The derived amino(thio)esters, methods for their preparation, pharmaceutical composition and method of reception

 

(57) Abstract:

Describes new derivatives of amino(thio) ethers of the formula (I), where X represents oxygen, sulfur, or, if R0and R1together are not alkalinous chain with 1-3 atoms, CH2; Z represents -(CH2)n1-(CHA)n2-(CH2)n3and n1= 0, 1, 2 or 3, n2= 0 or 1, n3= 0, 1, 2 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, or R0and R1together represent alkylenes chain with 1-3 carbon atoms or alkenylamine chain of 2-3 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, thiophene unsubstituted, mono - or disubstituted by A, OA, OH, F, Cl, Br, or other thienyl group; R5represents a phenyl group which is unsubstituted or mono-, di-, tri-, Tetra-, or pentamidine F, CF3that part is et a H, A, OA, phenoxy, OH, F, Br, I, CN, CF3, NO2, NH2, Ph, Cl and/or R1and R6together represent alkylenes chain with 3-4 carbon atoms, A represents alkyl with 1-6 carbon atoms, Ph represents a phenyl, unsubstituted or substituted R5, 2-, 3 - or 4-pyridium or phenoxyl group; and physiologically acceptable salts of these derivatives. New connections have an effect on the Central nervous system, especially as agonists and antagonists of serotonin. They can be used as active ingredients tranquilizers, antidepressants, neuroleptics and/or antihypertensive drugs. Describes how compounds of formula (I), pharmaceutical composition and a method of obtaining a composition. 5 C. and 4 h.p. f-crystals, 1 PL.

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;
3, 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 other thienyl group);

R5represents a phenyl group which is unsubstituted or mono-, 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 atamet an 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 salt derivatives thereof.

The purpose of the present invention is new derivatives of amino(thio)esters, which have valuable pharmacological properties and can be used for the preparation of drugs.

Found that the compounds of formula 1 and their biologically compatible acid salts, which are addition products, have valuable pharmacological properties. In particular, they have an effect on the Central nervous system, especially as agonists and antagonists of serotonin. These compounds inhibit the binding of tritium-labeled serotonin ligand with the receptor in the hippocampus (Cossery et al., European J. Pharmacol. 140 (1987), 143-155). These compounds alter the accumulation of 3-4-hydroxyphenylglycine in the corpus, the striatum (striped body) and the accumulation of 5-NTR in the binding of nuclei (Seyfried et al., European J. Pharmacol. 160 (1989), 31-41). They also have analgesic and anti-hypertensive effects: for example, in rats, which introduced the catheter and which POS (1960), 646-648), directly measured blood pressure was reduced after oral administration of the compounds. They are applicable also for the prevention and treatment of the consequences of cerebral infarction (Apoplexia cerebri), such as strokes and cerebral ischemia.

These compounds can be used for the treatment of diseases that are associated with interventions in serotoninergicescuu and dopaminergic systems, and related receptor-like receptor 5-hydroxytryptamine (type 5HTIA) and/or dopamine (D 2).

These compounds suitable for treating disorders of the Central nervous system such as anxiety, stress and depression, sexual disorders caused by Central nervous system disorders, sleep disorders or absorption of food. Moreover, these compounds can be used to correct various types of mental disability, to improve the ability to doctrine and memory, as well as for the treatment of Alzheimer's disease. These compounds can be used for psychosis (schizophrenia).

Thus, the compounds of formula I and their biologically compatible acid salts, which are addition products can be used as active ingredients of trich connections to other pharmaceutically active ingredients.

The present invention relates to derivatives of amino(thio)ethers of the formula I and their biologically compatible acid salts, which are products of the merger.

Radical And represents alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, especially with 1 to 2 carbon atoms, preferably methyl, but also ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. OA represents preferably methoxy, and ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, NHA represents preferably methylamino and ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino or tert-butylamino. NA2represents preferably dimethylamino, N-ethyl-N-methylamino, diethylamino, -n-propylamino, diisopropylamino or di-n-butylamino.

Ac represents preferably alkanoyl with 1-6 carbon atoms, in particular 1, 2, 3 or 4 carbon atoms, preferably formyl or acetyl, and then (preferably) propionyl, butyryl, isobutyryl, pentanoyl or hexanoyl, and preferably benzoyl, o -, m - or p-toluyl, 1 - or 2-naphtol.

X preferably represents oxygen or sulfur,e is preferably-CH2- (CHCH3), -(CH2)2-(CHCH3), -CH2-(CHCH3)-CH2- or -(CHCH3)-(CH2)2.

The remainder R0represents preferably H or methyl, but R0and R1together represent alkylenes chain, preferably comprising 2 carbon atoms. If R1has a different meaning, in addition to the above, it preferably represents hydrogen, A, OA, CONH2or CN.

R2represents preferably H or A, and R3represents preferably 2-, 3 - or 4-pyridylmethyl or phenyl substituted by another phenyl, or, further, R3is thienyl, preferably substituted another thienyl group.

The radical R3matters, mainly, 2, 3 or 4-pyridylmethyl, 5-phenyl-3-pyridylmethyl, 3-biphenylyl, 5-(forfinal)-3-pyridylmethyl, 5-(methoxyphenyl)-3-pyridylmethyl, 4'-fluoro-3-biphenylyl, or 4-(thienyl)-2-thienylmethyl. Further, the radical R3preferably has a value of 2, 4, 5 or 6-(m-forfinal)-3-pyridylmethyl, 3, 4, 5 or 6-(m-forfinal)-2-pyridylmethyl or 2 or 3-(m-forfinal)-4-pyridylmethyl, where instead of "m" are prefixes "mono", "di", "tri -, Tetra or Penta".

R6, R7, R preferably together represent alkylenes chain with 4 carbon atoms. Next, another preferred value: two neighboring residue selected from R6, R7, R8and R9together constitute alkylenes chain with 3-4 carbon atoms.

The invention relates in particular to such compounds of formula I in which at least one of these radicals has one of the abovementioned meanings, especially the preferred meanings. Some preferred groups of compounds can be expressed as the following partial formulas Ia to Ii, which conform to the formula I and in which the radicals and the remaining parameters correspond to the radicals and parameters of the formula I, except for the following:

in Ia X owl is oxygen, R0and R1together represent -(CH2)2Z represents a methylene, and R6, R7, R8and R9represent hydrogen;

in Ib X represents oxygen, R0and R1together represent -(CH2)2-, Z represents a methylene, and R4represents pyridyl or biphenyl, unsubstituted or monosubstituted;

in Ic X represents a key is UP> represents 5-(4-forfinal)-3-pyridyl;

in Id X represents oxygen, R0and R1together represent a methylene, and R4represents 5-(4-forfinal)-3-pyridyl;

Ie X represents oxygen, R0represents hydrogen, Z represents methylene, and R4represents 5-(4-forfinal)-3-pyridyl;

If X represents oxygen, R0and R1represent hydrogen, Z is a methylene, and R4represents 5-(4-verfeil)-3-pyridyl;

in Ig, X represents oxygen, R0represents hydrogen, R1represents chlorine, ethyl or methoxy, Z is a methylene, a R4represents 5-(4-forfinal)-3-pyridyl;

in Ih X represents oxygen, Z is a methylene, and R4represents 5-phenyl-3-pyridyl;

in Ii, X represents oxygen and Z represents -(CH2)2-, -(CH) - or -(CHCH3)-, and R4represents 5-(4-forfinal)-3-pyridyl;

as well as salts of these compounds.

The most preferred compounds are compounds having the partial formula Ik and Iak - Iik, which correspond to the partial formulae I and is it the invention relates also to a method for producing derivatives of imino(thio)ethers of the formula I and their salts and is the compound of formula II

< / BR>
where G represents Cl, Br, I, OH or an OH group, a functionally modified prior to the formation of chemically active groups, especially the deleted group and the radicals R0, R1, R6, R7, R8, R9, X and Z have the above values, interact with the amine of formula III

HNR2R3< / BR>
where R2and R3have the above values,

or the fact that the compounds of formula IV

< / BR>
where M represents H, Li+, Na+, K+, NH4+or other suitable metal ion, and X, R1, R6, R7, R8and R9have the above values, interact with the compound of the formula V

< / BR>
where G' has the same values as G, and R0, R2, R3and Z have the above meanings, or the fact that the compound of formula VI

< / BR>
where R0and R1together represent alkylenes chain with 1-3 carbon atoms, and R2, R3, R6, R7, R8, R9, X, Z, M and G have the meanings indicated above is subjected to cyclization reaction to education aminopyrrolo or aminothiophenol derivative of the formula I, or the fact that the compound of formula I, with the exception of those compounds of formula I is more additional bonds C-C and/or C-N, is treated with a reducing agent, or the fact that the compound of formula I, with the exception of those compounds of formula I in which one or more hydrogen atoms replaced by one or more groups that can react of solvolysis, is treated with a reagent that causes the solvolysis reaction and/or the fact that the OA group may be split before the formation of the OH group, and/or the fact that the group Ar is converted into another group Ar, and/or those that received a base or acid of the formula I is converted into one of its salts upon treatment with acid or base.

The compound of the formula I can also be obtained by other known methods such as described in the literature methods (for example, works such as Houben-Weyl, Methods der Organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc, New York), namely with the use of such reaction conditions which are known and suitable for the said reactions. It is also possible to use other known variants. If desired, the starting materials for the method according to the invention can be obtained on the spot, while they are not isolated from the reaction medium, but immediately carry out further reactions to produce compounds of formula I.

In derivatives of the formula II G p modified to obtain a reactive group, especially alkylsulfonate with 1-6 carbon atoms (for example, methanesulfonate) or arylsulfonate with 6-10 carbon atoms (for example, benzosulfimide, R toluensulfonate, naphthalene-1 or 2-sulfonyloxy).

Some of the compounds of formula II and, in particular, of the formula III are known; the unknown compounds of formulas II and III can be easily obtained by the same methods as known compounds of these formulas.

Primary alcohols of the formula II can be obtained, for example, by restoring the corresponding carboxylic acids or esters. Treatment with thionyl chloride, hydrogen bromide, tribromide phosphorus or similar halogen compound gives the corresponding halides compounds of formula II. Appropriate sulfonyloxy connection can be obtained from alcohols of formula II by reacting with the appropriate sulphonylchloride.

Iodine compounds of formula 7 can be obtained, for example, by reacting potassium iodide with the appropriate ester of p-toluenesulfonic acid.

Most derivatives of amines of the formula III are known and can be obtained, for example, by alkylation or acylation of amines known.

what Yu amines. Components can be fused together in the absence of a solvent in a sealed tube or, if necessary, in an autoclave. But you can make the interaction of the compounds and in the presence of an inert solvent. Examples of suitable solvents are hydrocarbons, such as benzene, toluene or xylene; ketones, such as acetone or butanone, alcohols, such as methanol, ethanol, isopropanol or n-butanol; ethers, such as tetrahydrofuran (THF) or dioxane, amides, such as dimethylformamide (DMF) or N-methyl-pyrrolidone, or NITRILES, such as acetonitrile or other, mixtures of these solvents with each other or with water. Sometimes it is desirable to add a reagent that binds acid, such as hydroxide of alkali metal or alkaline-earth metal carbonate or bicarbonate or another salt of an alkaline or alkaline-earth metal weak acid, preferably potassium, sodium or calcium salt, or to add an organic base such as triethylamine, dimethylaniline, pyridine or gitalin, or amine component in an excessive amount. The time of reaction from a few minutes up to 14 days, depending on the selected conditions, and the reaction temperature is from about 0 to 150ousually from 20 an Association of the formula G' (CHR0)-Z-NR2R3(V). Some of the compounds of the formula V and, in particular, of the formula IV are known; the unknown compounds can be easily obtained by the same methods as known. Thus, the compounds of formula IV can be easily obtained by the reaction of methylation of phenol or thiophenol with, for example, hydrides, such as NaH, KH, or phenyllithium or methyllithium. Connection type compounds of formula IV can also be obtained by oxidation of thiophenols to get sulfanilic or sulfanilic connections.

Amines of the formula V can be obtained using as a starting compound, a primary amine, using various known methods of alkylation or acylation of amines. You can also turn the corresponding substituted nitro-compound in amines of formula V by recovery with subsequent alkylation.

The interaction of compounds IV and V is carried out using methods known from the literature on the formation of simple esters, thioesters or esters. Components can be fused with one another together directly, without solvent, in a closed properly test tube or in an autoclave, under normal or elevated pressure, and to increase the pressure is the absence of an inert solvent. Suitable are solvents mentioned above for the reactions of compounds II with compounds III. A positive effect can be additive reagent that binds acid. Suitable are the same reasons listed for the reactions of compounds II with compounds III.

Depending on the chosen reaction conditions, the optimum reaction time is from several minutes to 14 days, and the reaction temperature can be from about 0 to 150ousually from 20 to 130o.

Further, the compound of the formula I can be obtained by cyclization of compounds of formula VI, where R0and R1together represent alkylenes chain with 1-3 carbon atoms.

The compounds of formula VI can be obtained, for example, by restoring ketones, similar to compound VI, where CHG-group is replaced by a carbonyl group.

The cyclization reaction of the compounds of formula VI is produced by the methods described above for the interaction of compounds IV and V and under similar conditions.

The compound of the formula I can also be obtained by processing the original substance in which the hydrogen atoms replaced by one or more recoverable groups and/or one or more additional bonds C-C and/or C-N, Voss the second solvent.

The recovered groups (groups that can be replaced by hydrogen) are, in particular, oxygen in a carbonyl group, hydroxyl, arylsulfonate (for example, p-toluensulfonate), N-benzazolyl, N-benzyl or O-benzyl.

In principle, compounds containing only one of the above groups or additional bonds, or compounds containing two or more of the above or additional bonds adjacent to one another, can be converted to a compound of formula I by recovery, and at the same time you can restore the substituents in the group Ind, which are present in the initial compound. This is carried out, for example, using the evolving hydrogen or complex hydrides of metals, or by using a reduction reaction of wolf-Kishner, or when recovering gaseous hydrogen when using a transition metal as a catalyst.

The preferred raw materials for the reaction of recovery are the compounds of formula VII

< / BR>
where Z' is a chain corresponding to the radical Z, except that one or more of the groups-CH2substituted by a group-CO - and/or one or more hydrogen atoms substituted by Cl, Br, F, S is the Idov or esters of primary or secondary amines. It is preferable to make the interaction of the free carboxylic acid with the amine under the conditions used for the synthesis of peptides. This reaction is preferably carried out in the presence of a desiccant, such as a carbodiimide, such as dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N-ethylcarbodiimide, or papapostolou anhydride (see Angew Chem. 92, 129 (1980)), diphenylphosphinite or 2-ethoxy-N-etoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example halogenosilanes hydrocarbon, such as methylene chloride, complex ether, for example tetrahydrofuran or dioxane, in amide, for example dimethylformamide or dimethylacetamide, or a nitrile, such as acetonitrile, at temperatures from about -10o40oC, preferably from 0o30oC.

The evolving hydrogen is used as reducing agent; this can be accomplished, for example, by treating metals with weak acids or bases. You can, for example, to use a mixture of zinc from a solution of the hydroxide of an alkali metal or a mixture of iron and acetic acid. You can also use sodium or another alkali metal in an alcohol, such as ethanol, isopropanol, butanol, amyl or isoamyl or phenol. You can also use anal. For obtaining of hydrogen can also be used sodium or aluminum amalgam in aqueous-alcoholic or aqueous solution. The reaction can also be carried out in a heterogeneous phase, and in this case it is convenient to use an aqueous phase and a benzene or toluene phase.

Other reducing agents which are preferred according to the present invention, are complex metal hydrides, such as LiAlH4, NaBH4the hydride diisobutylaluminum or NaAl (OCH2CH2OCH2)2H2and DIBORANE, and if desired, can be added such catalysts as BF3, AlCl3or LiBr. Among the solvents suitable in this case, ethers, such as diethyl ether, di-n-butyl ether, tetrahydrofuran, dioxane, diglyme or 1,2-dimethoxyethane, and also hydrocarbons, such as benzene. To restore using the NaBF4use as solvents primary alcohols, such as methanol or ethanol, and water and aqueous solutions of alcohols. The restoration of these methods is preferably carried out at temperatures from -80 to +150 degrees, especially from about 0 to about 100 degrees. Recovery groups-CO amido acids (for example, formula VI, GI using LiAlH4in tetrahydrofuran at temperatures from about 0oup to 66oC. you Can also restore one or more carbonyl groups to CH2way of the wolf-Kishner, for example by treatment with anhydrous hydrazine in absolute ethanol under pressure at temperatures from about 150o250oC. as the catalyst, it is preferable to use a sodium alcoholate. Recovery can be produced according to the method of Huang-Minlon by interacting with hydrazinehydrate in water-soluble high-boiling solvent such as diethylene glycol or triethylene glycol, in the presence of alkali, such as sodium hydroxide. The reaction mixture is usually boiled for about 3-4 hours. Then the water is distilled off and the resulting hydrazone decompose at temperatures up to about 200oC, response recovery wolf-Kishner can also be carried out with hydrazine in dimethyl sulfoxide at room temperature.

Moreover, certain of reduction reaction can be performed using gaseous H2in the presence of transition metals as catalysts, for example skeletal Nickel catalyst for hydrogenation or Pd. In this case, for example, Cl, Br, I, SH, or in some cases lytic hydrogenation with Pd/H2in methanol.

Compounds having formula I, with the exception of those compounds in which one or more H atoms substituted by one or more groups which are reactive to the solvolysis can be subjected to reactions of solvolysis, especially hydrolysis, to obtain compounds of formula I. the starting materials for the solvolysis can be obtained, for example, by reacting compounds of the formula III with compounds having the formula II, with the exception of compounds in which one or more H atoms substituted by one or more groups which are reactive of solvolysis. Thus, in particular, derivatives of 1-acylamino having formula I, except for compounds containing 1 position of radical acyl group, preferably alkanoyl, alkylsulfonyl or arylsulfonyl with a maximum of 10 carbon atoms in each case, such as methanesulfonyl, benzazolyl or p-toluensulfonyl, can be subjected to hydrolysis to obtain the corresponding derivatives of secondary amines, for example, in acid or preferably neutral or alkaline medium at temperatures from 0 to 200 degrees. As the base used sodium hydroxide, potassium or calcium, sodium carbonate or potassium or ammonia. Among the solvents before the of oxen; sulfones such as tetramethylsilane or mixtures thereof, especially mixtures containing water. The hydrolysis can also be just water, especially at the boiling point.

The compound of the formula I can be further converted into another compound of formula I by known methods.

The compounds of formula I, in which, for example, the radical R2represents hydrogen, can be converted into compounds with tert-amino groups by alkylation or acylation of the remainder, consisting of a secondary amine, in the dead solvent, for example in halogenosilanes hydrocarbon, such as methylene chloride, an ether such as tetrahydrofuran or dioxane, in amide, such as dimethylformamide or dimethylacetamide, or a nitrile, such as acetonitrile, at temperatures from about -10 boiling point of the solvent, preferably from 0 to 70 degrees. Moreover, other primary amino group can be converted into a secondary amino group or tertiary amino group by known alkylation reactions.

The compounds of formula I can be converted to other derivatives of formula I by transformation of the radical Ar. Esters of the formula I in which the radical Ph mono - or Disaese O-alkyla the market by treatment with dimethyl sulfide complex-tribromide boron, for example in toluene, ethers, such as tetrahydrofuran or dimethyl sulfoxide, or by fusion with pyridine or bilingualization, preferably by pyridinecarboxamide, at temperatures of about 150 to 250 degrees. If you want to exclude adverse reactions of compounds of formula I, the radicals Ph can be gloriavale, bronirovat or alkilirovanii in terms of reactions Friedel -, by interacting with the corresponding halogen or alkylchloride or alkylbromides in the presence of Lewis acids as catalysts such as AlCl3, FeBr3or Fe, at temperatures from 30o150oC, preferably from 50o150oC in an inert solvent, for example hydrocarbons, tetrahydrofuran or carbon tetrachloride, and the compound of formula I is obtained as a derivative. In addition, using known reactions it is possible to restore the nitro group to the amino group. The compounds of formula I may have one or more centers of asymmetry. Thus, these compounds can be obtained in the form of racemates or optically-active form when using optically active starting materials. In the synthesis of compounds with two or more centers askme is for example, using recrystallization from inert solvents. If desired, the racemates obtained chemically or by crystallization conglomerates were cleaved by known methods, receiving the optical antipodes. In a preferred embodiment of the invention diastereoisomer formed from a racemate by interacting with the optically-active digestive agent. As a decomposing agent used optically-active acid, such as D - and L-forms of protected derivatives of amino acids, such as totalpaid, tartaric acid, dibenzoyltartaric acid, diatsetilvinny acid, camphor-sulfonic acid, mandelic acid, malic acid, or lactic acid. Various forms of diastereoisomers split in a known manner, for example fractionated crystallization, and optically active compounds of formula I release from diastereoisomers in a known manner.

The basis of a formula I can use acid to convert into the corresponding acid salt. For this reaction, suitable acids, which provide a biologically compatible salt. It is possible to use inorganic acids, for example sulfuric acid, kaleidotrope acids, such as chloride-hydrogen acid or methyl-HEU, as well as organic acids, specifically aliphatic acyclic analiticheskie, aromatic or heterocyclic oneonone or politonalnye carboxylic, sulfonic and sulfuric acids, such as formic acid, acetic acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionate acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methanesulfonate acid, or econsultancy acid, ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, p-toluensulfonate acid, naphthalenesulfonic acid and naphthalenedisulfonic acid, and louisanna acid.

If desired, the free base of formula I can be obtained from the salts of these compounds by treatment with strong bases such as sodium hydroxide or potassium hydroxide, or carbonate of sodium or potassium, provided that the molecule has no other acid groups. In those cases, when soedineniya basis. Suitable bases are hydroxides of alkali metals, hydroxides of alkaline-earth metals or organic bases as primary, secondary or tertiary amines. Further, the present invention relates to the use of compounds of formula I and biologically compatible salts of these compounds for the production of pharmaceutical drugs, particularly non-chemical way. For this purpose, these compounds can be divided into appropriate dose and to connect at least one filler or, if necessary, auxiliary means; in combination with one or more additional active ingredient.

Further, the present invention relates also to compositions, especially pharmaceutical preparations containing at least one compound of the formula I and/or one of its biocompatible salts of these compounds. These drugs can be used as drugs for medical and veterinary purposes. As fillers can be organic or inorganic substances suitable for internal (e.g. oral), parenteral or local purposes, and which does not enter into reaction with the new compounds; examples of such fillers t is for or starch, magnesium stearate, talc and petroleum jelly. Tablets, tablets in the wafers, capsules, syrups, juices, drops and candles are used for parenteral administration, solutions, preferably oily or aqueous, and also suspensions, emulsions or implants are used for parenteral administration, and ointments, creams or powders are used for local purposes. The new compounds can also be liofilizirovanny and received lyophilizate can be used, for example, for the production of drugs for injection. These preparations can be sterilized and/or they may contain auxiliary agents such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts, influencing the osmotic pressure, buffer substances, colorants, flavorings and/or flavorings. If desired, they may contain one or more additional active ingredient, for example one or more of the vitamin. The compounds of formula I and their biologically compatible salts can be used for the treatment of humans or animals and to fight diseases. These compounds suitable for treating disorders of the Central nervous system, as well as anxiety, stress and depression and/or psychosis, is measured in endocrinology and gynecology, for example for the treatment of acromegaly, hypogonadism, secondary amenorrhoea, premenstrual syndrome and unwanted paperline lactation, as well as for the prevention and treatment of cerebral disorders (e.g., migraine headaches), especially in geriatrics, similarly certain ergotalkaloids, and for the treatment of the consequences of cerebral infarction (Apoplexia cerebri) such as stroke and cerebral ischemia.

Further, the compounds according to the invention is suitable for removing mental disability, to improve capacity for teaching and memory, as well as for the treatment of Alzheimer's disease. In the treatment of these diseases substance of the formula I according to the invention is usually administered as known commercially available preparations (e.g., parlodel, dihydroergocornine), preferably in dosages of from about 0.2 to 500 mg, especially from 0.2 to 50 mg per dose. The preferred daily dosage is from about 0.001 to 10 mg/kg of body weight. Low doses (from about 0.2 to 1 mg per dose, from about 0.001 to 0.005 mg/kg of body weight) are particularly suitable for drugs migraine; dosage from 10 to 50 mg per dose preferable to other cases. However, the specific dose for each individual patient depends on a large number of different Pakhomova, sex, diet, time and route of administration, rate of excretion and the severity of the disease, which applies this therapy. It is preferable to oral administration. In the examples below, the term "conventional treatment" means the following: if necessary, add water, conduct extraction with methylenechloride, the organic phase is separated, dried with sodium sulfate and filtered, the filtrate is evaporated and the residue purified by chromatography on silica gel and/or crystallization. Temperatures are indicated in degrees Celsius.

EXAMPLE 1

A solution of 2.8 g of 2-aminomethyl-chromane, which can be obtained by reacting 3-(2-hydroxyphenyl)-propanol with KCN followed by catalytic regeneration 2-lanocreme and 2.2 g of 3-(chloromethyl)-pyridine in 250 ml of dimethylformamide is stirred with 1 g of N-methyl-research for 12 hours at 20oC and subjected to conventional processing to obtain N-(3-pyridylmethyl)-N- (2-chromanol-methyl)-amine. After stirring with 0.5 parts of maleic acid in 100 ml of ethanol maleate, melting point which 163-164oC.

The following compounds have a similar way: 2-aminomethyl-chromane and 3-(chloromethyl)-5-(4-methoxyphenyl)- piediluco;

2-aminomethyl-chromane and 3-(chloromethyl)-5-phenylpyridine received N-(5-phenyl-3-pyridylmethyl)-N-(2-Romanelli)-amine maleate, melting point 184;

from 2-amino-ethyl-chromane and 3-(chloromethyl)-biphenyl received N-3-biphenylyl-N-(2-Romanelli)-amine maleate, melting point 162;

2-aminomethyl-6-phenyl-chromane and 3-(chloromethyl)-5-(4-fluoro-phenyl)-pyridine receive N-[5-(4-forfinal)-3-pyridylmethyl] -N-(6-phenyl-2-Romanelli)-amine maleate, melting point 222-224oC;

2-aminomethyl-chromane and 3-(chloromethyl)-5-(4-forfinal)- pyridine receive N-[5-(4-forfinal)-3-pyridylmethyl]-N- (2-Romanelli)-amine maleate, melting point 182-183oC;

2-aminomethyl-chromane and 3-(chloromethyl)-biphenyl receive N-3-biphenylyl-N-(2-chloranilide)-amine maleate, melting point 174-175oC;

2-aminomethyl-chromane and 3-(chloromethyl)-4'-forbefore get N-(4'-fluoro-3-biphenylyl)-N-(2-Romanelli)-amine maleate, melting point 183-184oC;

2-aminomethyl-8-methoxypropane and 3-(chloromethyl)-5-(4-forfinal)-pyridine receive N-[5-(4-forfinal) -3-pyridylmethyl]-N-[(8-methoxy-2-chromanol)methyl]- amine maleate having a melting point of 160-165oC;

2-aminomethyl-7-methoxypropane and 3 - maleate, temperature 170,5-172oC;

2-aminomethyl-6-methoxypropane and 3-(chloromethyl)-5-(4-forfinal)-pyridine receive N-[5-(4-forfinal)-3-pyridylmethyl] -N-[(6-methoxypropan-2-yl) methyl]-amine maleate;

2-aminomethyl-5-methoxypropane and 3-(chloromethyl)-5-(4-forfinal) -pyridine receive N-[5-(4-forfinal) -3-pyridylmethyl]-N- [(5-methoxypropan-2-yl)methyl]-amine maleate, melting point 181-183oC;

2-aminomethyl-8-nitropropane and 3-(chloromethyl)-5-(4-forfinal)-pyridine receive N-[5-(4-forfinal) -3-pyridylmethyl]- N-[(8-nitropropan-2-yl)methyl] -amine maleate;

2-aminomethyl-2,3,4,5-tetrahydro-1-benzoxazine and 3-(chloromethyl)-5-(4-forfinal)-pyridine receive N-[5-(4-forfinal)- 3-pyridylmethyl]-N-[2-(2,3,4,5-tetrahydro-1-benzoxazin methyl] -amine maleate, melting point 194-195oC;

2 aminoethylamino and 3-(chloromethyl)-5-(4-forfinal)-pyridine receive N-[5-(4-forfinal) -3-pyridylmethyl] -N-(2-formanilide)-amine maleate, melting point 160oC;

from 3-amino-2,3,4,5-tetrahydro-1-benzoxazine and 3-(chloromethyl)- -5-(4-forfinal)-pyridine receive N-[5-(4-forfinal)- 3-pyridylmethyl] -N-3-(2,3,4,5-tetrahydro-1-benzoxazine)-amine maleate, melting point 179-180oC;

2-aminomethyl-8-hydroxypropane and 3-(chloromethyl)-5-(4-forfinal the deposits 173oC;

2-aminomethyl-8-methoxypropane and 3-(chloromethyl)-4'-forbefore get N-(4'-fluoro-3-biphenylyl)-N-[(8-methoxy-2-chromanol)methyl] -amine maleate, melting point 176oC;

2-aminomethyl-6-ferroman and 3-(chloromethyl)-5-(4-forfinal)-pyridine receive N-[5-(4-forfinal)-3-pyridylmethyl] -N-[(6-fluoro-2-chromanol)methyl] - amine maleate, melting point 169-170oC;

2-aminomethyl-chromane and 3-(2-pyridyl)-chloromethylbenzene receive N-[3-(2-pyridyl)-phenylmethyl] -N-2-chromanol-methylamine maleate, melting point 201oC;

2-aminomethyl-chromane and 3-(3-pyridyl)-chloromethyl-benzene receive N-[3-(pyridyl)-phenylmethyl] -N-2-chromanol-methylamine maleate, melting point 120oC;

2-aminomethyl-8-methoxypropane and 3-(3-pyridyl)-chloromethylbenzene receive N-[3-(3-pyridyl)-phenylmethyl] - N-(8-methoxy-2-chromanol)-methyl]-amine maleate, melting point 85oC;

2-aminomethyl-8-methoxypropane and 3-(2-pyridyl)-chloromethylbenzene receive N-[3-(2-pyridyl)phenylmethyl]-N-(8-methoxy-2-chromanol)-methyl]-amine maleate, melting point 167oC.

The following compounds have a similar way (instead of the maleic acid compound is treated with 0.1 G. HCl solution until received the l)-N-2-chromanol-methyl-amine hydrochloride melting point 206-207oC;

2 aminomethylpropanol and 3-(chloromethyl)-4'-methoxybiphenyl get N-(4'-methoxy-3-biphenylyl)-N-2-chromanol-methyl-amine hydrochloride, melting point 191-192oC;

2 aminomethylpropanol and 3-(chloromethyl)-4'-triptoreline get N-(4'-trifluoromethyl-3-biphenylyl)-N-2-chromanol-methyl-amine hydrochloride, melting point 181-182oC;

2 aminomethylpropanol and 3-(chloromethyl)-3'-triptoreline get N-(3'-trifluoromethyl-3-biphenylyl)-N-2-chromanol-methyl-amine hydrochloride, melting point 161-162oC;

2-aminomethyl-8-methoxypropane and 3-(chloromethyl)-4'-triptoreline get N-(4'-trifluoromethyl-3-biphenylyl) -N-[(8-methoxy-2-chromanol)- methyl]amine hydrochloride, melting point 206-207oC;

2-aminomethyl-8-methoxypropane and 3-(chloromethyl)-3'-triptoreline get N-(3'-trifluoromethyl-3-biphenylyl) -N-[(8-methoxy-2-chromanol)- methyl]amine hydrochloride, melting point 206oC;

2-aminomethyl-8-methoxypropane and 3-(chloromethyl)-4'-methylbiphenyl get N-(4'-methyl-3-biphenylyl) -N-[(8-methoxy-2-chromanol) -methyl]-amine hydrochloride, melting point 188-189oC;

2-aminomethyl-8-methoxypropane ironlore, the melting point of 186-187oC;

2-aminomethyl-8-methoxypropane and 3-(chloromethyl)biphenyl get N-(3-biphenylyl) -N-[(8-methoxy-2-chromanol) -methyl] -amine hydrochloride, melting point 211-212oC;

2-aminomethyl-6-nitropropane and 3-(chloromethyl)-5-(4-forfinal)- pyridine receive N-[5-(4-forfinal) -3-pyridylmethyl] -N-[(6-nitropropan - 2-yl)-methyl]-amine maleate;

2-aminomethyl-7-nitropropane and 3-(chloromethyl)-5-(4-forfinal)- pyridine receive N-[5-(4-forfinal) -3-pyridylmethyl] -N-[(7-nitropropan - 2-yl)-methyl]-amine maleate;

2-aminomethyl-8-chloramine and 3-(chloromethyl)-5-(4-forfinal)- pyridine receive N-[5-(4-forfinal)-3-pyridyl methyl] -N-[(8-nitropropan-2-yl)-methyl] -amine maleate;

2-aminomethyl-6-chloramine and 3-(chloromethyl)-5-(4-forfinal)- pyridine receive N-[5-(4-forfinal)-3-pyridylmethyl] -N-[(6-Harriman - 2-yl)-methyl] -amine, melting point 78-80oC;

2-aminomethyl-7-chloramine and 3-(chloromethyl)-5-(4-forfinal)- pyridine receive N-[5-(4-forfinal)-3-pyridylmethyl] -N-[(7-Harriman - 2-yl)-methyl] -amine maleate;

2-aminomethyl-8-ceanography and 3-(chloromethyl)-5-(4-forfinal)- pyridine receive N-[5-(4-forfinal)-3-pyridylmethyl] -N-[(8-lanocreme - 2-yl)-methyl] -amine maleate;

2-aminomethyl-6-lanocreme the ina maleate;

2-aminomethyl-5-ceanography and 3-(chloromethyl)-5-(4-forfinal)- pyridine receive N-[5-(4-forfinal)-3-pyridylmethyl] -N-[(5-lanocreme - 2-yl)-methyl] -amine maleate;

2-aminomethyl-5-ferroman and 3-(chloromethyl)-5-(4-forfinal)- pyridine receive N-[5-(4-forfinal)-3-pyridylmethyl] -N-[(5-ferroman - 2-yl)-methyl] -amine maleate;

2-aminomethyl-6-ferroman and 3-(chloromethyl)-5-(4-forfinal)- pyridine receive N-[5-(4-forfinal)-3-pyridylmethyl] -N-[(6-ferroman - 2-yl)-methyl] -amine maleate;

2 aminomethylpropanol and 3-(chloromethyl)-5-(3,4-differenl)- pyridine receive N-[5-(3,4-differenl) -3-pyridylmethyl] -N-(2-chromameter)-amine maleate, melting point 175-177oC;

2 aminomethylpropanol and 3-phenoxybenzaldehyde get N-(3-phenoxybenzyl)-N-(2-chromameter)-amine maleate, melting point 150-152oC;

2 aminomethylpropanol and 2-(chloromethyl)-4-phenylpyridine get N-(4-phenyl-2-pyridylmethyl)-N-[2-chromameter)-amine maleate, melting point 156-158oC;

2-aminomethyl-6-brahaman and 3-(chloromethyl)-5-(4-forfinal)- pyridine receive N-[5-(4-forfinal)-3-pyridylmethyl] -N-[2- (6-brahaman)-methyl]-amine maleate;

2-aminomethyl-benzofuran and 3-(chloromethyl)-5-(4-forfinal)- pyridine get N-(5-(4-forfinal)-3-pyridyl and 3-(chloromethyl)-5-(4-forfinal)- pyridine receive N-[5-(4-forfinal)-3-pyridylmethyl] -N- [(7-ferroman-2-yl)-methyl] -amine maleate;

2-aminomethyl-8-ferroman and 3-(chloromethyl)-5-(4-forfinal)- pyridine receive N-[5-(4-forfinal)-3-pyridylmethyl] -N- [(8-ferroman-2-yl)-methyl] -amine maleate;

2-aminomethyl-6-cryptomelane and 3-(chloromethyl)-5-(4-forfinal)-pyridine receive N-[5-(4-forfinal) -3-pyridylmethyl]-N-[(6-cryptomelane-2-yl-methyl]-amine maleate;

2-aminomethyl-8-cryptomelane and 3-(chloromethyl)-5-(4-forfinal)-pyridine receive N-[5-(4-forfinal) -3-pyridylmethyl]-N-[(8-cryptomelane-2-yl)methyl]-amine maleate.

EXAMPLE 2

Interacting 2-aminomethyl-2,3-dihydrobenzofuran with 3-(chloromethyl)-5-(4-forfinal)-pyridine as in Example 1, to obtain N-[5-(4-forfinal)-3-pyridylmethyl] -N- [(2,3-dihydrobenzofuran-2-yl)methyl] -amine maleate, melting point which 178-180oC.

The following compounds have a similar way:

2-aminomethyl-2,3-dihydrobenzofuran and 3-(chloromethyl)-5- (4-methoxyphenyl)-pyridine receive N-[5-(4-methoxyphenyl)- 3-pyridylmethyl] -N-[(2,3-dihydrobenzofuran-2-yl)-methyl]-amine maleate;

2-aminomethyl-2,3-dihydrobenzofuran and 3-(chloromethyl)-5- (3,4-acid) pyridine receive N-[5-(3,4-acid)- 3-pyridylmethyl]-N-[(2,3-dihydrobenzofuran-2-yl) -methyl]-amine maleate;

2-a-pyridylmethyl]-N-[(2,3-dihydrobenzofuran-2 - yl)-methyl]-amine maleate;

2-aminomethyl-2,3-dihydrobenzofuran and 3-(chloromethyl)-5- (3,4,5-tryptophanyl)-pyridine receive N-[5-(3,4,5-tryptophanyl)- 3-pyridylmethyl]-N-[(2,3-dihydrobenzofuran-2-yl) -methyl]-amine maleate;

2-aminomethyl-2,3-dihydrobenzofuran and 3-(chloromethyl)-5- (2,3,4,5,6-pentafluorophenyl)-pyridine receive N-[5-(2,3,4,5,6-pentafluorophenyl) -3-pyridylmethyl]-N-[(2,3-dihydrobenzofuran-2-yl)-methyl]-amine maleate.

EXAMPLE 3

A mixture consisting of 2.2 g of 3-METHYLPHENOL, preferably its sodium salt, and 5.6 g of N-(2-chloroethyl)-N-[5-(4 - forfinal)-3-pyridylmethyl] amine ("A") [derived from palmitoleic salt by interaction with 5-(4-forfinal)-3-chloromethyl-pyridine, the cleavage product with hydrazine and subsequent interaction with 1,2-dichloroethane] in 50 ml of acetonitrile is stirred for 5 hours at 50oC and subjected to normal processing.

Receive N-[2-(3-methoxyphenoxy)-ethyl] -N-[5-(4-forfinal)-3 - pyridylmethyl] -amine. After stirring with 0.5 parts of maleic acid get maleate, melting point which 152-154oC.

The following compounds have a similar way:

of the sodium salt of 2,4-dichlorophenol and connections "And" receive N-[2-(2,4-dichlorophenoxy)-ethyl] -N-[5-(4-forfinal)-3 - pyridyl-methyl] -s which are N-[2-(3-methoxyphenoxy)-ethyl] -N-[5-(4-forfinal)-3 - pyridylmethyl]-amine maleate, melting point 122-124oC;

of the sodium salt of 4-methoxyphenol and connections "And" receive N-[2-(4-methoxyphenoxy)-ethyl] -N-[5-(4-forfinal)-3-pyridylmethyl] -amine, melting point of 94-96oC;

of the sodium salt of 3-chlorophenol and connections "And" receive N-[2-(3-chlorophenoxy)-ethyl] -N-[5-(4-forfinal)-3-pyridylmethyl]-amine maleate, melting point 150-152oC;

of the sodium salt of 2-chlorophenol and connections "And" receive N-[2-(2-chlorophenoxy)-ethyl] -N-[5-(4-forfinal)-3-pyridylmethyl]-amine maleate, melting point 153 to 155oC;

of the sodium salt of 2-methoxyphenol and connections "And" receive N-[2-(2-methoxyphenoxy)-ethyl] -N-[5-(4-forfinal)-3-pyridylmethyl] - -amine maleate, melting point 134-136oC;

of the sodium salt of 4-chlorophenol and connections "And" receive N-[2-(4-chlorphenoxy)-ethyl]-N-[5-(4-forfinal)-3-pyridylmethyl]- -amine maleate, melting point 163-164oC;

of the sodium salt of 2-ethylphenol and connections "And" receive N-[2-(2-ethyleneoxy)-ethyl]-N-[5-(4-forfinal)-3-pyridylmethyl]- -amine maleate, melting point 128-130oC;

of the sodium salt of 3-cyanophora and connections "And" receive N-[2-(3-cianfrocca)-ethyl] -N-[5-(4-forfinal)-3-pyridylmethyl] - -amine oxalate, melting point 245ooC;

of the sodium salt of the phenol and N-(3-phenoxybenzyl)-amine get N-(2-phenoxyethyl)-N-(3-phenoxybenzyl)-amine maleate, melting point 166-168oC;

of the sodium salt of phenol and connections "And" receive N-(2-phenoxyethyl)-N-[5-(4-forfinal)-3-pyridylmethyl]-amine, melting point of 84-86oC.

EXAMPLE 4

By reacting 2-aminomethyl-6-methoxypropane with 3-(chloromethyl)-5-(4-forfinal)-pyridine carried out as in Example 1, to obtain N-[5-(4-forfinal)3-pyridylmethyl] -N- [(6-methoxy-2-chromanol)-methyl] -amine. In the stirring with hydrochloric acid to obtain the dihydrochloride, melting point which 205-206oC.

EXAMPLE 5

By reacting 2-aminomethylpropanol with 3-(chloromethyl)-5- (4-forfinal)-pyridine carried out as in Example 1, to obtain N-[5-(4-forfinal)-3-pyridylmethyl] -N-(2-Romanelli)-amine. In the result of mixing with hydrochloric acid to obtain the dihydrochloride-hemihydrate, melting point which 210-213oC.

EXAMPLE 6

A solution of 1.8 g of 3-aminomethyl-biphenyl, which can be obtained by restoring the 3-cyanobiphenyl and 1.6 g of 2-chloro-ethyl-phenyl ester, which can be obtained by which the temperature value and subjected to conventional processing to obtain N-(3-biphenylyl)-2-phenoxyethyl-amine. After stirring with 0.5 parts of maleic acid in 100 ml of ethanol maleate, melting point which 178-180oC.

Nigelegashie connection get a similar manner, 3-aminomethyl-4'-forbefore and 2-chloroethyl-phenyl ester receive N-(4'-fluoro-3-biphenylyl)-N-2-phenoxyethyl-amine maleate, melting point 194-196oC;

3-aminomethyl-2'-4'-diversifolia and 2-chloroethyl-phenyl ester receive N-(2'-4'-debtor-3-biphenylyl)-N-2-phenoxyethyl-amine;

3-aminomethyl-5-vinylpyridine and 2-chloroethyl-phenyl ester receive N-(5-phenyl-3-pyridylmethyl)-N-2-phenoxyethyl-amine, melting point 77-79oC;

2-aminomethyl-4(3-thienyl)-thiophene and 2-chloroethyl-phenyl ester receive N-[4-(3-thienyl)-2-thienylmethyl]-N-2-phenoxyethyl-amine, melting point 96-98oC;

2-aminomethyl-4-methylthiophene and 2-chloroethyl-phenyl ester receive N-(4-methyl-2-thienylmethyl)-N-2-phenoxyethyl-amine;

2-aminomethyl-4-methoxythiophene and 2-chloroethyl-phenyl ester receive N-(4-methoxy-2-thienylmethyl)-N-2-phenoxyethyl-amine;

2-aminomethyl-4-ethylthiophene and 2-chloroethyl-phenyl ester receive N-(4-ethyl-2-thienylmethyl)-N-2-phenoxyethyl-amine;

2-aminomethyl-4-chlorothiophene and 2-chloroethyl-foradil-(3-cyanophenyl)ether get N-(4'-fluoro-3-biphenylyl)-N-2-(3-cyanobenzoate)-amine, the melting point of which 158-160oC;

3-aminomethylpyridine and 2-chloroethyl-(2-methoxyphenyl)ether get N-(3-biphenylyl)-N-2-(2-methoxyphenoxy)ethylamine, melting point which 72-74oC;

3-aminomethylpyridine and 2-chloroethyl-2-biphenyl-ether to obtain N-(3-biphenylyl)-N-2-(2-biphenyloxy)ethylamine, maleate melting point which 146-148oC;

3-aminomethyl-5-(4-forfinal)-pyridine and 2-chloroethyl- -(2-biphenylyl)-ether obtain N-[5-(4-forfinal-3-pyridylmethyl)] -N-2- -(2 biphenyloxy)ethylamine, melting point which 134-136oC;

3-aminomethylpyridine and 2-chloroethyl-(2-hydroxyphenyl)-ether get N-(3-biphenylyl)] -N-2-(2-hydroxyphenoxy)ethylamine, melting point which 88-90oC.

EXAMPLE 7

A solution of 1.2 g of 2-hydroxybenzonitrile and 2.5 g of N-2-chloroethyl-N- (5-phenyl-3-pyridylmethyl)-amine, which can be obtained by reacting 2-hydroxyethylamine with 3-chloromethyl-5-phenyl-pyridine and subsequent conversion of the reaction product 2-chloraniline connection by interacting with PCl3in 200 ml of acetonitrile is stirred for 5 hours at room temperature and subjected to conventional processing to obtain N-[2-(2-cianfrocca)-ethyl]-N-(5-phenyl-3-pretura whose melting point 208oC.

The following compounds have a similar way:

of 2-chlorophenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)-amine receive N-[2-(2-chlorophenoxy)-ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

2-METHYLPHENOL and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)- amine receive N-[2-(2-methylphenoxy)-ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

of 4-chlorophenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)-amine receive N-[2-(4-chlorophenoxy)ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

4-cyanophora and N-2-chloroethyl-N-(5-phenyl-N-pyridylmethyl)-amine receive N-[2-(4-cianfrocca)ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

3-ethylphenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)-amine receive N-[2-(3-ethyleneoxy)ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

4-triptoreline and N-2-chloroethyl-N- (5-phenyl-3-pyridylmethyl)-amine receive N-[2-(4-triptoreline)ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

2-bromophenol and N-2-chloroethyl-N- (5-phenyl-3-pyridylmethyl)-amine receive N-[2-(2-bromophenoxy)ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

2-aminomethylphenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)-amine receive N-[2-(2-aminomethylphenol)ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

4-methoxyphenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)-amine receive N-[2-(4-methyl)-amine receive N-[2-(3-aminomethylphenol) ethyl]-N-(5-phenyl-3-pyridylmethyl)amine;

4-aminomethylphenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)-amine receive N-[2-(4-aminomethylphenol)ethyl] -N-(5-phenyl-3-pyridylmethyl)amine.

EXAMPLE 8

A mixture of 3.1 g of N-[2-(2-cianfrocca)ethyl]-N-(5-phenyl-3-pyridylmethyl)amine, 3 g NaOH, 50 ml of water and 40 ml of monoethylene ether of diethylene glycol is stirred for 3 hours at a bath temperature of 140oC. the Mixture is cooled and subjected to conventional processing, and receive N-[2-(2-carboxy-aminophenoxy)ethyl] -N-(5-phenyl-3-pyridylmethyl)amine. After stirring with 0.5 parts of oxalic acid in 100 ml of ethanol oxalate, melting point 230 whichoC.

EXAMPLE 9

By the way, is similar to that described in Example 8, to obtain N-(5-phenyl-3-pyridylmethyl)amine by the partial hydrolysis of N-[2-(4-cianfrocca)ethyl]-N-(5-phenyl-3-pyridylmethyl)amine.

EXAMPLE 10

Using as the starting material N-[2-(4-cianfrocca)ethyl]-N-(5-phenyl-3-pyridylmethyl)amine in a manner analogous to the one described in Example 8, using boiling for 16 hours and subsequent normal processing of receive N-[2-(4-carboxyphenoxy)ethyl]-N-(5-phenyl-3-pyridylmethyl)amine.

EXAMPLE 11

Using as the starting material N-[2-(2-cianfrocca) -ethyl]-N-( 16 hours and subsequent normal processing of receive N-[2-(2-carboxyphenoxy)-ethyl] -N-(5-phenyl-3-pyridylmethyl)amine.

EXAMPLE 12

In the manner similar to that described in Example 7, a solution of 2.3 g of sodium phenolate and 2.5 g of N-3-chloropropyl-N-[5-(4-forfinal)-3-pyridylmethyl]amine, which can be obtained by reacting 3-hydroxypropylamino with 3-chloromethyl-5-(4-forfinal)-pyridine followed by conversion of the reaction product 3-chloropropylene connection by interacting with PCl3in 200 ml of acetonitrile is stirred for 5 hours at room temperature and subjected to conventional processing to obtain N-(3-phenoxypropan)-N-[5-(4-forfinal)-3-pyridylmethyl] amine. After stirring with 0.5 parts of oxalic acid in 100 ml of a mixture of ethanol/water get the oxalate hemihydrate, melting point 217 whichoC.

The following compounds have a similar way: from the phenolate sodium and N-4-chlorobutyl-N-[5-(4-forfinal)-3-pyridylmethyl] -amine get N-(4-phenoxybutyl) -N-[5-(4-forfinal) -3-pyridylmethyl]amine maleate, melting point 143 whichoC;

from the phenolate sodium and N-2-chloroisopropyl-N-[5-(4-forfinal) -3-pyridylmethyl] -amine get N-(2-phenoxyisopropyl) -N-[5-(4-forfinal)-3-pyridylmethyl]amine maleate, melting point of 123 - 125oC;

from thiophenolate sodium and N-2-chloroethyl-N-[5-(4-fluoro what the atur whose melting point 230oC;

from thiophenolate sodium and N-4-chlorobutyl-N-(5-phenyl-3-pyridylmethyl)amine get N-(4-thiopheneacetyl)-N-(5-phenyl-3-pyridylmethyl)amine;

from thiophenolate sodium and N-3-chloropropyl-N-(5-phenyl)-3-pyridylmethyl)amine get N-(3-thiophenoxide) -N-(5-phenyl-3-pyridylmethyl)amine;

from thiophenolate sodium and N-2-chloroisopropyl-N-(5-phenyl)-3-pyridylmethyl)amine get N-(2-thiopheneacetyl)-N-(5-phenyl-3-pyridylmethyl)amine.

EXAMPLE 13

By the way, is similar to that described in Example 7, you receive the following connections:

from 2-chloro-thiophenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)amine receive N-[2-(2-chlorothiophene)-ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

from 2-methyl-thiophenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)amine receive N-[2-(2-methylchlorosilanes)-ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

4-Harl-thiophenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)amine receive N-[2-(4-chlorothiophenol)-ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

from 4-cyano-thiophenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)amine receive N-[2-(4-cyanothiophene)-ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

3-ethyl-thiophenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)amine receive N-[2-(3-ethylthiophene)-ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

4-Tr is-(5-phenyl-3-pyridylmethyl)amine;

from 2-bromo-thiophenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)amine receive N-[2-(2-bromothiophene)-ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

2-aminomethyl-thiophenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)amine receive N-[2-(2-aminomethylpropanol) -ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

from 4-methoxy-thiophenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)amine receive N-[2-(4-methoxythiophene)-ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

3-aminomethyl-thiophenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)amine receive N-[2-(3-aminomethylpropanol) -ethyl] -N-(5-phenyl-3-pyridylmethyl)amine;

4-aminomethyl-thiophenol and N-2-chloroethyl-N-(5-phenyl-3-pyridylmethyl)amine receive N-[2-(4-aminomethylpropanol) -ethyl] -N-(5-phenyl-3-pyridylmethyl)amine.

EXAMPLE 14

A solution of 2.8 g of N-[2-(2-methoxyphenoxy)-ethyl] -N-[5-(4-forfinal)-3-pyridylmethyl]-amine, which can be obtained by the method described in Example 3 and one equivalent part 3-chloromethyl-5-(4-forfinal)pyridine in 125 ml of acetonitrile is stirred for 6 hours at 40oC and subjected to conventional processing to obtain N-[2-(2-methoxyphenoxy)-ethyl] -N,N-bis-[5-(4-forfinal)-3 - pyridylmethyl]-amine, melting point which is 90 - 92oC.

The following compounds have the anl-3-pyridylmethyl)-amine-N-(4-phenoxybutyl)- N-(5-phenyl-3-pyridylmethyl) -N-[5-(4-forfinal)-3-pyridylmethyl]-amine;

N-(2-phenoxyisopropyl)-N-(5-phenyl-3-pyridylmethyl)-amine-N-(2-phenoxyisopropyl)- N-(5-phenyl-3-pyridylmethyl) -N-[5-(4-forfinal)-3-pyridylmethyl]-amine;

N-(2-thiopheneacetyl)-N-(5-phenyl-3-pyridylmethyl)-amine-N-(2-thiopheneacetyl)- N-(5-phenyl-3-pyridylmethyl) -N-[5-(4-fluoro-phenyl)-3-pyridylmethyl]-amine;

N-(4-thiopheneacetyl)-N-(5-phenyl-3-pyridylmethyl)-amine-N-(4-thiopheneacetyl)- N-(5-phenyl-3-pyridylmethyl) -N-[5-(4-forfinal)-3-pyridylmethyl]-amine.

EXAMPLE 15

In the manner similar to that described in Example 7, a solution of 2.3 g of 1 naphthalate sodium and 2.9 g of N-2-chloroethyl-N-[5-(4-forfinal)-3-pyridylmethyl]amine, which can be obtained by reacting 2-hydroxyethylamine with 3-chloromethyl-5- (4-forfinal)-pyridine followed by conversion of the reaction product 2-chloraniline connection by interacting with PCl3in 200 ml of acetonitrile is stirred for 5 hours at room temperature and subjected to conventional processing to obtain N-[2-(1-naphthyloxy)-ethyl]-N-[5-(4-forfinal)-3-pyridylmethyl] amine, melting point of which 92 - 94oC.

The following compounds have a similar way by reacting 2-naphtholate :

N-2-chloroethyl-N-[5-(4-forfinal)-3-pyridylmethyl] amine: N-[2-(2-naphthoxy)-ethyl] -N-[5-(4-florfenicol]amine: N-[2-(2-naphthoxy)-ethyl]-N-[5-(2,4-differenl)-3-pyridylmethyl]amine.

EXAMPLE 16

A solution of 2.1 g of N-(2-phenoxyethyl)-N-[5-forfinal)-3-pyridylmethyl]amine, which can be obtained by the method described in Example 3, in 100 ml of tetrahydrofuran is treated with 2 ml of methyliodide under stirring for 3 hours. After normal processing of receive N-(2-phenoxyethyl)-N-[5-(4-forfinal)-3-pyridylmethyl] -N-methylamine oxalate, melting point of which 159 - 161oC.

The following compounds have a similar way by alkylation of secondary amines:

N-[5-(4-forfinal)-3-pyridylmethyl] -N-(2-Romanelli)-N-methylamine, the melting point of which 71oC;

N-3-biphenylyl-N-(2-Romanelli)-N-methylamine.

EXAMPLE 17

By reacting N-[5-(4-forfinal)-3-pyridylmethyl] -amine with 1-chloro-3-phenylpropane according to the method described in Example 1, to obtain N-[5-(4-forfinal)-3-pyridylmethyl] -N-(3-phenylpropyl)-amine, melting point which is < 50oC.

EXAMPLE 18

In a manner analogous to the method described in Example 3, by reacting salts of sodium phenolate with N-(2-chlorethyl)-N-3-(2-pyridyl)-chloromethylbenzene receive N-[3-(2-pyridyl)-phenylmethyl] -N-[2-(phenoxy)-ethyl] -amine maleate, melting point 170 whichoC, salts of sodium phenolate with N-(2-mperature whose melting point 123 - 125oC.

Obtaining the enantiomeric compounds.

EXAMPLE 19

A solution of 4.5 g of 2-aminomethyl-chromane, which can be obtained by reacting 3-(2-hydroxyphenyl)propanol with KCN and subsequent catalytic recovery 2-ceanography, and 3.9 g of desipramine in 190 ml of ethanol is heated under reflux for 15 minutes. After this, the solution is cooled to 5oC under stirring. In the cooling process, add a few crystals of pure (R)-2-aminomethyl-chromane. The temperature of the solution is maintained at the level of 5oC, the solution is stirred for 18 hours, after which separates the pure enantiomer (R)-2-aminomethyl-chromane. The crystallization process was repeated twice with crystals obtained from the first crystallization, to obtain excess enantiomers in excess of 99%. Then (R)-2-aminomethyl-chroman interact with 3-(chloromethyl)-5-(4-forfinal)pyridine as described in Example 1 to obtain (R)-(-)2-[5-(4-forfinal)-3-pyridyl-methylaminomethyl] -chromane [=(R)-(-)-1N-[5-(4-forfinal)-3-pyridylmethyl]-N-(2-Romanelli) -amine] . After dilution with 0.1 N. hydrochloric acid get dihydrochloride, melting point of which 234 -235oC;

[20] = -65o(c = 1, methane is m get: (S)-(+)-2-[5-(4-forfinal)-3-pyridyl-methylaminomethyl] -chroman [= (S)-(+)-1N-5-(4-forfinal)-3-pyridylmethyl] -N-(2-Romanelli)- amine] . After dilution with 0.1 N. hydrochloric acid get dihydrochloride, melting point of which 227 - 228oC;

[20] = + 62o(c = 1, methanol).

Similarly interacting (S)-2-aminomethyl-8-methoxypropan with 3-(chloromethyl)-5- (4-forfinal)pyridine get: (S)-(+)-2-[5- (4-forfinal)-3-pyridyl - methylaminomethyl]-8-methoxy-chroman [=(S)-(+)-1N- [5-(4-forfinal)-3-pyridylmethyl] -N-[2-(8-methoxypropanol) -methyl] - amine] . After dilution with 0.1 N. hydrochloric acid get dihydrochloride, melting point of which 214 - 215oC.

Similarly interacting (R)-2-aminomethyl-8-methoxypropan with 3-(chloromethyl)-5-(4-forfinal)pyridine get: (R)-(-)-2-[5-(4-forfinal) -3-pyridyl-methylaminomethyl] -8-methoxypropan [= (R)-(-)-1N -[5-(4-forfinal)-3-pyridylmethyl] -N-[2-(8-methoxypropanol)- methyl]-Amin. After dilution with 0.1 N. hydrochloric acid get dihydrochloride, melting point 214 whichoC.

EXAMPLE 20

A solution containing 5 g of (R)-2-aminomethylpropanol obtained by the interaction of 2-carboxylate with (+)-phenethylamine, Department crystalline diastereoisomer, purification by recrystallization from ethanol, the conversion in atilhan LiAlH4or VitrideTMin tetrahydrofuran to obtain (R)-2-aminomethylpropanol interacts with 3-(chloromethyl)-5-phenylpyridine the same way as in Example 1 to obtain (R)-(-)-2-[5-phenyl-3-pyridyl-methylaminomethyl] Romana [=(R)-(-)-1N- (5-phenyl-3-pyridylmethyl)-N-(2-Romanelli) amine]. After dilution with 0.1 N. hydrochloric acid get dihydrochloride, melting point which 243-244oC.

In a similar way by reacting (S)-2-aminomethyl-chroman with 3-(chloromethyl)-5-phenylpyridine get: (S)-(+)-2-(5-phenyl)-3-pyridyl-methylaminomethyl-chroman [= (S)-(+)-1N-(5-phenyl-3-pyridyl-methyl)-N-(2-Romanelli)-amine] . After dilution with 0.1 N. hydrochloric acid get dihydrochloride, melting point which 244-245oC.

In a similar way by reacting (S)-2-aminomethyl-8-methoxypropan with 3-(chloromethyl)-4'-forutenom get: (S)-(+)-2-[4'-3-biphenylyl-methylaminomethyl]-8-methoxy-chroman [=(S)-(+)-1N-[4'-fluoro-3-biphenylyl-methyl] -N-[2-(8-methoxypropanol)- methyl] -amine] . After dilution with 0.1 N. hydrochloric acid get dihydrochloride, melting point which 189-190oC;

[20] = +74o(c = 1, methanol).

In a similar way by reacting the yl] -8-methoxypropan [=(R)-(-)-1N-[4'-fluoro-3-biphenylyl-methyl] -N-[2-(8-methoxypropanol)- methyl]-amine]. After dilution with 0.1 N. hydrochloric acid get dihydrochloride, melting point which 189-190oC;

[20] = -74,3o(c = 1, methanol).

The following examples relate to pharmaceutical preparations.

Example a: ampoules for injection

the pH of a solution of 100 g of the active compounds of formula I and 5 g of dinatriumfosfaatti in 3 l of double-distilled water was adjusted to 6.5 using 2 N. hydrochloric acid, filtered and sterilized, then the solution is filled ampoules for injection and sterile conditions are lyophilization, after which the ampoule sealed under sterile conditions. Each ampoule for injection contains 5 mg of active compound.

EXAMPLE B: candles

A mixture consisting of 20 g of active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of coconut oil, the mixture is then poured into molds and leave to cool. Each suppository contains 20 mg of active compound.

EXAMPLE C: a solution of

A solution of 1 g of the active compounds of formula I, 9, 38 g of NaH2PO4H2O, 28,48 g Na2HPO412H2O and 0.1 g of benzalkonium prepared in 940 ml of double-distilled water. the pH of the solution was adjusted to 6.8, receiving a total volume of 1 l, C is the EXAMPLE D: ointment

500 mg of the active compounds of formula I in aseptic conditions are mixed with 99.5 g of petroleum jelly.

EXAMPLE E: tablets

A mixture of 100 active compounds of the formula I, 1 kg of lactose, 600 g of microcrystalline cellulose, 600 g of maize starch, 100 g of polyvinylpyrrolidone, 80 g of talc and 10 g of magnesium stearate is pressed in the usual way to obtain tablets so that each tablet contained 10 mg of active compound.

EXAMPLE G: coated Tablets

Tablets are pressed as described in Example E, then the usual way is applied a coating of sucrose, maize starch, talc, tragakant and dye.

EXAMPLE C: capsules

Hard gelatin capsules are filled active compound of formula I in the usual way so that each capsule contains 5 mg of active compound.

EXAMPLE H: spray for inhalation

14 g of the active compounds of formula I are dissolved in 10 l of isotonic NaCl solution, then the solution fill vials of industrial manufacturing, with the pumping mechanism. The solution to irrigate the mouth or nose. One spray (about 0.1 ml) corresponds to a dose of about 0.14 mg

Test data are given in the table.

1. The derived amino(thio)ethers form alkalinous chain 1 3 atoms, CH2;

Z represents -(CH2)n1- (CHA)n2- (CH2)n3and n1= 0, 1, 2 or 3; n2= 0 or 1; n3= 0, 1, 2 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, acetoxy with 1 to 4 carbon atoms, carboxamido,

or

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

R2represents hydrogen, And, Sa or-CH2-R4;

R3represents-CH2-R4or-SLEEP-R4;

R4is a Ph, 2-, 3 - or 4-pyridyl, unsubstituted or monosubstituted R5or thiophene, unsubstituted, mono - or disubstituted by A, OA, HE, F, Cl, Br, or other thienyl group;

R5represents a phenyl group which is unsubstituted or mono-, di-, tri-, Tetra-, or pentamidine F, CF3partially or fully fluorinated And a and/or OA;

R6, R7, R8and R9each independently represents H, A, OA, phenoxy, HE, F, Br, I, CN carbon;

And represents alkyl with 1 to 6 carbon atoms;

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

and physiologically acceptable salts of these derivatives.

2. The derived amino(thio)ethers under item 1, characterized in that they are

a) N-(3-pyridylmethyl)-N-2-chromanol-methylamine;

b) N-(5-phenyl-3-pyridylmethyl)-N-2-chromanol-methylamine;

C) N-[5-(4-methoxyphenyl)-3-pyridylmethyl]-N-2-chromanol-methylamine;

d) N-[5-(4-forfinal)-3-pyridylmethyl]-N-2-chromanol-methylamine;

e) N-(4'-fluoro-3-biphenylyl)-N-2-chromanol-methylamine;

f) N-(3-biphenylyl)-N-2-chromanol-methylamine;

g) N-[5-(4-forfinal)-3-pyridylmethyl]-N-2-(1-naphthyloxy)-ethanamine;

3. The derived amino(thio)ethers under item 1, characterized in that they are

a) N-[5-(4-forfinal)-3-pyridylmethyl]-N-(3-phenoxypropan)-amine;

b) N-[5-(4-forfinal)-3-pyridylmethyl]-N-(4-phenoxybutyl)-amine;

C) N-[5-(4-forfinal)-3-pyridylmethyl]-N-(2-phenylthiomethyl)-amine;

d) N-(5-phenyl-3-pyridylmethyl)-N-[(2-cianfrocca)-ethyl]amine;

e) N-[5-(4-forfinal)-3-pyridylmethyl] -N-[(8-methoxy-2-chromanol)-methyl] -amine;

f) N-[5-(4-forfinal)-3-pyridylmethyl]-N-[2-(3-methylphenoxy)-ethyl]-amine;

g) N-[5-(4 the response.

4. Compounds of General formula I on p. 1, characterized in that they are enantiomers.

5. The method of obtaining derivatives of amino(thio)ethers of the formula I on p. 1 and their salts, characterized in that the compound of formula II

< / BR>
where G represents Cl, Br, I, OH or a group of functionally modified prior to the formation of chemically active groups, especially the deleted group and the radicals R0, R1, R6, R7, R8, R9, X and Z have the above values, interact with the amine of formula III

HNR2R3,

where R2and R3have the above values, and/or received by a base or acid of the formula I is converted into one of its salts in the treatment with an acid or a base.

6. The method of obtaining the compounds of formula I on p. 1 and their salts, characterized in that the compound of formula IV

< / BR>
where M represents H, Li+, Na+, K+, NH4+or other suitable metal ion, and X, R1, R6, R7, R8and R9have the above values,

interact with the compound of the formula V

< / BR>
where G1has the same values as G, and R0, R2, R3and Z have the above value is LOTOS or base.

7. The method of obtaining pharmaceutical compositions, characterized in that the compound of the formula I and/or one of its biocompatible salts of this compound in the appropriate dosage is combined with at least one solid, liquid or semi-liquid excipient or auxiliary means.

8. Pharmaceutical composition having an effect on the Central nervous system, including an active ingredient and a pharmaceutically acceptable carrier or adjuvant, wherein as the active ingredient use effective amount derived amino(thio)esters or their salts.

9. The compounds of formula I under item 1 or a physiologically acceptable salt with effect on the Central nervous system.

 

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