Derivatives nicotinebuy acids as substances that prevent blood clots

 

(57) Abstract:

Compounds based on the structure of fibrinogen formula I, where X1and X2- N2or O; Y is (CH2)mCH(NR3)-(CH2)mCH(NH2(CH2)m; AND - OTHER1C(:NH)NH2or piperidine or pyrrolidine; Z - (CH2)nCH(CO2R4) (CH2)n; R1Is h, alkyl or CH(NH )NH2; R2Is h, alkyl; R3- alkoxy or alkyl, R4is alkyl or arylalkyl, R6Is h, alkyl or arylalkyl, m is an integer 0-3, n is an integer of 0-2, are platelet aggregation inhibitors, useful for the treatment of blood clotting disorders. 7 C.p. f-crystals, 4 PL.

The background to the invention.

This application is a continuation application N 08/364896, filed December 27, 1994 , which in turn is a continuation application N 08/213772 filed March 16, 1994

Platelet aggregation is the beginning of a hemostatic responses aimed at stopping the bleeding caused by damage to the vessel. However, the pathological extension of the normal hemostatic process can lead to the formation of a blood clot.

Usually the final stage and is of Titov. Agents that inhibit the binding of fibrinogen to the platelet glycoprotein IIa/IIIa (IIb/IIIa), therefore, inhibit platelet aggregation. Thus, these agents are applicable for the treatment of disorders of blood coagulation mediated by platelets, such as thrombosis of arteries and veins, acute myocardial infarction, unstable angina, reocclusion after thrombolytic therapy and angioplasty, inflammation, and a number of vasoocclusive violations. The fibrinogen receptor (IIb/IIIa) are activated by an appropriate stimulus, such as ADP, collagen and thrombin, exposing the binding domains for two different peptide sections of the fibrinogen - chain of Arg-Gli-ASP (RGD) and - chain-GIS-GIS - Lei-Gli-Gli-Ala-Lys-GLn-Ala-Gli-ASP-Val (HHLGG AKQ AGDY, 400-411). Since it is shown that these peptide fragments out of fibrinogen are antagonists (inhibitors) of the binding of fibrinogen with IIb/IIIa inhibitors, mimetics of these fragments are also such antagonists. In fact, before the advent of the present invention were discovered powerful antagonists, which RGD - mimetic or mimetics based on RGD, which inhibit the binding of fibrinogen with IIb/IIIa and platelet aggregation.

Some of these agents have shown activity POI therapy (for example, t-PA or streptokinase).

Description of the invention.

The present invention relates to compounds represented by the General formula (I):

< / BR>
where X1X2, Y, Z, R2and A hereinafter defined in the text.

Such compounds based on the structure of fibrinogen 400-411, are platelet aggregation inhibitors, useful for treating disorders of blood coagulation mediated by platelets, such as thrombosis of arteries and veins, acute myocardial infarction, reocclusion after thrombolytic therapy and angioplasty, inflammation and unstable angina, as well as a number vasoocclusive violations. These compounds are useful as antithrombotic agents when used in combination with fibrinolytic therapy (e.g., t-PA or streptokinase). Pharmaceutical compositions containing such compounds, are also part of the present invention.

Detailed description of the invention.

The present invention relates to compounds of the following formula (I):

< / BR>
where X1and X2the same or different and represent H2or O. Preferably, each of X1and X2is ABOUT;

Y is (CH22or cycloalkyl ring containing nitrogen and selected from the group piperidine-2-yl, piperidine-3 - yl, piperidine-4-yl, pyrrolidin-2-yl and pyrrolidin-3-yl. More preferably, the ring is chosen from the group piperidine-2-yl, piperidine-3-yl and piperidine-4-yl;

Z is (CH2)nor CH(CO2R4)(CH2)n. Preferably Z is (CH2)2;

R1represents H, alkyl or CH(NH)NH2. More preferably R1represents H or alkyl. Most preferably, R1represents hydrogen;

R2represents H or alkyl. Preferably R2represents hydrogen;

R3is alkoxy or alkyl. Preferably R3is t-butoxy or methyl. Most preferably, R3is t-butoxy;

R4represents alkyl or arylalkyl, such as benzyl. Preferably R4is methyl;

R6represents H, alkyl or arylalkyl, such as benzyl. When R6is not hydrogen, it is in the form of prodrugs;

m represents an integer of 0, 1, 2 or 3;

n represents the integer 0, 1 or 2.

Unless otherwise specified, alkyl or alkoxy, as samostoyatelnymi, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy radicals are oxygen esters formed by the previously described straight or branched chain alkyl groups. Cycloalkyl groups contain in the ring of 5-8 carbon atoms, preferably 6 or 7 carbon atoms.

The term "aryl", used by themselves or in combination with other terms, refers to an aromatic hydrocarbon group such as phenyl or naphthyl.

The term "arylalkyl" means alkyl group, substituted aryl group.

Compounds of the present invention can also be represented in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salt usually takes the form in which the nitrogen in the 1-protonated piperidine inorganic or organic acid. However, if X2is H2the nitrogen ring may also form a salt. Examples of organic or inorganic acids include hydrochloric, Hydrobromic, idiscovered, perchloric, sulfuric, nitric, phosphoric, acetic, propion, econsultancy, hydroxyethanesulfonic, benzosulfimide, oxalic acid, Paveway, 2-naphthalene-sulfonic, p-toluensulfonate, cyclohexanesulfamic, salicylic acid, sugar or triperoxonane acid.

Particularly preferred compounds of the present invention include compounds represented by the formula:

< / BR>
where R= H; m=3; n=2; R5=L-NH; R6represents benzyl (Bn) (compound 1);

R=H; m=3; n=2; R5=L-NH; R6is H (compound 2);

R=H; m=3; n=2; R5=D-NH; R6is H (compound 3);

R=H; m=3; n=2; R5=L-NH2; R6is H (compound 4);

R=H; m=3; n=2; R5=H; R6is H (compound 5);

R=H; m=3; n=1; R5=L-NH; R6is H (compound 6);

R=H; m=3; n=2; R5=L-NH; R6is H (compound 7);

R=C(NH)NH2; m=2; n=2; R5=L-NH R6is H (compound 8);

R=H; m=3; n=3; R5=L-NH; R6is H (compound 9);

R=H; m=3; n=2; R5=D-NH2; R6is H (compound 10);

R=H; m=3; n=3; R5=D-NH; R6is H (compound 11);

R=H; m=3; n=1; R5=D-NH; R6is H (compound 12);

R=H; m=3; n=2; R5=D-NH; R6is H (compound 15);

3-R-isomer of compound 3; R6is H (compound 16);

< / BR>
< / BR>
< / BR>
Compounds of the present invention can be prepared from commercially available starting materials according to the following schemes reactions AA, AB, AC and AD.

Compounds of the present invention, in which X1and X2each represents oxygen, can be prepared according to the following scheme AA. In this scheme on nicotinebuy acid (racemic mixture or a single enantiomer) you can operate the lower alkilany alcohol and a catalytic amount of acid, from room temperature to heating with vertical refrigerator, to obtain the ether derivative AA1 in the form of acid salts. Typical alcohols include ethanol, methanol, isopropanol and butanol, and can be combined with acid catalysts such as p-toluensulfonate acid, HCl or sulfuric acid. The preferred reagents are methanol and HCl. Derived AA1 can be allerban nitrogen ring different allerease agents for deriving AA2. Typical reaction conditions include the effect on the AA1 Alliluyeva agent and the equivalent amount of organic osnovannymi agents are aminosidine amino acids or aminosidine aminoalkylsilane acid, activated interfacing reagents such as DCC (1,3-dicyclohexylcarbodiimide) and BOP-C1 (bis(2-oxo-3-oxazolidinyl)phosphine chloride). However, you can use and aminosilane acid derivatives, such as anhydrides, N-oxysuccinimide and acid chlorides. Convenient protective groups include lower allylcarbamate, branched allylcarbamate, benzylcarbamoyl, acetamide and substituted acetamide. The choice Alliluyeva agent and his aminoamide group (s) is the determinant of the substituents Y and R1in the compounds of formula I, where X1and X2are Acting In scheme AA-protected amino acid is diaminotoluene formula NH(Side)CHCO2H(CH2)n-N(CBZ), which makes it possible election deprotection two amino groups in the last step of the scheme. This choice serves only the purpose of illustration only and is not restrictive.

Contingent AA2 is possible to operate the base and a suitable mixture of solvents to obtain a salt derived AA3. Suitable inorganic bases include NaOH, KOH, Mg(OH)2, LiOH, Na2CO3and NaHCO3that can be combined with THF and water at room temperature for 1-6 hours to obtain the desired ylethylamine and tetramethylguanidine. These grounds can be used with organic solvents at room temperature and to heat with vertical refrigerator for 1 to 6 hours to obtain salt AA3.

The preferred reaction conditions (which is illustrated) are on AA2 LiOH, water and THF at room temperature for 1 hour. You can use other suitable inorganic bases, such as NaOH, KON, Mg(OH)2, Na2CO3and NaHCO2. If you use such other Foundation, Li in AA3 is, of course, replaced by other suitable metal. Contingent AA3 can act carboxyamide carboxymethylamino or carboxyterminal amino acid under standard amino acids conditions mates to obtain disubstituted nikotinovoi derived AA4. Suitable mating conditions include the use of peptide interfacing agents, such as DCC, BOP-C1 and EDC (ethyldimethylamine - HCl). Suitable carboxyamide group include benzylcarbamoyl, substituted benzylcarbamoyl, allylcarbamate and branched allylcarbamate, and the choice of protecting groups is obvious to a person skilled in the field of chemical synthesis. Proillyustriroval the HOICE of amino acids and its carboxyamide group determines the substituents R2and Z in the compounds of formula I, where X1and X2are About. Derived AA4 may be selectively deprived of protection in accordance with the requirements of amino - or carboxyamide group. In the illustrated example, the protecting group at the 3-carboxy group and one of the amine groups at the same time removed by catalytic hydrogenation using Pd/C in an atmosphere of H2to obtain the derived AA5.

Scheme AB illustrates the preparation of compounds of formula 1 in which X1is O, and X1is H2. On nicotinebuy acid (racemic mixture or a single enantiomer) can act alkilany alcohol and a catalytic amount of acid at a temperature of from room temperature to heating with vertical refrigerator to obtain the ether derivative AB1 in the form of acid salts. Typical alcohols include ethanol, methanol, isopropanol and butanol. Acid catalysts include p-toluensulfonate acid, HCl, and sulfuric acid; the preferred reagents methanol and HCl. Derived AB1 can be allievate nitrogen ring different allerease agents for deriving AB2. Typical reaction conditions include the effect on AB1 allermuir agent is of from 15 minutes to 2 hours. Preferred allerease agents are amino protected amino acid or aminosidine aminoalkylsilane acid, activated interfacing agents such as DCC (1,3 - dicyclohexylcarbodiimide) and BOP-C1 (bis(2-oxo-3 - oxazolidinyl)phosphine chloride). You can also apply aminosidine acid derivatives, such as anhydrides, N-oxysuccinimide and acid chlorides. Suitable protecting groups include lower allylcarbamate, branched allylcarbamate, benzylcarbamoyl, acetamide and substituted acetamide. The choice of amino acids and its aminoamide group (s) is the determinant of the substituents Y and R1in the compounds of formula I. In scheme AB-protected amino acid is diaminotoluene formula: NH(Side)CHCO2H(CH2)N-N(Side); this choice is only for the purposes of illustrating the present invention and does not limit it. Derivative AB2 is possible to hydrolyze the substrate and a suitable mixture of solvents to obtain a derived AB3. Suitable inorganic bases include NaOH, KON, Mg(OH)2, LiOH, Na2CO3and NaHCO3that can be combined with mixtures of THF and water at room temperature for 1-6 hours to obtain the desired product. Of the amine and tetramethylguanidine. These grounds can be used with organic solvents at room temperature and to heat with vertical refrigerator for 1-6 hours to get AB3. 3-carboxypropyl derived AB3 can be restored to obtain the aldehyde derivative AB4, using a variety of reaction conditions. These conditions include the use of lithium-t-diisopropylamide with GET/THF as solvent, -78o0oC, N,N-demethylchlortetracycline and hydride lithium-t - butoxyaniline with pyridine as solvent at -78oC and standard conditions recovery of Rosenmund. The preferred reaction conditions, the use of N, N'-carbonyldiimidazole, then hydride diisobutylaluminum at -10oC, to obtain the aldehyde derivative AB4. On AB4 can act carboxyamide carboxymethylamino or carboxyterminal amino acid, and then reducing agent to obtain disubstituted nikotinovoi derived AB5. Suitable carboxyamide group include benzylcarbamoyl, substituted benzylcarbamoyl, lower allylcarbamate and branched allylcarbamate; the choice of protecting groups is obvious to a person skilled in the field of chemical synthesis. Woshan, tetrabutylammonium cyanoborohydride and Pd/C with acid solvent; the choice of reducing agent used is determined by protective groups. The illustrated example uses the NH2(CH2)nCO2(BSL) as protected amino acids and cyanoborohydride sodium as a reducing agent. This choice of amino acids and its carboxyamide group determines the substituents R2and Z in the compound and serves the purposes of illustration, but not limitation. Derived AB5 may be selectively deprived of protection in accordance with the requirements of amino - or carboxyamide group. In the illustrated example, the protecting group at the 3-carboxyl group and two amino groups are removed simultaneously by catalytic hydrogenation in the presence of Pd/C in an atmosphere of H2to obtain the derived AB6.

Compounds of the present invention, in which X1represents oxygen, and X2is H2can be prepared according to the following scheme AC. In this scheme on nicotinebuy acid (racemic mixture or the individual enantiomers) can act on the lower alkilany alcohol and a catalytic amount of acid, from room temperature to heating under vertically is ethanol, methanol, isopropanol and butanol. Acid catalysts include p-toluensulfonate acid, HCl, and sulfuric acid; the reagents of choice are methanol and HCl. Derived AC1 can be alkilirovanii nitrogen ring alkylating agent to obtain a derived AC2. Alkylating reagents include synthons of haloalkylthio, such as bromeliifolia and bromuconazole, or protected aminoaldehyde, by a process of reductive amination (see the AD schema). Typical reaction conditions include the effect on AC1 base, such as sodium hydride, or the catalyst transfer between phases, such as tetrabutylammonium fluoride, and an alkylating agent in an inert solvent, at room temperature for from 15 minutes to 2 hours, and then the routine protection of the amino group of the 3-substituent any of the mentioned suitable protecting groups. The choice of alkylating agent and his aminoamide group is a factor in determining the substituents Y and R1. In the scheme of AC 1 position is substituted (CH2)NH(CBS); this choice is only illustrates the present invention but does not limit it. Contingent AC2 you can act a base and a suitable mixture of solvents to obtain the derived A and other suitable inorganic bases, including NaOH, KOH, Mg(OH)2, Na2CO3and NaHCO3that can be combined with mixtures of THF and water at room temperature for 1-6 hours to obtain the desired product. Organic bases which can be used include triethylamine, tributylamine, diisopropylethylamine and tetramethylguanidine. These grounds can be used with organic solvents at room temperature and to heat with vertical (reverse) refrigerator for 1 to 6 hours, to obtain a salt AC3. Preferred reaction conditions (illustrated) provide for the effect on AC2 LiOH, water and THF at room temperature for 1 hour. Contingent AC3 can act carboxyamide carboxymethylamino or carboxyterminal amino acid under standard conditions combinations of amino acids to obtain disubstituted nikotinovoi derived AC4. Acceptable mating conditions include the use of peptide interfacing agents, such as DCC, BOP-C1 and EDC (HCl). Suitable carboxyamide group include benzylcarbamoyl, substituted benzylcarbamoyl, allylcarbamate and branched allylcarbamate; the choice of the protecting group of awlays2)nCO2(BSL) as protected amino acids. And again the choice of amino acids and its carboxyamide group determines the substituents R2and Z in the compounds of formula I. Derived AC4 can be selectively deprived of protection in accordance with the requirements of amino - or carboxyamide group. In the illustrated example, the protecting group at the 3-carboxyl group and 1-amino groups are removed simultaneously by catalytic hydrogenation using Pd/C in an atmosphere of H2to obtain the derived AS.

Compounds of the present invention, in which X1and X2each is H2can be prepared according to the following scheme AD. In this scheme on nicotinebuy acid (racemic mixture or the individual enantiomers) can act on the lower alkilany alcohol and a catalytic amount of acid from room temperature to heating with vertical refrigerator to obtain the ester derivative AD1 in the form of acid salts. Typical alcohols include ethanol, methanol, isopropanol and butanol. Acid catalysts include p-toluensulfonate acid, HCl, and sulfuric acid. The preferred reagents are methanol and HCl. Manufacturers shall eagency include synthons of haloalkylthio, such as bromeliifolia and bromuconazole or protected aminoaldehyde, by a process of reductive amination (see the AD schema). Typical reaction conditions include the effect on AD1 base, such as sodium hydride, or the catalyst transfer between phases, such as tetrabutylammonium fluoride, and an alkylating agent in an inert solvent, at room temperature for from 15 minutes to 2 hours, and then the routine protection of the amino group of the above-mentioned suitable protecting groups. The choice of alkylating agent and its amino-protecting group is a factor in determining the substituents Y and R1. In the circuit AD1 position substituted (CH2)NH(CBS); this choice is only for the purposes of illustrating the present invention. Derived AD2 is possible to hydrolyze the substrate and a suitable mixture of solvents to obtain a derived AD3. Suitable inorganic bases include NaOH, KOH, Mg(OH)2, LiOH, Na2CO3and NaHCO3that can be combined with mixtures of THF and water at room temperature for 1-6 hours to obtain the desired product. Organic bases which can be used include triethylamine, tributylamine, diisopropylethylamine and the ur and to heating with vertical refrigerator for 1-6 hours to get AD3. 3-carboxyl group derived AD3 can be restored to obtain the aldehyde derivative AD4 through the use of a number of reaction conditions. These conditions include the use of lithium-diisopropylamide with GET/THF as solvent, at temperatures from -78oC and 0oC, N,N-dimethylformamidine chloride and hydride lithium-t-butoxyaniline with pyridine as solvent at a temperature of -78oC and standard conditions recovery of Rosenmund. Preferred reaction conditions include the use of N,N'-carbonyldiimidazole, and then applying hydride diisobutylaluminum at a temperature of -10oC to obtain the aldehyde derivative AD4.

Contingent AD4 can act carboxyamide carboxymethylamino or carboxyterminal amino acid, and then reducing agent to obtain disubstituted nikotinovoi derived AD5. Suitable carboxyamide group include benzylcarbamoyl, substituted benzylcarbamoyl, lower allylcarbamate and branched allylcarbamate; the choice of protecting groups is obvious to a person skilled in the field of chemical synthesis. Reducing agents include cyanoborohydride sodium, cyanoborohydride l is the; the choice of reducing agent is determined by the used protecting groups. The illustrated example uses the NH2(CH2)nCO2(BSL) as protected amino acids and cyanoborohydride sodium as a reducing agent. This choice of amino acids and its carboxyamide group determines the substituents R2and Z in the compound and serves the purposes of illustration, but not limitation. Derived AD5 can be selectively deprived of protection in accordance with the requirements of amino - or carboxyamide group. In the illustrated example, the protecting group at the 3-carboxyl group and the amino group is removed simultaneously by catalytic hydrogenation using Pd/C in an atmosphere of H2to obtain the derived AD6.

The source materials for all schemes, the majority of amino acids and aminoalkylphosphonic acids needed to produce compounds in which a is other1are commercially available and require only the introduction of the protective groups to obtain the desired compounds of formula I. However, to obtain the compounds of the present invention, in which a represents cycloalkyl ring containing a nitrogen atom, the substituent in position 1 (piperidine) is where the substituent in the 1 position is C(O)(CH2)2-4-yl-piperidine derivatives AA1 or AB1 acelerou 3-(4-pyridyl)acrylic acid to obtain the acylated derivatives of AA2 and AB2, using the above acylation processes. These derivatives undergo transformations as described in schemes to obtain AA4 and AB5. Derivatives AA5 and AB6, you can get action on AA4 and AB5 a suitable reducing agent, which in this case removes the protecting group for carboxyl group in the 3 position and restores ethylenamine pyridine to obtain the desired compound. The preferred reducing agent that removes protection is PtO2. 2 - and 3-yl-piperidine can be obtained by modification of a derivative of acrylic acid using standard techniques.

To obtain compounds in which the substituent in the 1 position is C(O)(CH2)2-3-yl-pyrrol derivatives AA1 or AB1 acelerou 3-(1-benzylpyrrolidine-3-yl) acrylic acid to obtain the acylated derivatives of AA2 and AB2 using the above-mentioned acylation processes. It substituted derivative of pyrrole and acrylic acid can be obtained by hydrolysis of the corresponding nitrile derivative in an aqueous solution of acid, 3-(1-benzylpyrrolidine-3-yl)act as links. These derivatives was affected, as described above (for six-membered case), to obtain the compounds of the present invention, in which a represents a five-membered ring containing the nitrogen atom.

To obtain diastereomeric enriched end-compounds containing BOC-D-Lys and one of the R - or S-nepokorennyh groups (see connections 14 and 16), at the beginning of the synthesis was applied appropriate enantiomerically enriched methyl ester nicotinebuy acid. Enantiomerically enriched methyl ester nicotinebuy acids were separated by chiral separation of the racemic material, as published (A. M. Akkerman, Rec. Traw. Chim. Pays-Bas 1951, 70 899).

To prepare the pharmaceutical compositions of the present invention, one or more compounds of the formula I or their salts of the present invention as the active ingredient was mixed to homogeneity with a pharmaceutical carrier using standard pharmaceutical techniques; this media can represent various forms depending on the desired method of administration, e.g. oral, or parenteral (intramuscular, etc). In the preparation of compositions for oral Ave is designated for oral administration, for example, suspensions, elixirs or solutions, suitable carriers and any additives include water, glycols, oils, alcohols, flavouring agents, preservatives, dyes, etc.; for solid preparations for oral administration, such as powders, capsules, lozenges, gelatin capsules and tablets, suitable carriers and any additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, etc., Tablets and capsules, due to the simplicity of their introduction, are the most convenient dosage form for oral administration, for which, of course, use solid pharmaceutical carriers. If desired, tablets may be coated sugar or intersolubility the membrane using standard techniques. For parenteral forms of media usually comprise sterile water, although it may include other ingredients, for example to improve the solubility or for preservation. You can also prepare the suspension for injection what is it used for liquid media, suspendresume agents, etc., the Pharmaceutical compositions of the present invention in the dosage form at one time, for example in tablet, capsule, powder, injection, chain is as described above. The pharmaceutical compositions of the present invention in the dosage form at one time, for example in tablet, capsule, powder, injection, suppository, teaspoonful, etc., will contain from about 0.03 mg to 100 mg/kg (preferably 0.1 to 30 mg/kg) and may be administered at a dose of from about 0.1 to 300 mg/kg / day (preferably 1-50 mg/kg / day). Doses, but may change depending on how much you want a particular patient, the severity of the condition requiring treatment, and used for the connection.

The introduction can be daily or periodical.

Pharmacology.

Compounds of the present invention inhibit the binding of fibrinogen to glycoprotein IIb/IIIa (GP IIb/IIIa) platelets and thus inhibit platelet aggregation. Such compounds are therefore useful for treating disorders of blood coagulation mediated by platelets, such as thrombosis of arteries and veins, acute myocardial infarction, reocclusion after thrombolytic therapy and angioplasty, and several vasoocclusive violations. As the final stage of normal platelet aggregation is the binding of fibrinogen to activated exposed GP IIb/IIIa inhibition of such hydrogen bonds of various incentives, such as ADP, collagen and thrombin, exposing binding domains to connect to two different peptide regions of the fibrinogen - chain of Arg-Gli-ASP (RGD) and - chain 400-411. As shown by the results of the pharmacological studies described later in this document, the compounds of the present invention demonstrated the ability to block the binding of fibrinogen isolated IIb/IIIa (IR503-5800 nm) to inhibit platelet aggregation in vitro in the presence of various agents stimulating platelets, and in addition inhibited platelet aggregation ex vivo in experimental animals.

Research associate in vitro glycoprotein IIb/IIIa, purified by solid-phase method.

96-well microtiter tablet Immulon-2 (Dynatech-Immulon) were covered IIb/IIIa, purified by affinity RGD, in the amount of 50 μl per well (effective range of 0.5-10 µg/ml) in 10 mm HEPES, 150 mm NaCl, 1 mm at a pH of 7.4. The tablet was covered and incubated overnight at 4oC. the Solution IIb/IIIa was removed, was added 150 μl of 5% ABS and incubated at room temperature for 1-3 hours. Tablet extended washed with buffer, modified by way Tyrodes. Biotinylated fibrinogen (25 μl per well) in double the nd concentration. The tablet was covered and incubated at room temperature within 2-4 hours. Twenty minutes before the end of the incubation was added one drop of reagent A (set with horseradish peroxidase Vecta Stain ABC Horse Radish, Vector Laboratories, Inc.) and reagent B in a mixture with 5 ml of buffer, modified by way Tyrodes, and left to stand. Ligand solution was removed and the plate is washed (h μl per well) modified by way Tyrodes buffer, was added to the reagent HRP-Biotin-avidin Vecta Stain HRP (50 μl per well, as prepared above) and incubated at room temperature for 15 minutes. The solution Vecta Stain was removed and washed (h l per well) modified by way Tyrodesf buffer. Added manifest buffer (10 ml of 50 mm citrate-phosphate buffer @ pH 5.3, 6 mg of o-phenylenediamine, 6 μl of 30% H2O2; 50 μl per well) and incubated at room temperature for 3-5 minutes, and then added 2 NH2SO4(50 µl per well). Take into account the absorption at 490 nm.

The results are presented in table 1.

In vitro thrombin-induced platelet aggregation after gel filtration.

The percentage of platelet aggregation was calculated as the increase in light transmission through platelet concentrate, processing what was given from normal donors, not taking drugs, in tubes containing of 0.13 M sodium citrate. Plasma enriched with platelets (SWEAT), collected by centrifugation of whole blood at 200 x g for 10 minutes at 25oC. FIVE (5 ml) was filtered through a gel sepharose 2B (volume of granules 50 ml) and the platelet count was brought to 2107platelets in the sample. In siliconized cuvette were added the following components: concentrated platelet filtrate and the buffer Tyrode's (of 0.14 M NaCl, 0.0027 M KCl, 0,012 M NaHCO3, 0.76 mm Na2HPO4, 0,0055 M glucose, 2 mg/ml anti-lock brakes and 5.0 mm HEPES @ pH 7.4) in an amount equal to 350 ál, 50 ál of 20 mm calcium and 50 μl of the test compounds. Aggregation was determined by aggregometry BIODATA within 3 minutes after the addition of agonist (thrombin in the amount of 50 μl at a concentration of 1 unit per ml). The results are presented in table 1.

Research on dogs ex vivo

Adults nechistoplotnym dogs (8-13 kg) produced analgesia by pentobarbital sodium (intravenous 35 mg/kg) and translated them on artificial lung ventilation. Blood pressure and heart rate were measured using a catheter of Milara introduced into the femoral artery. Another sensor Melara was placed in the left Gosti attack. The electrocardiogram in the second discharge was recorded from electrodes on the limbs. In the femoral artery and vein were introduced catheters for sampling of blood and infusion of drugs, respectively. The reaction was monitored for a long time using a data acquisition system Modular Instruments.

Samples of arterial blood (5-9 ml) was collected in tubes containing 3.8% of sodium citrate, for the preparation of plasma, platelet-rich (SWEAT) and to determine the influences on the parameters of coagulation: prothrombin time (PT) time and activated partial thromboplastin (PAST). Individual blood samples (1.5 ml) were placed in EDTU for determining the hematocrit and the number of blood cells (platelets, red blood cells and white blood cells). Bleeding time was measured using scarificing device and batmanesque filter paper on the buccal surface.

Aggregation SWEAT was performed aggregometry BioData. Aggregation whole blood was performed aggregometry impedance Chronolog. PV and the GUYS were determined using BioData or the analyzer AC 3000 + coagulation. Cells were counted using a Sysmex K-1000.

Compound 17 was dissolved in a small volume of dimethylformamide (DMF) and the automatic syringe Harvard. Each animal was administered a dose of 0.3, 1.3 and 10 mg/kg) cumulative scheme. Each dose was administered with an interval of 15 minutes at a constant speed the introduction of 0.33 ml/min Data were obtained after each dose and after 30 and 60 minutes after drug administration.

Compound 17 was caused pronounced inhibition of platelet aggregation ex vivo. Thus, whole blood connection 17 inhibited caused by collagen aggregation in doses of 0.3-10 mg/kg with a pronounced inhibition caused by collagen ATP release by platelets in a dose of 10 mg/kg IN SWEAT connection 17 is also inhibited caused by collagen platelet aggregation with pronounced activity at a dose of 0.3 mg/kg Aggregation SWEAT induced gamma-thrombin, oppressed at doses of 3.0 mg/kg and above. As in the case of POT, and in the case of whole blood, platelet function began to recover within 30-60 minutes, which testified to the relatively short duration of action of drugs. Compound 17 had no measurable hemodynamic actions in doses up to 10 mg/kg intravenously. This drug caused increase in standard time bleeding at doses of 3 and 10 mg/kg with a quick recovery after treatment. During impact Lekarstvo and erythrocytes did not change at all doses of compound 17.

The results (see tab. 1 in the end of the description) indicate that the connection 17 is a highly effective inhibitor of platelet aggregation ex vivo, acting as an antagonist as collagen and thrombin way, after intravenous administration of doses ranging from 0.3 to 10 mg/kg Antiplatelet effect was relatively short and was accompanied by an increase in bleeding time at higher doses. Other hemodynamic or hematological effects were not.

Research on dogs in vivo

Compound 16 was tested on dogs in vivo to determine therapeutic activity. Surgical preparation of animals.

Adults nechistoplotnym dogs of both sexes weighing 9-13 kg produced anesthetic pentobarbital sodium (35 mg/kg, intravenously) and translated to the ventilation air through endotracheal tube (12 respiratory movements per minute, 25 mg/kg). To determine blood pressure in the left carotid artery was injected filled with saline polyethylene catheter (PE-200) and coupled it with a Statham pressure transducer (P231D, Oxnard, CA). Determined blood pressure diastolic blood. For customizine electrocardiogram through electrodes on the limbs. In the jugular vein was also introduced catheter (RC-200) for drug administration. The left femoral artery and left a watchful vein was catheterizable treated with silicone (Sigmacote, Sigma Chemical Co., St. Louis, MO) filled with saline catheter (PE-200) and connected with a 5-cm segment treated with silicone tubing (PE-240) for education extracorporeal arteriovenous shunt (A-B). The patency of the shunt is controlled using a flow-through system Doppler (model VF-1, Crystal Biotech Inc., Hopkinton, MA) proximal from the bypass. All parameters long were observed using a polygraph (Gould TA-4000, Oxnard, CA) at a speed of movement of the paper 10 mm per minute.

Protocol.

At the end of the 15-minute post-operative period of stabilization was formed obtenerse thrombus by introducing a shunt thrombogenic surface (fastened by a loop of silk thread length 5 cm, Eticon, Inc., Somerville, NJ). It was taken 4 consecutive period of bypass surgery, the first of which consisted of infusion media, and then increasing concentrations of compounds 16, SC-47643, physiological solution with DMF or saline solution with citric acid, is introduced in the form of a bolus, followed by 5-minute infusion d is of the silk thread was carefully removed and weighed. To assess the stability of the patency of the shunt used fifth bypass surgery immediately after the introduction of total cumulative therapeutic dose, which was reflected by the time to complete obturation. The weight of the thrombus was calculated by subtracting the weight of the silk to be placed in the shunt of the total weight of silk after you remove it from the shunt. Arterial blood was taken prior to the first bypass and after each period of the bypass to determine the platelet aggregation induced by collagen, in whole blood, platelet degranulation induced by thrombin (release ATP platelets), prothrombin time and platelet count. Standard coagulation time was determined in the first 10 minutes of each period of the bypass.

Hematological studies.

The number of platelets, leukocytes and erythrocytes and hematocrit was determined in whole blood, collected in 2 mg/ml disodium-EDTA using SysmexTMK 1000 (Baxter Laboratories, McGraw Park, IL).

Platelet aggregation and ATP release in whole blood was measured using lomearogetyj, and the release of ATP was measured using lumichrome (Chrono-log, Havertown, PA) by determining the impedance changes (platelet aggregation) and light transmission (release ATP) which were collected in 0.01 M sodium citrate and diluted in half with saline with 0.5 mm Ca (25 μm 0.02 M CaCl2and 20 μm of luciferase (Chrono-log, Havertown, PA). The final volume was 1 ml Aggregation induced by collagen (2 μg/ml) in a separate sample, the degranulation of platelets was observed with thrombin (0.5 in units/ml) (Chrono-log, Havertown, PA), and impedance changes and luminescence was recorded for 6 minutes. Prothrombin time (PT) was determined by using a coagulation analyzer microsamples intestinal (Ciba Corning 512, Corning NY). Standard bleeding time was assessed by applying a cut on the gums (Surgicutt, ITC Corp, Edison, NJ), and fixing the time of the formation of a clot.

Drugs.

The connection 16; 1+0.03, 3+0.1 and 5+0.3 mg/kg, IV (bolus) + mg/kg/h, IV (infusion) was dissolved in physiological solution + DMF (5%) and serially diluted to achieve appropriate concentrations, expressed as parent compound.

The statistical analysis.

The results are presented in table. 2 at the end of the description. All values are expressed as mean and standard error of the mean. Statistical significance of changes was evaluated using the main ANOVA and t-student criterion. Differences between values were considered significant at P < 0,05.

Examples.

Protected amino acids were purchased from a company Bachem Bioscience Inc. Priene 14). Enantiomerically enriched methyl ester nicotinebuy acid was isolated using chiral separation of the racemic material, as published (A. M. Akkerman, Rec. Traw. Chim. Pays-Bas. 1951, 70, 899). All other chemicals were purchased from the company Aldrich Chemical Company, Inc. Spectra intensive field1H NMR were recorded on a spectrometer Bruker AC-360 360 MHz, and interfacing constants are given in Hertz. The melting temperature was determined by the device for determining the melting temperature of Mel-Temp// and not corrected. The analyses were performed at Robertson Microlit Laboratories, Inc., Madison, New Jersey or R. W. Jonson Phamaceutical Research Institute Analitical Department. Final compounds were purified by recrystallization/precipitation of the usual organic solvents and/or chromatography on a column of silica gel-60 Merck. Purity was assessed through a combination of system GWHR Beckman/waters and column Phenomenex-Ultracarb 5 ODS (30) (100 x 4.6 mm) using the combined acetonitrile mobile phase (usually 10% MeCN/90% water). In the examples and throughout this application, the following abbreviations have the meanings given below:

AC = acetyl

Bn or BZL = benzyl

Side = t-butoxycarbonyl

BOP-C1 = bis(2-oxo-3-oxazolidinyl)phosphine chloride

CBS = benzyloxycarbonyl

Dibal = BR> EDTU = ethylenediaminetetraacetic acid

HOBT = hydroxybenzotriazole

and-PR = isopropyl

NMM = N-methylmorpholine

Nip = nipecotic (if not stated otherwise, the racemate 3 position)

PTS = p-toluensulfonate

TFU = triperoxonane acid

Example 1. N- BOC-D-Lys-S-(+)-Nip -- Ala-OH (compound 14)

To a mixture of N- BOC-D-Lys(CBZ)-OH (2.9 g, 7,74 mmol) and CH2Cl2(80 ml) and 5oC was added BOP-C1 (1,96 g, 7.7 mmol) and NMM (or 0.83 ml, 7.7 mmol). This mixture was stirred for 30 minutes, acted on it by the hydrochloride of the methyl ester of S-(+)- nicotinebuy acid (1.39 g, 7.7 mmol) and NMM (0,83 ml) was stirred for 2 hours at 5oC and diluted with saturated NH4Cl (50 ml). The organic layer was separated from the aqueous layer, dried MgSO4and evaporated to obtain a glassy solid. This solid was purified by flow chromatography (4% ethanol/CH2Cl2) to obtain the N- BOC-D-Lys(CBZ)-S-(+)-Nip-OMe as a white foam:

1H NMR(CDCl3) : 7.30 (m, 5H), 5.50 (m, 1H), 5.09 (s, 2H), 4.61 (m, 1H), 3.92 (m, 1H), 3.66 (s, 3H), 3.20 (m, 4H), 2.79 (m, 1H), 2.51 (m, 1H), 2.51(m1H), 2.12 (m, 1H), 1.50-1.80 (m, 10H), 1.39 (s, 9H).

MS m/e 506 (MN+).

To a solution of N- BOC-D-the water) dropwise over 3 minutes. This solution was stirred for 6 hours and evaporated to obtain a white foam. This foam was mixed with CH2Cl2(80 ml) at room temperature and worked on it consistently H -- Ala-Anpdc (2,34 g, 7.0 mmol), HOBT (5 mg), HCl (1.98 g, 10.4 mmol) and N (0,76 ml, 7.0 mmol). This mixture was stirred for 13 hours, diluted with saturated NH4Cl (50 ml) and layers were separated. The organic layer was dried MgSO4and evaporated to obtain a white foam. This foam was purified by flow chromatography (3-4% ethanol/CH2Cl2) to obtain the N- BOC-D-Lys(CBZ)-S-(+)Nip -- Ala-OBN as a white foam:

1H NMR (CDCl3) : 7.35 (m, 10), 6.29 (m, 1H), 5.45 (m, 1H), 5.12 (s, 2H), 5.05 (s, 2H), 5.00 (m, 1H), 4.55 (m, 1H), 4.32 (m, 1H), 3.48 (m, 2H), 3.19 (m, 4H), 2.53 (m, 3H), 2.21 (m, 1H), 1.84 (m, 1H), 1.48-1.72 (m, 9H), 1.42 (s, 9H).

MS m/e 653 (MH+).

To a solution of N- BOC-D-Lys(CBZ)-S-(+)-Nip -- Ala-OBN (0,80 g, 1,22 mmol) in THF (15 ml) in a Parr flask under nitrogen atmosphere was added acetic acid (5 ml), water (10 ml) and Pd/C (10%, 0.09 g). This mixture was hydrogenosomal at 50 psi and room temperature for 21 hours, filtered through celiby filter and evaporated to approximately 5 ml of this solution worked diethyl ether (60 ml) to yield a white precipitate, which ochiltree

1H NMR (DMSO-d6) : 7.85 (m, 1H), 6.83 (d, J=7.1 H), 4.34 (d, J=12.1 H), 4.22 (m, 1H), 3.60 (m, 2H), 3.41 (m, 2H), 2.98 (t, J=11.1 H), 2.88 (m,1H), 2.69 (m, 2H), 2.35 (m, 2H), 2.12 (m, 1H), 2.03 (m, 1H), 1.70 (m, 2H), 1.4-1.6 (m, 8H), 1.35 and 1.38 (pr.s 8.5:1.9 H), 1.16 (m, 2H),

IR (KBr): 3450-2860, 1709, 1641 cm-1,

MS m/e 429 (MH+)

[]2D5- 15,20o(0.63, MeOH),

Analysis for C20H36N4O6C2H4O2(488,6)

Calculated: at 54.08, H 8.25, N 11.47

Found: 54.64, H 8.26, N, 10.79.

Example 2. N- BOC-L-Lys (CBZ)-Nip -- Ala-OBN (compound 1)

Compound 1, prepared, starting N- BOC-L-Lys(CBZ)-and racemic methyl ester nicotinebuy acid, as in example 1, was isolated in the form of a vitreous substance:

1H NMR (CDCl3) : 7.29 (m, 10H), 6.51 (m,1H), 5.39 (m, 1H), 5.11 (s, 2H), 5.06 (s, 2H), 4.94 (m, 1H), 4.54 (m, 2H), 4.18 (m, 1H), 4.02 (d, J=10.1 (H), 3.61 (m, 1H), 3.48 (m, 2H), 3.17 (m, 4H), 2.54 (m, 3H), 2.20 (m, 1H), 1.83 (m, 1H), 1.67 (m, 2H), 1.51 (m, 4H), 1.39 (s, 9H),

MS m/e 653 (MH+)

Analysis for C35H48N4O81,5 H2O: (679.8)

Calculated: 61.84, H 7.56, N 8.24

Found: From 62.00, H 7.25, N 8.23

Example 3. N- BOC-L-Lys-Nip -- Ala -- HE (compound 2)

Compound 2, prepared by hydrogenolysis of compound 1, as in example 1, was selected as a white foam(m,10 H), 1.34 and 1.36 (ps.s, 1:1.9 H), 1.23 (m, 2H),

MS m/e 429 (MH+)

[]2D5+ 0,85o(c0.82, MeOH),

Analysis for C20H36N4O61,5 H2O: (518,6):

Calculated: 53.27, H 8.16, N 10.80

Found: 53.61, H 8.18, N 10.47

Example 4. N- BOC-D-Lys-Nip -- Ala-OH (compound 3)

N- BOC-D-Lys(CBZ)-Nip -- Ala-OBN, prepared starting from racemic methyl ester nicotinebuy acid and N- BOC-D-Lys(CBZ) as in example 1, was isolated as a white foam:

1H NMR (CDCl3) : 7.32 (m, 10H), 6.59 (m, 1H), 5.45 (m, 1H), 5.12 (s, 2H), 5.07 (s, 2H), 4.94 (m, 1H), 4.56 (m, 1H), 4.12 (m, 1H), 3.51 (m, 2H), 3.17 (m, 3H), 2.57 (m, 2H), 2.21 (m, 1H), 1.89 (m, 1H), 1.45-1.79 (m, 11H), 1.41 (S, 9H),

MS m/e 653 (MH+).

Compound 3, prepared by hydrogenolysis of N- BOC-D-Lys(CBZ)-Nip -- Ala-OBN, as in example 1, was isolated in the form of colorless flakes with a melting point of 48 - 54oC.

1H NMR (DMSO-d6) : 7.96 (m, 1H), 6.82 (m, 1H), 4.30 (m, 2H), 3.81 (m, 1H), 3.12 (m, 4H), 2.69 (m, 2H), 2.56 (m, 1H), 2.33 (m, 2H), 2.14 (m, 2H), 1.80 (m, 2H), 1,4-1,7 (m, 9H), 1.32 and 1.34 (pr.s. 1:1.9 H), 1.22 (m,2H),

IR (KBr): 3580-2770, 1711, 1642 cm-1,

MS m/e 429 (MH+)

[]25D/- 7.78o(1.71, MeOH),

Analysis for C20H36N4O62C2H4- BOC-D-Lys-Nip-L-ASP-OMe (compound 18)

N- BOC-D-Lys(CBZ)-Nip-L-ASP(OBN)-OMe, prepared from H-L-ASP(OBN)-OMe and N- BOC-D-Lys(CBZ)-Nip-IT, as in example 1, was isolated as a glassy substance:

1H NMR (CDCl3) : 7.36 (m, 10H), 6.84 (m, 1H), 5.40 (m, 1H), 5.14 (s, 2H), 5.09 (s, 2H), 4.88 (m, 2H), 4.54 (m, 1H), 4.30 (m, 1H), 3.68 (m, 3H), 3.19 (m, 3H), 3.03 (m, 1H), 2.89 (m, 1H), 2.29 (m, 1H), 1.43-2.06 (m, 12H), 1.40 (s, 9H);

MS m/e 711 (MH+);

The connection 18 prepared by hydrogenolysis of N- BOC-D-Lys(CBZ)-Nip-L-ASP(OBN)-OMe as in example 1, was selected as a white foam:

1H NMR (DMSO-d6) : 8.33 (m, 1H), 6.77 (d, J=7.1 H), 4.32 (m, 3H), 3.82 (m, 1H), 3.59 (s, 3H), 2.96 (m, 2H), 2.73 (m, 3H), 2.46 (m, 2H), 2.34 (m, 1H), 1.79 (m, 3H), 1.4-1.7 (m, 8H), 1.34 and 1.37 (pr.s, 1:1.9 H), 1.27 (m, 2H);

MS m/e 487 (MH+); []2D5is 3.57o(0.56 MeOH).

Analysis for C22H38N4O8C2H4O2H2O (564,6):

Calculated: 51.05, H 7.85, N 9.92

Found: 50.89, H 7.88, N 9.74

Example 6. H-L-Lys-Nip -- Ala -- HE (compound 4)

To a solution of compound 2 (a 0.30 g, 0.70 mmol) in MeOH (10 ml) and water (10 ml) at room temperature was added HCl (0,50 ml, conc.). This solution was stirred for 1 hour and evaporated to obtain approximately 2 ml of oily liquid. To this oily which means 4 in the form of a white powder with a melting point 65o-75oC.

1H NMR (DMSO-d6) : 8.23 (m, 3H), 8.06 (m, 3H), 4.33 (m, 2H), 3.73 (m, 4H), 3.25 (m, 2H), 3.01 (m, 1H), 2.72 (m, 2H), 2.44 (m, 1H), 2.34 (m, 2H), 1.5-1.8 (m, 6H), 1.35 (m, 4H);

MS m/e 329 (MH+);

Analysis for C15H28N4O42HCl 2H2O (437,4):

Calculated: 41.19, H 7.84, N 12.81

Found: 40.97, H 7.75, N 12.44

Example 7. N-(N- aminocaproyl)-Nip -- Ala -- HE (compound 5)

N-(N- aminocaproyl)-Nip -- Ala-OBN, prepared starting from racemic methyl ester nicotinebuy acid and ether N-oxysuccinimide and N- Side-by-aminocaproic acid, as in example 1, was isolated in the form of oily solids:

1H NMR (CDCl3) : 1.34 (m, 5H), 6.51 (m, 1H), 5,12 (s, 2H), 4.60 (m, 1H), 4.39 (m, 1H), 3.90 (m, 1H), 3.71 (t, 1H), 3.52 (m, 3H), 3.19 (m, 4H), 2.59 (m, 2H), 2.30 (m, 2H), 1.85 (m, 3H), 1.63 (m, 2H), 1.51 (m, 2H), 1.42 (s, 9H), 1.34 (m, 2H);

MS m/e 504 (MH+).

Compound 5, prepared by hydrogenolysis, and then acid hydrolysis of N-(N- Side-aminocaproyl)- Nip -- Ala-OBN, as in example 1, was isolated in the form of a vitreous substance:

1H NMR (DMSO-d6) : 8.18 (t, J=5.1 H), 8.04 (br.s, 3H), 4.28 (m, 2H), 3.78 (m, 2H), 3.20 (m, 3H), 2.99 (t, J=12.1 H), 2.71 (d, J=6.2 H), 2.39 (m, 2H), 2.31 (m, 2H), 2.16 (m, 1H), 1.79 (m, 1H), 1.61 (m, 4H), 1.42 (t, J=6.2 H), 1.28 (m, 2H), 1.19 (m, 1H);

MS m/e 314
Found: 45.91, H 7.63, N 11.17

Example 8. N-[3-(4-piperidinophenyl)]-Nip- -- Ala -- HE (compound 17)

N-[3-(4-pyridinethiol)] -Nip -- Ala-OBN, prepared starting from 3-(4-pyridine)acrylic acid and racemic methyl ester nicotinebuy acid, as in example 1, was isolated as a glassy substance:

1H NMR (CDCl3) : 8,61 (d, J=4 Hz, 2H), 7.52 (d, J=15 Hz, 1H), 7.35 (m, 7H), 7.03 (d, J=15 Hz, 1H), 6.58 (m, 1H), 5.12 (m, 2H), 4.40 (m, 1H), 3.89 (m, 1H), 3.51 (m, 2H), 3.38 (m, 2H), 2.60 (t, J=6 Hz, 2H), 2.31 (m, 1H), 1.97 (m, 2H), 1.74 (m, 1H), 1.56 (m, 1H);

MS m/e 422 (MH+).

To a solution of N-[3-(4-pyridinethiol)]-Nip -- Ala-OBN (0.56 g of 1.33 mmol) in ethanol (20 ml) and water (10 ml) under nitrogen atmosphere was added HCl (0,66 ml, 4.0 M in dioxane) and platinum oxide IV (to 0.060 g). This mixture was hydrogenosomal at 50 psi/RT at room temperature for 22 hours, filtered through celiby filter and evaporated to approximately 5 ml of this solution worked MeCN (30 ml), was filtered, washed with diethyl ether (3h20 ml), and dried to obtain 17 in the form of a pale yellow foam:

1H NMR (DMSO-d6) : 9.02 (br.s, 2H), 8.03 (m, 1H), 7.46 (m, 1H), 4.28 (t, J= 7.1 H), 4.11 (m, 1H), 3.79 (m, 1H), 3.44 (t, J=7.1 H), 3.19 (m, 3H), 3.06 (t, J=12.1 H), 2.75 (d, J=11.1 H), 2.53 (m, 1H), 2.32 (m, 4H), 2.12 (m, 1H), 1.77 (m, 2H), 1.4-1.7 (m, 7H), 1.27 (m, 2H), 1.18 (t, J=6, 1H);

MC m/e 340 (MH+);

Analysis for Cis CNA protonated mass, calculated for C17H29N3O4: 340,2236 amu, found: 340,2245 amu.

Example 9. N- AC-L-Lys-Nip-Gli-HE (compound 6)

N- AC-L-Lys(Side)-Nip-Gli-OBN prepared starting from N- AC-L-Lys(Side)-and racemic methyl ester nicotinebuy acid (see 14), was isolated as a glassy substance:

1H NMR (CDCl3) : 7.35 (m, 5H), 6.97 (m, 1H), 6.38 (m, 1H), 5.14 (m, 2H), 4.70 (m, 1H), 4.46 (m, 1H), 4.06 (dd, J=5, 16 Hz, 2H), 3.71 (m, 1H), 3.10 (m, 2H), 1.99 (s, 3H), 1.91 (m, 2H), 1.64 (m, 1H), 1.41-1.60 (m, 1H), 1.39 (s, 9H);

MS m/e 547 (MH+).

Compound 6 prepared by hydrogenolysis of N- AC-L-Lys(Side)-Nip-Gli-OBN as in example 2, and then TFU-mediated removal of the Side (the way see M. Bodanszky, The Practice. of Peptide Synthesis Springer-Verlag: New York, 1984), was allocated in the form of a yellowish - brown powder with a melting point 40o-55oC.

1H NMR (DMSO-d6) : 8.24 (t, J=6, 1H), 8.03 (d, J=8, 1H), 7.75 (br.s, 3H), 4.24 (m, 1H), 3.72 (t ,J=6, 2H), 3.61 (m, 2H), 2.72 (m, 2H), 1.83 (s, 3H), 1.78 (m, 2H), 1.63 (m, 2H), 1.4-1.6 (m, 8H), 1.28 (m, 4H);

MS m/e 357 (MH+);

Analysis for C16H28N4O53C2HF3O2(698,5):

Calculated: 37.83, H 4.47, N 8.02

Found: 37.91, H 4.89, N 8.47

Example 10. NAnd the - AC-L-Lys(Side)-and racemic methyl ester nicotinebuy acid, as in example 1, was isolated as a white foam:

1H NMR (CDCl3) : 7.34 (m, 5H), 6.53 (m, 2H), 5.12 (s, 2H), 4.58 (m, 1H), 4.10 (m, 1H), 3.72 (m, 1H), 3.54 (m, 2H), 3.11 (m, 3H), 2.59 (m, 2H), 2.24 (m, 1H), 2.01 (s, 3H), 1.88 (m, 1H), 1.73 (m, 2H), 1.52 (m, 8H), 1.40 (s, 9H), 1.31 (m, 1H);

MS m/e 561 (MH+).

Compound 7 prepared by hydrogenolysis of N- AC-L-Lys(Side)-Nip -- Ala-OBN, as in example 1, and then acid hydrolysis as in example 6, was selected as a white foam with a melting point 53-67oC.

1H NMR (DMSO-d6) : 8.13 (m, 1H), 8.00 (m, 1H), 7.91 (d, J=15, 3H), 4.64 (m, 1H), 4.36 (m, 1H), 3.87 (m, 1H), 3.66 (m, 2H), 3.23 (m, 3H), 2.99 (m, 1H), 2.68 (m, 2H), 2.59 (m, 1H), 2.38 (m, 2H), 2.11 (m, 1H), 1.80 (s, 3H), 1.63 (m, 1H), 1.4-1.6 (m, 5H), 1.24 (m, 3H);

MS m/e 371 (MH+);

Analysis for C17H30N4O52HCl2H2O (479,4)

Calculated: 42.59, H 7.57, N 11.69

Found: 43.83, H 7.79, N 10.91

Example 11. N- BOC-L-Arg-Nip -- Ala -- HE (compound 8)

N- BOC-L-Arg(CBZ)-Nip -- Ala-OBN, prepared starting from N- BOC-L-Arg(CBZ2)-OSu and racemic methyl ester nicotinebuy acid, as in example 1, was isolated as a glassy substance:

1H NMR (CDCl3) : 7.33 R>
MS m/e 681 (MH+).

Compound 8 prepared by hydrogenolysis of N- BOC-L-Arg(CBZ)-Nip -- Ala-OBN, as in example 1, was selected as a white foam with a melting point 47-55oC.

1H NMR (DMSO-d6) : 9.53 (m, 1H), 7.85 (m, 2H), 6.96 (m, 1H), 4.32 (m, 2H), 3.84 (m, 1H), 3.38 (m, 2H), 3.03 (m, 4H), 2.20 (m, 3H), 1.74 (m, 2H), 1.4-1.7 (m, 8H), 1.35 (s, 9H), 1.24 (m, 2H);

MS m/e 457 (MH+);

Analysis for C20H36N6O61,5 C2H4O2(546,6):

Calculated: 50.54, H 7.74, N 15.37

Found: 50.24, H 7.96, 15.26

Example 12. N- BOC-L-Lys-Nip -- aminobutyric acid (compound 9)

Benzyl ester of N- BOC-L-Lys(CBZ)-Nip -- aminobutyric acid, prepared starting from N- BOC-L-Lys(CBZ)-and racemic methyl ester nicotinebuy acid (see 1-1 and 1-2), was isolated as a glassy substance:1H NMR (CDCl3) : 7.33 (m, 10H), 6.48 (m, 1H), 6.16 (m, 1H), 5.40 (m, 1H), 5.11 (s, 2H), 5.08 (s, 2H), 4.89 (m, 1H), 4.58 (m, 1H), 4.07 (m, 1H), 3.22 (m, 5H), 2.52 (m, 1H), 2.40 (m, 2H), 1.50-2.30 (m, 12H), 1.42 (s, 9H), 1.33 (m, 1H);

MS m/e 667 (MH+).

Compound 9 prepared by hydrogenolysis of benzyl ester of N- BOC-L-Lys(CBZ)-Nip -- aminobutyric acid, as in example 1, was selected as Bel (m, 2H), 3.15 (m, 2H), 2.98 (m, 3H), 2.69 (m, 2H), 2.10 (m, 3H), 1.76 (m, 3H), 1.4-1.7 (m, 9H), 1.31 (s, 9H), 1.21 (m, 2H);

MS m/e 443 (MH+);

Analysis for C21H38N4O62 C2H4O2(562,7):

Calculated: 53.37, H 8.24, N 9.96

Found: 53.94, H 8.17, N 9.70

Example 13. H-D-Lys-Research -- Ala -- HE (compound 10)

Compound 10 prepared by acid hydrolysis of 3, as in example 6, was allocated in the form of a cream-coloured powder with a melting point 108-128oC.

1H NMR (DMSO-d6) : 8.28 (m, 3H), 8.05 (m, 3H), 4.31 (m, 2H), 3.84 (m, 2H), 3.25 (m, 2H), 3.09 (m, 2H), 2.72 (m, 3H), 2.37 (m, 3H), 1.80 (m, 1H), 1.5-1.7 (m, 6H), 1.33 (m, 4H);

MS m/e 329 (MH+);

Analysis for C15H28N4O42HCl C2H4O2(461,4):

Calculated: 44.26, H 7.43, N 12.14

Found: 43,98, H 7.27, N 12.29

Example 14. N- BOC-D-Lys-Nip -- aminobutyric acid (compound 11)

Benzyl ester of N- BOC-D-Lys(CBZ)-Nip -- aminobutyric acid, prepared starting from N- BOC-D-Lys(CBZ)-and racemic methyl ester nicotinebuy acid, as in example 1, was isolated as a glassy substance:

1H NMR (CDCl3) : 7.31 (m, 10H), 6.51 (m, 1H), 5.48 (m, 1H), 5.10 (s, 1H), 5.06 (s, 2H), 4.90 (m, 1H), 4.55 (m, 1H), 4.10 (m, 1H), 3.59 (m, 1H), 3.23 (m, 5H), 2.39 (m, 2H), 2.23 (m, STV hydrogenolysis of benzyl ester of N- BOC-D-Lys(CBZ)-Nip- -- aminobutyric acid, as in example 1, was isolated in the form of a yellowish-brown powder with a melting point 50-57oC.

1H NMR (DMSO-d6) : 7.97 (m, 1H), 6.91 (m, 1H), 4.32 (m, 1H), 4.22 (m, 1H), 3.82 (m, 1H), 3.02 (m, 3H), 2.71 (m, 2H), 2.52 (m, 1H), 2.29 (m, 1H), 2.17 (m, 2H), 1.84 (m, 5H), 1.4-1.7 (m, 9H), 1.33 (s, 9H), 1.19 (m, 2H);

MS m/e 443 (MH+);

Analysis for C21H38N4O6C2H4O20.5 H2O (571,7):

Calculated: at 52.53, H 8.29, N 9.80

Found: 52.91, H 8.21, N 9.39

Example 15. N- BOC-D-Lys-Nip-Gli-OH (compound 12)

N- BOC-D-Lys(CBZ)-Nip-Gli-OBN prepared starting from N- BOC-D-Lys(CBZ)-and racemic methyl ester nicotinebuy acid, as in example 1, was isolated as a glassy substance:

1H NMR (CDCl3) : 7.39 (m, 10H), 6.87 (m, 1H), 5.42 (m, 1H), 5.19 (s, 2H), 5.13 (s, 2H), 4.93 (m, 1H), 4.60 (m, 1H), 4.20 (m, 1H), 4.09 (m, 1H), 3.40-4.00 (m, 3H), 3.21 (m, 2H), 2.61 (m, 1H), 2.43 (m, 1H), 1.45-2.20 (m, 10H), 1.39 (s, 9H);

MS m/e 639 (MH+).

Connection 12 prepared by hydrogenolysis of N- BOC-D-Lys(CBZ)-Nip-Gli-OBN as in example 1 was allocated in the form of white flakes with a melting point 66-80oC:

1H NMR (DMSO-d6) : 7.82 (m, 1H), 6.81 (d, J=4, 1H), 4.34 (m, 2H (MH+);

Analysis for C19H34N4O62 C2H4O2(tune 534.6):

Calculated: at 51.67, H 7.92, N 10.48

Found: 52.06, H 8.33, N 10.19

Example 16. N- AC-D-Lys-Nip -- Ala -- HE (compound 13)

N- AC-D-Lys(CBZ)-Nip -- Ala-OBN, prepared starting from N- AC-D-Lys(CBZ)-and racemic methyl ester nicotinebuy acid, as in example 1, was isolated as a glassy substance:

1H NMR (CDCl3) : 7.32 (m, 10H), 6.54 (m, 1H), 6.36 (m, 1H), 5.10 (s, 2H), 5.02 (s, 2H), 4.89 (m, 2H), 4.48 (m, 1H), 4.04 (m, 1H), 3.69 (m, 1H), 3.52 (m, 2H), 3.17 (m, 3H), 2.57 (m, 2H), 2.20 (m, 1H), 1.98 (s, 3H), 1.25-1.90 (m, 10H);

MS m/e 595 (MH+).

Compound 13 is prepared by hydrogenolysis of AC-D-Lys(CBZ)-Nip -- Ala-OBN, as in example 1, was isolated in the form of a vitreous substance with a melting point 46-59oC.

1H NMR (DMSO-d6) : 8.11 (m, 3H), 4.70 (m, 1H), 4.33 (m, 1H), 3.74 (m, 1H), 3.38 (m, 1H), 3.19 (m, 4H), 3.00 (m, 1H), 2.68 (m, 2H), 2.21 (m, 4H), 1.82 (s, 3H), 1.76 (m, 2H), 1.4-1.7 (m, 7H), 1.24 (m, 2H);

MS m/e 371 (MH+);

Analysis for C17H30N4O52,5 C2H4O2(520,6):

Calculated: 50.76, H 7.74, N 10,76

Found: 51.12, H 8.04, N 10.75

Example 17. N- BOC-L-Lys(I-PR)-Nip -- Ala -- HE (compound 15)

N

1H NMR (CDCl3) : 7.33 (m, 10H), 6.58 (m, 1H), 5.10 (s, 2H), 5.08 (s, 2H), 4.55 (m, 1H), 4.21 (m, 1H), 3.73 (m, 1H), 3.50 (m, 2H), 3.17 (m, 3H), 2.55 (m, 2H), 2.18 (m, 1H), 1.50-2.00 (m, 13H), 1.40 (s, 9H), 1.13 (d, J=8 Hz, 6H);

MS m/e 695 (MH+).

Compound 15 is prepared by hydrogenolysis of N- BOC-L-Lys(I-PR)(CBS)-Nip -- Ala-OBN, as in example 1, was isolated in the form of white flakes with a melting point 90-123oC:

H NMR (DMSO-d6) : 7.93 (m, 1H), 6.81 (d, J=7, 1H), 4.36 (m, 1H), 4.24 (m, 1H), 3.60 (m, 1H), 3.37 (m, 1H), 3.10 (m, 1H), 2.91 (m, 3H), 2.62 (m, 3H), 2.39 (m, 2H), 2.14 (m, 1H), 2.05 (m, 1H), 1.4-1.8 (m, 9H), 1.34 and 1.37 (pr.s, 1:1, 9H), 1.26 (m, 3H), 1.13 (d, J=5, 6H);

IR (KBr) 3500-2830, 1704, 1638 cm-1;

MS m/e 471 (MH+);

Analysis for C23H42N4O62 C2H4O2(590,7)

Calculated: 54.90, H 8.53, N 9.48

Found: 54.67, H 8.65, N 9.79

Example 18. N- BOC-D-Lys-R-(-)-Nip -- Ala -- HE (compound 16)

Compound 16 is prepared starting from N- BOC-D-Lys(CBZ)-HE and methyl ester of R-(-)-nicotinebuy acid, as in example 1, was isolated in the form of colorless flakes melting temperature 42-51oC.

1H NMR (DMSO-d6) : 7.95 (m, 1H), 6.82 (d, J=7, 1H), 4.33 (m, 1H), 4.19 (m, 1H), 3.79 (m, 1H), 3.25 (m, 1H), 3.04 (t, J=10, 2H), 2.69 (m, 2H), 2.34 (mC20H36N4O42,5 C2H4O2(578,7)

Calculated; With at 51.89, H 8.01, N 9.68

Found: 52.05, H 7.98, N 9.58

Example 19. N-(N- aminocaproyl)-3-piperidine - methylaminopropane acid (compound 19)

To a solution of N-(N- Side-aminocaproyl)nicotinebuy acid (3.1 g, 9.0 mmol) and THF (50 ml) was added 1,1-carbonyldiimidazole (1.45 g, 9.0 mmol). This solution was stirred for 1 hour, cooled to -10oC, was added dropwise Dibal (36,0 ml, 1.0 M in toluene) for 20 minutes and stirred for another 2 hours. This solution worked aqueous solution of citric acid (5.0 g in 40 ml water) was diluted with CHCl3(200 ml) and the resulting layers were separated. The aqueous layer was extracted with CHCl3(100 ml) and the combined organic layers were dried, evaporated and purified by flow chromatography (4% ethanol/CH2Cl2) to obtain N-(N- Side-aminocaproyl)-piperidine-3-carboxaldehyde in the form of a vitreous substance.

1H NMR (CDCl3) : 9.65 (d, J=7 Hz, 1H), 4.58 (m, 1H), 4.10 (m, 1H), 3.65 (m, 1H), 3.45 (m, 1H), 3.22 (m, 1H), 3.14 (m, 2H), 2.46 (m, 2H), 2.33 (t, J= 7 Hz, 1H), 2.09 (m, 1H), 1.5-1.8 (m, 7H), 1.39 (s, 9H), 1.33 (m, 2H);

MS m/e 327 (MH+).

K the solution of N-(N- Side-aminocaproyl)piperidine-3 - ka is l) and NaC NBH3(0,13 g, 2,12 mmol). This mixture was stirred for 2.5 hours and evaporated to yield a white solid. This solid substance was divided between a saturated solution of NaHCO3(10 ml) and CH2Cl2(50 ml) and the layers were separated. The aqueous layer was extracted with CH2Cl2(G ml) and the combined organic layers were dried, evaporated and purified by flow chromatography (0.5% of NH4OH/ 4-10% ethanol/CH2Cl2) to obtain benzyl ester N-(N- Side-aminocaproyl)-3-piperidinecarbonitrile acid in the form of a vitreous substance.

1H NMR (CDCl3) : 7.33 (m, 5H), 5.13 (s, 2H), 4.61 (m, 1H), 4.28 (m, 1H), 3.70 (m, 1H), 3.11 (m, 3H), 2.85 (m, 3H), 2.5 (m, 4H), 2.31 (t, J=4 Hz, 2H), 1.5-1.9 (m, 8H), 1.42 (s, 9H), 1.29 (m, 3H), 0.89 (m, 1H);< / BR>
MS m/e 490 (MH+).

To a solution of benzyl ester of N-(N- Side-aminocaproyl)-3 - piperidinecarbonitrile acid (0.28 g, or 0.57 mmol) and THF (10 ml) at room temperature was added aqueous HCl (3.4 ml, 1,0 H). This mixture was stirred for 22 hours, evaporated to a glassy solid, triturated with diethyl ether (CH ml) and dried to yield a white powder. This powder was dissolved in THF (5 ml) and water (10 ml), transferred into a flask Parr under atmosphere and is filtered through celiby filter and evaporated to approximately 5 ml This solution worked MeCN (25 ml), was filtered, washed with diethyl ether (CH ml), and dried to obtain 19 in the form of a colorless glassy substance (GWHR purity > 95%) with a melting point 65oC-7oC.

1H NMR (DMSO-d6) : 9.31 (m, 2H), 8.12 (br.s, 3H), 4.18 (m, 2H), 3.70 (m, 1H), 3.04 (m, 2H), to 2.67 (m, 5H), 2.51 (m, 1H), 2.35 (m, 3H), 1.87 (m, 2H), 1.58 (m, 4H), 1.42 (m, 2H), 1.30 (m, 4H);

MS m/e 300 (MH+).

Accurate protonated mass calculated for C15H29N3O32HCl (372,3): 300,2287 amu. Found: 300,2306 amu.

1. The connection represented by the General formula I

< / BR>
in which x1and x2the same or different and represent H2or O;

Y are selected from (CH2)mCH(NHCOR3)(CH2)mor CH(NH2)(CH2)m;

Choose from A other1C(:NH)NH2or cycloalkyl ring containing a nitrogen atom which is selected from piperidine-2-yl, piperidine-3-yl, piperidine-ILA, pyrrolidin-2-yl and pyrrolidin-3-yl;

Z is selected from (CH2)nor CH(CO2R4) (CH2)n;

R1selected from H, alkyl, or CH(NH)NH2;

R2selected from H or alkyl;

R3selected from alkoxy or alkyl;

R4predstave, 1, 2 or 3;

n represents the integer 0, 1 or 2,

or its enantiomers or its pharmaceutically acceptable salt.

2. Connection on p. 1, where Z is (CH2)2.

3. Connection on p. 1, where R1represents H.

4. Connection on p. 1, where R2represents H.

5. Connection on p. 1, where R3is t-butoxy.

6. Connection on p. 1, where R4represents methyl.

7. Connection on p. 1, where Z represents CH(CO2R4)(CH2).

8. Connection on p. 1, selected from the group:

N-BOC-L-Lys(CBZ)-Nip--Ala-OBN (compound 1);

N-BOC-L-Lys-Nip--Ala -- HE (compound 2);

N-BOC-D-Lys-Nip--Ala -- HE (compound 3);

H-L-Lys-Nip--Ala -- HE (compound 4);

N-(N-aminocaproyl)-Nip--Ala -- HE (compound 5);

N-AC-L-Lys-Nip-Gli-HE (compound 6);

N-AC-L-Lys-Nip-is-Ala-HE (compound 7);

N-BOC-L-Arg-Nip--Ala -- HE (compound 8);

N-BOC-L-Lys-Nip--aminobutyric acid (compound 9);

H-D-Lys-Nip--Ala -- HE (compound 10);

N-BOC-D-Lys-Nip--aminobutyric acid (compound 11);

N>BOC-D-Lys-S-(+)-Nip--Ala -- HE (compound 14);

N-BOC-L-Lys(I-PR)-Nip--Ala -- HE (compound 15);

N-BOC-D-Lys-R-(-)Nip--Ala -- HE (compound 16);

N-[3-(4-piperidinophenyl)]-Nip--Ala -- HE (compound 17);

N-BOC-D-Lys-Nip-L-ASP-OMe (compound 18) or

N-(N-aminocaproyl)-3-piperidinylcarbonyl acid (compound 19).

Priority points:

16.03.94 - p. 1;

27.12.94 - PP.2 - 8 (clarification of signs).

 

Same patents:

The invention relates to novel 2,6-dimethylaniline N - cyclopropylmethyl-2-carboxylic acid f-ly I, where R is cyclopropyl or methylcyclopropyl in the form of a racemic mixture or the individual enantiomers or their salts, which exhibit increased antiarrhythmic and local anestesiologia properties and can find application in medicine

The invention relates to new cycloalkenes and cycloalkanes, suitable as pharmaceutically active substances, more particularly to derivatives of 1,3-substituted of cycloalkene and cycloalkane formula (I)

Z-CH2-Y (I)

where Z stands for a group

< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

Y - group

< / BR>
where R is the specified value,

mixtures of their isomers or the individual is

The invention relates to a method for producing (+) (2R)-endo-norbornene and (-)-(2S)-endo-norbornene and their subsequent transformations, respectively, in pharmaceuticals, 5-(3-[(2S)-endo-norbornene and their subsequent transformations, respectively, in pharmaceuticals, 5-(3-[(2S)-Exo-bicyclo [2.2.1] gate-2-yloxy] - 4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2 (1H)he is of the formula:

,

and its enantiomer, 5-(3- [(2R.) -Exo-bicyclo [2.2.1.]hept-2 - yloxy]- 4 - methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2 (1H)-he, of the formula:

The invention relates to new derivatives isoindoline General formula:

< / BR>
in which the radicals R represent hydrogen atoms or together form a single bond; the radical R' represents a hydrogen atom or easily removable and the radicals R" are identical, represent phenyl radicals which may be substituted by a halogen atom or a methyl radical in the ortho - or meta-position, as well as their salts

The invention relates to polycyclic aminecontaining compounds, to their optically pure enantiomers, the way they are received, to Farmaceutici on their basis, as well as to new intermediate compounds for the synthesis of polycyclic compounds

The invention relates to new carboxamides f-ly 1, where E-N, G-H, lower alkyl, lower alkylene COOH, COO-lower alkyl, lower alkanoyl, lower alkanoyloxy, lower alkoxy, aryl-lower alkoxy, СОNH2and others, M-H, lower alkyl, lower alkenyl, aryl, heteroaryl, cycloalkyl, L-H, lower alkyl, aryl, cycloalkyl, or M and L together with the atoms to which they are linked, form a group - N (het), or E and G spot form a methylene or carbonyl group, and M represents H, lower alkyl, lower alkenyl, aryl, heteroaryl, cycloalkyl, L-H, lower alkyl, aryl , cycloalkyl, A-H, alkyl, aralkyl, Q represents a group of formula Q1or Q2T-CH2or Oh, R6and R7- H, cerboneschi alkoxy, HE

The invention relates to novel 1,2,4-substituted piperidines formula 1, where R1is unsubstituted or substituted with halogen and/or trifluoromethyl phenyl or diphenyl-C1-C4-alkyl, ; 9-fluorenyl, pyridil-C1-C4-alkyl; chinolin-C1-C4-alkyl; 5-chloro-2-[1H-1,2,4-triazolyl-1-yl]-phenoxy-C1-C4-alkyl, unsubstituted or substituted C1-C4-alkyl, C1-C4-alkoxyl, hydroxyl, halogen, trifluoromethyl, di-C1-C4-alkylamino-group and/or cyano benzoyl; naphtol; 2-fluorenyl; phenyl - or diphenyl-C2-C4-alkanoyl; naphthyl-C2-C4-alkanoyl; dimethylcyclohexanols; hinolincarbonova; pyridyl-C2-C4-alkanoyl; benzyloxycarbonyl, unsubstituted or substituted by acetyl or 4-carboxymethylation phenylalanine or phenylcarbamoyl; 2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indol-3-yl-carbonyl; R2is unsubstituted or substituted with halogen phenyl or naphthyl; R3is hydrogen, C1-C4-alkyl, cyclohexyl or phenylcarbamoyl, or 3-aminocarbonylmethyl; R4- if necessary substituted C1-C4-alkyl or C1-C4-alkoxyl phenyl, naphthyl, benzyl, pyridyl, if necessary, C-Zam the sludge; if necessary substituted C1-C4the alkyl benzothiophenes, dihydrobenzofuranyl or aniline group, X1- simple bond, methylene, hydroxymethylene or carbonyl, X2- a simple link, X3- simple bond, methylene, ethylene, benzylidene or carbonyl or their salts

The invention relates to new derivatives of arylalkylamines, as well as containing their farbkomposition, which can find application in pathological conditions involving the system of neurokinin

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, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid
Up!