamide.

Example 4: Tablets, each containing 50 mg of biologically active substances can be prepared as follows:

Composition (10000 tablets)

Biologically active substance - 500.0 g

Lactose - 500.0 g

Potato starch - 352,0 g

Gelatin - 8.0 g

Talc - 60,0

Magnesium stearate - 10.0 g

The silicon dioxide (viscozisers.) - 20,0 g

Ethanol - Sufficient

The biologically active substance is mixed with the lactose and 292 g of potato starch, the mixture is moistened with a solution of gelatin in ethanol and granularit through a sieve. After drying, mix the remainder of the potato starch, magnesium stearate, talc and silicon dioxide and the mixture is pressed into tablets, each of which weighs 145,0 mg and contains 50.0 mg of biologically active substances. If desired, tablets may be the dividing notches for finer dosage.

Example 5: Lacquered tablets, each containing 100 mg of biologically active substances can be prepared as follows:

Composition (for 1000 lacquered tablets)

Biologically active substances is the Hypromellose - of 2.36 g

Shellac - 0.64 g

Water - Enough

Methylene chloride is a Sufficient amount of

Prepare a mixture of the biologically active substance, lactose and 40 g of corn starch and moisten the paste prepared from 15 g of corn starch and water (with heating), and then granularit. The granulate is dried, add the remainder of the corn starch, the talc and calcium stearate and mixed with the granules. The mixture is pressed into tablets, each weighing 280 mg, and varnished with a solution of hydroxypropylmethylcellulose and the shellac in methylene chloride; final weight of the lacquered tablets 283 mg.

Example 6: Compound gelatin capsules, each containing 100 mg of biologically active substances can be prepared, for example, as follows:

Composition (for 1000 capsules)

Biologically active substance 100.0 g

Lactose - 250,0 g

Microcrystalline cellulose - 30,0 g

Sodium dodecyl sulfate - 2.0 grams

Magnesium stearate - 8.0 g

Sodium lauryl sulfate is passed through a sieve with apertures of 0.2 mm and added to liofilizirovannom biologically active substance. Both components are thoroughly mixed. Then add the first lactose, missed the hole sizes of 0.9 mm. Then again thoroughly stirred for 10 minutes. Finally, add magnesium stearate, passed through a sieve with holes of 0.8 mm in three minutes, during which was further mixing, gelatine capsules (size 0) was filled with the obtained composition (390 mg).

Example 7: Suspension for inhalation containing gas-forming substance and 0.1 weight percent of a biologically active substance.

Composition - Weight percent

Biologically active ingredient, micronized - 0,1

Sarbatorile - 0,5

Gas-forming substance a (trichlorotrifluoroethane) - 4,4

Gas-forming substance B (DICHLORODIFLUOROMETHANE and 1,2-dichlorotetrafluoroethane) Respectively and 15,0 80,0

The biologically active substance is suspended in the conditions preventing ingress of moisture, using a conventional homogenizer with the addition of sorbitrate in trichlorotrifluoroethane and the suspension is placed in an aerosol container provided with a dispensing valve. Capacity clog the pressure of the fill gas-forming substance B.

The data of in vivo tests on the example compounds 3/7 by well-known methods, described in detail by Lundberg with TCS. in PNAS USA, so 80, pp. 1120-1124.

The General mechanism of pharmacological action described earlier, where, in particular, it conducted laboratory studies on animals, such as Guinea pigs. Thus, the braking effect of the activity of substance P was confirmed using known testing methods. It was unexpectedly found that by using the compounds of formula I strongly suppressed, for example, communication3H-substance P receptor neirokinina 1.

The compound from example 3/7 in this experience had IC50= 1,68 + of 0.24 nM, which clearly demonstrates that the representative compounds of the present invention is an antagonist neirokinina 1.

1. Derivative chromone formula I

< / BR>
in which ring a is unsubstituted or one-deputizing halogen and where the ring is unsubstituted or substituted by one to four substituents selected from the group consisting of lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio or halogen, and their salts.

2. The compound of formula I under item 1, in which ring a is unsubstituted or odnozamesheng group, consisting of lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio or halogen, and their salts used for preparation of medicines.

3. The compound of formula I under item 1, in which ring a is unsubstituted or one-deputizing chlorine and in which the ring is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of hydroxyl, lower alkoxyl, chlorine and bromine, and their salts used for preparation of medicines.

4. The compound of formula I under item 1, in which ring a is unsubstituted or one-deputizing chlorine and in which the ring is unsubstituted or one-deputizing chlorine or fluorine, and their salts used for preparation of medicines.

5. The compounds of formula I according to one of paragraphs.1 to 4, and the compounds of formula I are presented in the form of geometric isomers of the compounds of the ethylene series, as it is given in the formula Ia

< / BR>
6. (2R, 4S)-N-[1-(3,5-bistrifluormethylbenzene)-2-(4-chlorbenzyl)-piperidine-4-yl] -4-oxo-4H-1-benzopyran-2-carboxamid under item 1 or its salt used to prepare medicines.

7. (2R,4S)-N-[1-(3,5-bistrifluormethylbenzene)-2-benzylpiperidine-4-yl]-4-S="ptx2">

8. (2R, 4S)-N-[1-(3,5-bistrifluormethylbenzene)-2-(4-chlorbenzyl)-piperidine-4-yl] -6-fluoro-4-oxo-4H-1-benzopyran-2-carboxamid under item 1 or its salt used to prepare medicines.

9. Pharmaceutical drugs with antagonistic against neirokinina I and containing the connection at one PM.1 - 8 and at least one substance carrier.

10. Connection at one PM. 1 - 8, which has antagonistic activity against neirokinina I.

11. Connection at one PM.1 - 8 as an active ingredient to obtain a therapeutic agent for treating diseases that respond to inhibition of the activity of the receptor 1 PCS.

12. The method of obtaining the compounds of formula I on p. 1, characterized in that the compound of formula IIIA

< / BR>
in which ring a has given in the formula I is,

subjected to interaction with the compound of the formula IIIb

< / BR>
in which the ring is given in formula I value and Q1denotes optionally esterified with the formation of simple ether hydroxyl, such as lower alkoxygroup or optionally substituted fenoxaprop, or reactive R>
or its salt, and, optionally, the compound of formula I is transferred to another compound of formula I, and/or, if desired, the obtained Sol was transferred into the free compound or into another salt, and/or, if desired, the obtained free compound of formula I with salt-forming properties transferred to salt, and/or, if desired, the mixture of stereoisomers and geometric isomers of compounds of the ethylene series is divided into individual stereoisomers and geometric isomers of compounds of the ethylene series.

 

Same patents:

The invention relates to new derivatives of amino(thio)ethers of the formula I

< / BR>
where X represents oxygen, sulfur, sulfinil, sulfonyl or, if R0and R1together are not alkalinous chain with 1 to 3 atoms, CH2:

Z represents -(CH2)n1-(CHA)n2-(CH2)n3and

n1 = 0, 1, 2 or 3,

n2 = 0 or 1,

n3 = 0, 1, 3 or 3, provided that

n1 + n2 + n3 < 4;

R0represents hydrogen or A;

R1represents hydrogen, A, OA, phenoxy, Ph, OH, F, Cl, Br, CN, CF3, COOH, COOA, acyloxy with 1-4 carbon atoms, carboxamido, -CHNH2, -CH2NHA, -CH2NA2,

-CH2NHAc, -CH2NHSO2CH3,

or

R0and R1together represent alkylenes chain with 1 to 3 carbon atoms or alkenylamine chain with 2 to 3 carbon atoms;

R2represents hydrogen, A, Ac, or-CH2-R4;

R3represents-CH2-R4or-CHA-R4;

R4is a Ph, 2-, 3 - or 4-pyridyl (unsubstituted or monosubstituted R5) or thiophene (unsubstituted, mono - or disubstituted by A, OA, OH, F, Cl, Br, CN and/or CF3or the other what it is, di-, tri-, Tetra-, or pentamidine F, CF3partially or fully fluorinated A, A and/or OA;

R6, R7, R8and R9each independently represents H, A, OA, phenoxy, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NHA, NA2, Ac, Ph, cycloalkyl c 3-7 carbon atoms, -CH2NH2, -CH2NHA, -CH2NA2, -CH2N HAC or-CH2NHSO2CH3or two coming together constitute the remainder alkylenes chain with 3-4 carbon atoms, and/or R1and R6together predstavljaet a chain with 3 or 4 carbon atoms;

A represents alkyl with 1-6 carbon atoms;

Ac is alkanoyl with 1-10 carbon atoms or aroyl with 7 to 11 carbon atoms;

Ph represents phenyl (unsubstituted or substituted R5, 2-, 3 - or 4-pyridium or phenoxyl group);

and physiologically acceptable salts, their derivatives

The invention relates to new derivatives of phenyl-oxo-alkyl-(4-piperidinyl)benzoate of formula I, their N-oxide forms, salts and steric isomer forms, where R1- halogen, R2is hydrogen, R3- C1-6-alkyl, or R2and R3form together a bivalent radical of the formula -(CH2)2- or -(CH2)3-, Alk-C1-6-alcander, R4is hydrogen or C1-6-alkoxy, R5, R6and R7is hydrogen, halogen, C1-6-alkyl, C1-6-alkyloxy or R5and R6taken together , form a bivalent radical of the formula-NR8-C(O)-NR9- or-NH-C(NH-R10)=N-, where R8and R9is hydrogen, C1-6-alkyl, R10is hydrogen, C1-6-alkylsulphonyl, C1-6-allyloxycarbonyl

The invention relates to new N-substituted piperidinylmethyl f-ly I, their N-oxide forms, isomers, and salts, where R1- halogen, C1-6alkylsulfonamides And divalent radical-CH2-CH2; -CH2-CH2-CH2- or-CH=CH-; R2is hydrogen or C1-6alkyloxy; L is a radical of formula-Alk-R4, -Alk-OR5, -Alk-NR6R7; Alk-C1-12alcander; R4is hydrogen, cyano, C1-6alkylsulphonyl,1-6allyloxycarbonyl, etc

The invention relates to substituted azetidinone General formula I listed in the description

The invention relates to certain CIS - and TRANS-benzopyrane having substituted benzamide in position C-4, and to their use for the treatment and/or prevention (prophylaxis) of certain CNS disorders

The invention relates to new derivatives of (R)-(-)-methylphenylacetonitrile formula I, where R is a hydrocarbon residue with the number of C-atoms to 5, with ZNS activity and inhibiting TNF-product, and the way they are received, namely, that the racemate derived methylphenylacetonitrile together with optically active auxiliary substance is transferred into the mixture of diastereomers and then separating the optically active auxiliary substance

The invention relates to new nitrogen-containing heterocyclic compounds with valuable biological properties, in particular to new derivatives of 1,4-dihydropyridines with a cyclic bridge in positions 1,2, having biological activity

The invention relates to compounds of General formula I

< / BR>
in which X represents a hydrogen atom or halogen, (C1-C3)alkyl group, one or two (C1-C3)alkoxy group, or triptorelin group, Y is a hydrogen atom or halogen, (C1-C3)alkyl or (C1-C3)alkoxygroup, R represents a hydroxy group, a methoxy group, or a group of the General formula NR2R3in which R2and R3each independently represents a hydrogen atom, (C1-C4)alkyl group, 2-methoxyaniline group, 3-methoxyaniline group, 3-aminopropyl group, group 2-(dimethylamino)ethyl group, 3-(dimethylamino)propyl or 2-piperidine-2-retil, or R2and R3form together with the nitrogen atom to which they are connected, morpholine, pyrolidine or pieperazinove ring which may have in position 4 Deputy in the form of a methyl group or groups (1,1-dimethylmethoxy)carbonyl, in the form of free bases or salts formed by the addition of acid

The invention relates to the chemistry of biologically active compounds, selectively blocking M-holinoreaktivnye and have a weak inhibitory effect on the Central nervous system (CNS)

The invention relates to new derivatives of amino(thio)ethers of the formula I

< / BR>
where X represents oxygen, sulfur, sulfinil, sulfonyl or, if R0and R1together are not alkalinous chain with 1 to 3 atoms, CH2:

Z represents -(CH2)n1-(CHA)n2-(CH2)n3and

n1 = 0, 1, 2 or 3,

n2 = 0 or 1,

n3 = 0, 1, 3 or 3, provided that

n1 + n2 + n3 < 4;

R0represents hydrogen or A;

R1represents hydrogen, A, OA, phenoxy, Ph, OH, F, Cl, Br, CN, CF3, COOH, COOA, acyloxy with 1-4 carbon atoms, carboxamido, -CHNH2, -CH2NHA, -CH2NA2,

-CH2NHAc, -CH2NHSO2CH3,

or

R0and R1together represent alkylenes chain with 1 to 3 carbon atoms or alkenylamine chain with 2 to 3 carbon atoms;

R2represents hydrogen, A, Ac, or-CH2-R4;

R3represents-CH2-R4or-CHA-R4;

R4is a Ph, 2-, 3 - or 4-pyridyl (unsubstituted or monosubstituted R5) or thiophene (unsubstituted, mono - or disubstituted by A, OA, OH, F, Cl, Br, CN and/or CF3or the other what it is, di-, tri-, Tetra-, or pentamidine F, CF3partially or fully fluorinated A, A and/or OA;

R6, R7, R8and R9each independently represents H, A, OA, phenoxy, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NHA, NA2, Ac, Ph, cycloalkyl c 3-7 carbon atoms, -CH2NH2, -CH2NHA, -CH2NA2, -CH2N HAC or-CH2NHSO2CH3or two coming together constitute the remainder alkylenes chain with 3-4 carbon atoms, and/or R1and R6together predstavljaet a chain with 3 or 4 carbon atoms;

A represents alkyl with 1-6 carbon atoms;

Ac is alkanoyl with 1-10 carbon atoms or aroyl with 7 to 11 carbon atoms;

Ph represents phenyl (unsubstituted or substituted R5, 2-, 3 - or 4-pyridium or phenoxyl group);

and physiologically acceptable salts, their derivatives

The invention relates to methods of producing new derivatives of 1,4-dihydropyridines-3,5-dicarboxylic acid in the form of the R-isomers of General formula I, where R1and R3the same or different and mean C1-C8-alkyl which may be substituted C1-C6-alkoxyl or hydroxyl, R2is phenyl which may be substituted with halogen or cyano

The invention relates to new derivatives of 1,4-dihydropyridines F.-ly (I), where R1and R3denote C1-C8-alkyl, unsubstituted or substituted C1-C6-alkoxyl or hydroxyl, or C3-C7-cycloalkyl, R2denotes a substituted phenyl, and the Deputy is chosen from the group comprising halogen, cyano, ethinyl, triptoreline, methyl, methylthio, trifluoromethyl, or C1-C4-alkoxyl
The invention relates to the field of treatment of acute CNS, and in particular to methods of treatment OSPS in children, and can be used in clinical practice

The invention relates to medicine, in particular, neurology, and is the application selegilina (L-N-(1-phenylisopropyl)-N-methyl-N-Propylamine) or its pharmaceutically acceptable salts for the treatment of epileptic disorders
The invention relates to medicine and can be used for the treatment of neuroses and neurosis-like disorders

The invention relates to medicine and relates to a pharmaceutical composition having enteral action
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