Aminomethane - benzofuran and benzothiophene

 

(57) Abstract:

Aminomethane - benzofuran and benzothiophene General formula I

< / BR>
where one of the radicals X or Y is CH2and the other is selected from CH2, O or S; R1- lower alkyl, vanillasky alkyl, acyl, alkylsulfonyl, or R11R12NC(O)-, R11, R12- H, lower alkyl, C3-8-cycloalkyl, phenyl, possibly substituted with halogen; R2- H, lower alkyl; R3- R5- H or halogen; R6, R7- N; R8, R9- H, lower alkyl, C3-8-cycloalkyl - (lower) alkyl, phenyl - lower alkyl, indolyl - lower alkyl or a group of the formula A

< / BR>
R13- H, lower alkyl, C3-8-cycloalkyl, phenyl, forfinal; r = 2-6; W = O; or R8, R9linked together with the formation of a 3-7-membered ring containing one nitrogen atom, and their pharmaceutically acceptable salts, affect aminomethyl receptors 5-HT1Atherefore these compounds are useful for the treatment of common mental and neurological disorders. 2 s and 5 C.p. f-crystals, 1 table.

The present invention relates to a new class of substituted aminopyridines, -2,3-dihydrobenzofuran, -2,3-dihydrobenzofuran, -1,3-dihydrobenzofuran-1,3-digity useful for the treatment of common mental and neurological disorders.

Background of the invention

Previously in this area have been known for some aminomethane and their derivatives.

So, in the European patent 0281261 disclosed derivatives of 1-aminopyridine, 3-aminomethyltransferase and 3-aminomethylbenzoic with a hydroxy-group or substituted with a hydroxy-group in position 6 (indan) or in position 5 (benzofuran, benzothiophene). It turned out that these compounds have activity as Central dopamine agonists, in particular, they affect the presynaptic dopamine receptors.

The UK patent N 2093837 relates to a class of derivatives of 1-aminoalkyl of tetralin having one or more hydroxy or alkoxysubstituted in position 5, 6 and/or 7, and declared them adrenergic and dopaminergic effect, which makes them useful for the treatment of hypertension. DeBernardis et al (J. Med. Chem., 1985, 28(10), 1398 - 1404) discuss this kind of influence relative to the hydroxy substituted amino methyltyramine-indāni and benzocyclobutene.

In the European patent N 0402923 A2 disclosed derivatives of 2,5-diaminomethylene that are said to have agonistic activity on dopamine and different compounds that interact with the, such as effects on schizophrenia, hypertension, and Parkinson's disease.

In the patent De N 3924365 A1 describes a class of derivatives of 2-amino-7-carbamoylation that have the properties of presynaptic dopamine agonist and, therefore, have an antihypertensive effect, reduce heart rate and affect the Central nervous system.

In U.S. patent N 4500543 indicated that the usual 1-aminomethylphenol compounds demonstrate adrenergic effect and, therefore, antigipertenzivnye properties and to reduce the frequency of heart contractions. This patent covers compounds having substituents in position 5, 6 and/or 7.

French patent N 2548146 relates to derivatives of 3-aminomethylated and 3-aminomethyltransferase; claimed that these compounds have analgesic and/or anticonvulsive action.

None of these links is not discussed or is not expected that any of these compounds had activity relative to the receptor 5-HT1A.

Clinical trials of compounds, which are known to have agonistic activity relative to 5-HT1Asuch as 8-[4-[4-(2-pyrimidyl)Besarion, 2-[4-[4-(2-pyrimidyl)-1-piperazinil] butyl] -1,2-benzothiazol-3(2H)-one-1,1-dioxide showed that these compounds are useful for the treatment of anxiety States, such as General anxiety, panic condition and obsessive compulsive condition (Glitz, D. A., Pohl, R., Drugs, 1991, 41, 11). Preclinical trials have shown that compounds having an agonistic activity relative to 5-HT1Auseful in the treatment of the above disorders caused by anxiety (Schipper, Human Psychopharm., 1991, 6, S53).

There is also evidence, both clinical and preclinical, confirming that the effect of compounds with agonistic activity relative to 5-HT1Aon the treatment of depression, and also controlled disorders and alcohol abuse (van Herst, Psychopharm., 1992, 107, 474; Schipper et al. Human Psychopharm., 1991, 6, S53; Cervo et al, Eur. J. Pharm., 1988, 158, 53; Glitz, D. A., Pohl, R., Drugs, 1991, 41, 11).

Compounds with agonistic activity relative to 5-HT1Ainhibit in male mice aggression caused by isolation, indicating that these compounds are useful for the treatment of aggression (Sanchez et al., Psychopharmacology, 1992, is currently in press).

Moreover, it was reported that compounds with agonistic activity nsm, 1991, 83, 43; Ahlenius Pharm. Tox. , 1989, 64, 3; Lowe et al., J. Med. Chem., 1991, 34, 1860; New et al., J. Med. Chem. , 1989, 32, 1147; Martin et al., J. Med. Chem., 1989, 32, 1052).

Recent studies have also shown that the receptors 5-HT1Aimportant in serotonergic modulation catalepsy caused by haloperidol (Hicks, Life Science, 1990, 47, 1609). It is assumed that the agonists 5-HT1Auseful for treatment of side effects caused by conventional antipsychotic agents such as haloperidol.

It is shown that compounds with agonistic activity relative to 5-HT1Ahave neuroprotective properties (for modeling local and cerebral ischemia in rodents), and therefore these compounds can be useful in the treatment of ischemic conditions (Prehn, Eur. J. Pharm., 1991, 203, 213). Both in animal models and in clinical trials it was shown that agonists of 5-HT1Ahave antihypertensive effect via a Central mechanism (Saxena, villalon. Trends Pharm Sci., 1990, 11, 95; Gillis et al, J. Pharm. Exp. Ther., 1989, 248, 851). Thus, compounds with agonistic activity relative to 5-HT1Acan be applied with success for the treatment of cardiovascular disorders.

Therefore, compounds with agonistici extremely necessary.

Summary of the invention

Currently, it is found that some of the new aminomethane, -2,3-dihydrobenzofuran, -2,3-dihydrobenzofuran, -1,3-dihydroisobenzofuran-1,3-dihydrobenzofuran have agonistic effects on Central receptors 5-HT1A. Therefore, the present invention relates to a new class of compounds of General formula I

< / BR>
where one of X and Y is CH2and the other is selected from the group consisting of CH2, O and S;

R1is chosen from the group consisting of lower alkyl, lower alkenyl, lower quinil, recloak(EN)yl, recloak(EN)yl-lower ALK(EN/in)yl, aryl-lower alkyl, acyl, lower alkyl sulfonyl, trifloromethyl, arylsulfonyl, R10ZCO, where Z represents O or S, a R10represents alkyl, alkenyl, quinil, recloak(EN)yl, recloak(EN)illlil, or aryl, or R11R12NCO, where R11and R12are independently hydrogen, alkyl, alkenyl, quinil, recloak(EN)yl, recloak(EN)illc(EN/in)yl or aryl;

R2selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower quinil, recloak(EN)yl, recloak(EN)yl-lower ALK(EN/in)yl, aryl-lower alkyl;

R3- R5choose not the lower alkylsulfonyl, cyano, trifluoromethyl, cycloalkyl, cycloalkenyl or nitro;

R6R7each represents hydrogen or lower alkyl or by communicating with each other, they form a 3 - to 7-membered cycle;

R8and R9independently represent hydrogen, alkyl, alkenyl, quinil, recloak(EN)yl, cyclo-ALK(EN)yl-ALK(EN/in)Il, arylalkyl or group

< / BR>
where R13represents hydrogen, lower alkyl, lower alkenyl, lower quinil, recloak(EN)yl, recloak(EN)yl - lower ALK(EN/in)yl, aryl - lower alkyl or aryl, and W represents O or S and r = 2 to 6;

R8and R9connected, thus forming a 3 - to 7-membered ring containing one nitrogen atom;

any of those present alkyl, cycloalkyl or cycloalkenyl groups may be substituted by one or two hydroxy groups, which again can be subjected to esterification with aliphatic or aromatic carboxylic acid, and any of the present arithmetically may be substituted by halogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, lower alkylsulfonyl, cyano, trifluoromethyl, cycloalkyl, cycloalkenyl or nitro;

and pharmaceutically acceptable additive salts of these titiraupenga 8-hydroxy-2-dipropylenetriamine (8-OH-DPAT) and receptors 5-HT1Ain vitro. Moreover, it was shown that these compounds demonstrate activity relative to 5-HT1Ain vivo and that the use of animals as models they found the predicted antipsihoticescoe and anxiolytic properties, respectively. Therefore, the compounds of the present invention are useful as drugs for the treatment of psychosis, anxiety States, such as General anxiety, panic condition, alcohol abuse, obsessive compulsive condition, depression, controlled disorders, aggression, coronary disease and the side effects caused by conventional antipsychotic agents or cardiovascular disorders.

Therefore, another aspect of the invention is to provide a pharmaceutical composition comprising at least one new connection according to the present invention, as defined above, or pharmaceutically acceptable additive salts of these acids in therapeutically effective amounts in combination with one or more pharmaceutically acceptable carriers or diluents.

A further aspect of the present invention, javlaetsa this connection to obtain a pharmaceutical preparation for the treatment of psychosis, anxiety, depression, controlled disorders, alcohol abuse, aggression, coronary heart disease, side effects caused by conventional antipsychotic drugs or cardiovascular disorders.

A detailed description of the invention

Some compounds of General formula I can exist in the form of their optical isomers, and such optical isomers are also included in the present invention. As used herein, the term "alkyl" refers to straight or branched C1- C20group, similarly, the term "alkenyl" and "quinil" means a straight or branched chain hydrocarbon, C2- C20having one or more double or triple links, respectively. The term "cycloalkyl" denotes a carbocyclic ring containing 3 to 8 carbon atoms or a bicyclic or tricyclic carbocyclic ring, such as for example substituted. The terms "lower alkyl", "lower alkoxy", "lower alkylthio", etc. refer to such a branched or unbranched groups, which include 1 to 6 carbon atoms. Examples of such groups are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-propyl, methoxy, ethoxy, 1-propoxyethyl of alkenyl" and "lower quinil" refers to such groups, which include 2 to 6 carbon atoms and one or more double or triple bonds.

The term "ALK(EN/in)sludge" means that this group may be an alkyl, alkenyl or Altenilpe. The term "aryl" refers to mono - or bicyclic or heterocyclic aromatic group, such as phenyl, indolyl, thienyl, furanyl, thiazolyl, benzofuranyl, benzothiazol, benzothiazolyl and benzisoxazoles.

"Halogen" means fluorescent-, chloro-, bromo or iodo.

The term "acyl", as used here, refers to formyl, alkylsulphonyl, alkenylboronic, alkynylaryl, arylcarbamoyl, harilal(EN/in)ylcarbonyl, cycloalkylcarbonyl or cycloalkyl(EN/in)ylcarbonyl group.

In formula I, X is preferably CH2, O or S and Y is CH2.

R1is preferably aryl-lower alkyl group or acyl group, a lower alkylsulfonyl group or a group R11R12N-CO-, where R11represents hydrogen or lower alkyl, a R12represents hydrogen, alkyl, aryl or cycloalkyl. Most preferably, R1represents a benzyl or substituted benzyl, formyl, alkylsulphonyl, in particular acetyl, arika is no other hydrogen or lower alkyl, a R12represents hydrogen, lower alkyl, phenyl, substituted phenyl or C5-6cycloalkyl.

R2preferably is halogen or lower alkyl, preferably each R3, R4, R5represented a hydrogen or halogen and order and R6and R7both represent hydrogen.

R8preferably is hydrogen or lower alkyl, a R9preferably is lower alkyl, aryl - lower alkyl, cycloalkyl - lower alkyl or a group having the formula Ia, where W represents O, a R13represents hydrogen, lower alkyl, cycloalkyl or aryl, or R8and R9interconnected, forming a C3- C7-membered ring containing one nitrogen atom. Most preferably, R9represented a phenyl - lower alkyl, substituted phenyl - lower alkyl, indolyl - lower alkyl, cyclohexyl - lower alkyl or a group having the formula Ia, where W represents Oh, R13represents hydrogen or lower alkyl, cycloalkyl, phenyl or substituted phenyl group, or R8and R9connected, forming a pyrolidine or piperidino ring.

Acid salts in NC acids. Examples of such organic salts are salts of maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylanilinium, methansulfonate, ethicolegal, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, almond, cinnamon, tarakanovas, Espartinas, stearic, palmitic, takenaway, Gelikonov, p-aminobenzoic, glutamic, benzosulfimide and theophylline acetic acids, as well as 8-gluteofemoral, for example, 8-remotefile. Examples of such inorganic salts are salts of hydrochloric, Hydrobromic, sulfuric, sulfa, phosphoric and nitric acids.

Pharmaceutical compounds or compounds obtained according to the present invention, it is possible to use any suitable way, for example, orally in the form of tablets, capsules, powders, syrups etc., or parenterally in the form of solutions for injection. To obtain such compounds can be used are known in the field of methods and any acceptable pharmaceutical carriers, diluents, or other additives commonly used in this field.

Typically, compounds of the present invention are introduced in unit dosage form, content ukazannie preferably from 0.1 to 20 mg of active compound according to this invention. In addition, the invention concerns a method of obtaining new aminomethyl derivatives of indāni, 2,3-dihydrobenzofuran, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran and 1,3-dihydroisobenzofuran formula I, including:

a) acylation of amino having the formula II

< / BR>
where R2- R9X and Y are such as defined above, allerease agent type of carboxylic acid halide R1'CO-hal, and R1'CO is an acyl group containing the definitions of R1a hal represents a halogen, an hydride carboxylic acid or a mixed anhydride of the acid R1'CO-OCOR and R is an alkyl, aryl or alkoxy, isocyanate, isothiocyanate, or similar activated acylated derivative, is well known in this field;

b) alkylation of the amino derivatives of formula II to obtain the compounds of formula I in which R1represents lower alkyl, lower alkenyl, lower quinil, recloak(EN)yl-lower ALK(EN/in)yl or aryl-lower alkyl, as alkylating agents use alkylhalogenide type R1"-hal mesilate R1"OSO2CH3toilet R1"OSO2C6H4-CH3or analogichny, lower alkenyl, lower quinil, recloak(EN)yl, recloak(EN)yl - lower ALK(EN/in)yl or aryl-lower alkyl;

c) the restoration of the double bond in the compound of formula III

< / BR>
where R1-R9X and Y are such as defined above, at least one of X and Y is CH2and one or two dotted lines represent a double bond; or

d) alkylation of the amino derivatives of formula IV

< / BR>
where R1-R8X and Y are as defined above, with an alkylating agent, such as alkylhalogenide R9-hal mesilate R9OSO2CH3toilet R9OSO2C6H4or similar alkylating reagents with suitable chip off the group, where R9such as it was defined above; or

(e) recovering the amide derivative having the formula V:

< / BR>
where R2-R9X and Y are such as defined above, and R1"'CH2contains the group R1order to obtain the compounds of formula I, where R1is a previously defined group, having, however, in position I relative to amino methyl group; or

f) introduction of substituents R3, R4or R5vosstanovit, and the rest are as defined above for R3, R4or R5, a R6-R9X and Y are such as defined above, with the use of reagents of the type of halogen or halogenation agent, sulphurouses agent, nitrouse agent, or agent, generating ions Carbonia (RCO+, R+), where R represents alkyl, alkenyl, quinil, aryl, cycloalkyl or Ziklag(EN/in)Il.

Alkylation in section a) is usually carried out at low temperatures (for example below room temperature) in an inert solvent type, acetone, dichloromethane, tetrahydrofuran or dimethoxyethane when used in the reaction of carboxylic acid anhydrides, isocyanates or isothioscyanates. Formirovanie amines are obtained from the corresponding amines in the interaction of formic acid esters of formic acid or in the interaction with the mixed anhydride of formic acid, obtained in situ. Usually the temperature of reaction is between 0oC and boiling point compounds which are precursors of formyl.

The alkylation according to sections (b) and (d) is usually carried out by heating in a flask under reflux in a suitable solvent, such as the AK triethylamine or potassium carbonate.

Recovery of double bonds according to section (C) is usually carried out under catalytic hydrogenation at low pressure (less than 3 ATM.) in a Parr apparatus.

Recovery amides according to section e) is carried out usually using LiFlH4, AlH3or DIBORANE in an inert solvent, such as diethyl ether, tetrahydrofuran or dioxane at room or slightly elevated temperature. Halogenoalkane under section (f) is usually carried out using a chlorine, bromine or N-chlorosuccinimide, N-bromosuccinimide or other molecular predecessor of halogen in the presence of a catalyst, such as Fe ions or mineral acid.

Further, the present invention is illustrated by some examples, which, however, can not be considered as limiting.

Example 1.

1-(N,N-dipropylamino)-6-formylamino, oxalate 1a (method a).

The original connection 1-indocaribbean acid was obtained according to the process outlined V. Asham and W. H. Linnell, J. Chem. Soc., 1954, 4691 - 4693. The mixture intakebadboy acid (32.2 g), thionyl chloride (50 ml) and two drops of dimethylformamide in dichloromethane (100 ml) was heated for 3 hours in a flask with Obrochishte. To a solution of N,N-dipropylamine (50 ml) in dichloromethane, which was kept at 0 to 5oC, was added dropwise a solution of the crude carboxylic acid anhydride in dichloromethane (200 ml). The temperature was gradually raised to room, and the reaction mixture continued to be stirred throughout the night. The solvent was evaporated in vacuo, and the remaining viscous oil was purified by filtration through silica gel (elwira diethyl ether and dichloromethane 1:1). Exit N,N-dipropyl-1-indocarbocyanine 32, To a well stirred solution indocarbocyanine (20 g) in concentrated H2SO4(120 ml) which was kept at -10oC dropwise added a cooled mixture of 100% HNO3(6 g) and concentrated H2SO4(40 ml) at a temperature of from -15 to -10oC. was Allowed temperature rise to 5oC (not higher to prevent the formation of dinitrosobenzene) and the mixture is then poured on crushed ice (2 kg). The organic compound was extracted with diethyl ether (twice 200 ml), mixed organic phase is washed with a dilute solution of Na2CO3(3 x 50 ml). The organic phase was dried (anhydrous MgSO4and was treated with activated carbon. After evaporation of the diethyl ether in vacuum was obtained, the PRS was heated in a flask with reflux condenser and for 1 hour with vigorous stirring portions were added iron powder (10 x 2 g) and 6 M aqueous hydrochloric acid (10 x 0.2 ml). The mixture was heated for 1 hour in a flask with reflux condenser. Inorganic compound were filtered off while the mixture was still hot. The solution was treated with activated charcoal, and the solvent then evaporated in vacuum. The remaining solid compound was recrystallized from a mixture of diethyl and isopropyl ether 1:1, receiving 9.5 g of 6-amino-N, N-dipropyl-1-indocarbocyanine with a melting point of 100oC. To a suspension of LiAlH4(4 g) in dry tetrahydrofuran dropwise added the whole solution of 6-aminoindazole. The mixture was heated in a flask under reflux for 2 hours, and then cooled with ice. The mixture of water/tetrahydrofuran was added carefully, so as not to destroy the excess LiAlH4. The inorganic salt was filtered, and the filtrate was thoroughly washed with dichloromethane. The solvents are evaporated in vacuum. The remaining oil was dissolved in toluene and the excess water removed by evaporation of the toluene, in the form of oil was obtained 6-amino-1-(N,N-dipropylamino)indan. The release of 7.0, To formic acid (98%, 18 ml) was added 3.1 ml of acetic anhydride at a temperature slightly above the 0oC. the Entire 6-amino-1-(N,N-dipropylamino)indan dissolved in dichloromethane (15 ml) and relax the command ammonia (100 ml). The organic phase is separated and treated as remaining and mentioned in the title compound 1A in the form of oil. Oxalate salt was led from acetone. Output 7.4, melting point 150 - 152oC.

Similar were obtained by the following N,N-substituted-6-formula-1-amino-methylindene:

1-(N, N-dimethylaminomethyl)-6-formylamino, oxalate 1b. Melting point 163 - 164oC.

6 formylamino-1-(1-piperidinomethyl)indan, fumarate 1C. The melting point of 188 - 190oC.

6 formylamino-1-(1-pyrrolidinyl)indan, oxalate 1d. Melting point 176 - 179oC.

Example 2.

6-acetylamino-1-(N,N-dipropylamino)indan, hydrochloride 2A (method a).

To a solution of 6-amino-1-(N,N-dipropylamino)indane (9g), obtained as in example 1, in dichloromethane (50 ml) was added triethylamine (4.2-d). The solution acetylchloride (3.3 grams) in dichloromethane (10 ml) was added dropwise at 0 to 10oC. Then the mixture was stirred at room temperature for 1/2 hour and then poured into dilute aqueous NH4OH (100 ml). The organic phase is separated and has been given 11.0 g of crude product 2A specified in the title, in the form of oil. Cleaners containing hydrochloride salt was led from the matter of N,N-bisamidines 6 acylamino-1-aminomethyl indāni:

6-acetylamino-1-(N,N-dimethylaminomethyl)indan, hydrochloride 2b. Melting point 236 - 238oC;

1-(N, N-dipropylamino)-6-(4-perbenzoate) indan hydrochloride 2C. Melting point 217 - 220oC;

6-acetylamino-7-chloro-1-1 (N,N-dipropylamino)indan, oxalate 2f. The melting point of 77-79oC (contains 20% of 6-amino-7-chloro-1-1-(N,N-dipropylamino)indan, dioxalate);

1-(N,N-dipropylamino)-6-(methylsulfonylamino)indan, oxalate 2g. The melting point of more than 300oC;

7-chloro-1-(N,N-dipropylamino)-6- (methylsulfonylamino)indan, oxalate 2h. The melting temperature 80 - 84oC;

5-acetylamino-3-(1-piperidinomethyl)-2,3-dihydrobenzofuran 2i. The melting point of 126 - 128oC.

Example 3.

1-(N,N-dipropylamino)-6-ureido-indan 3A (method a).

To a solution of 6-amino-1-(N,N-dipropylamino)Indiana (5 g), obtained as in example 1, in methanol (10 ml), was added acetic acid (7.3 g). A solution of KOCN (3.3 g) in water (5 ml) was added dropwise at 0 to 10oC. Then the mixture was stirred at room temperature overnight. Added water (200 ml) and ethyl acetate (50 ml), the organic phase is separated and processed. Fumarate salt compounds 3A, indicated in the title, Cree is, Melting point 101oC.

Example 4

1-(N,N-dipropylamino)-6-(3-phenyl-1-ureido)indan 4A (method a).

To a solution of 6-amino-1-(N, N-dipropylamino)indane (4.9 g), obtained as in example 1, in dichloromethane (100 ml), added phenylisocyanate (3 g). The mixture was heated in a flask under reflux for 1.5 hours. During the reaction of compound 4A, indicated in the title, crystallized. The mixture was cooled with ice, and the precipitated product was filtered. Yield 4.0 G. of melting point 198 - 201oC.

In a similar way we have received the following N,N-bisamidines 6 ureido-1-aminomethane:

1-(N, N-dipropylamino)-6-(3-methyl-1-ureido)indan, hydrochloride 4b. Melting point 180 - 182oC;

6-(3,3-dimethyl-1-ureido)-1-(N, N-dipropylamino)indan, hydrochloride 4C;

1-(N, N-dipropylamino)-6-(3-nonyl-1 ureido)indan, hydrochloride 4d. Melting point 148 - 150oC;

6-(3-cyclopentyl-1 ureido)-1-(N, N-dipropylamino)indan 4E. Melting point 136 - 138oC.

Example 5.

3-(N,N-dipropylamino)-5-formylamino-2,3-dihydrobenzofuran, oxalate 5A (method a).

Starting material, 5-amino-2,3-dihydro-N,N-dipropyl-3 - benzothiophene is 8, 70, 1955, and J. Chem. Soc. (C), 1967, 1899. To a solution of carboxamide (10 g) in tetrahydrofuran (200 ml) was added tablets LiAlH4(3 x 1 g) and the mixture is gently heated in a flask under reflux for 2 hours. The excess LiAlH4carefully destroyed by adding 10% solution of water in tetrahydrofuran (25 ml) at 20oC. Inorganic salt was filtered, and the solvents evaporated in vacuo. The remaining oil (7.0 g) was used without further purification. To the thus obtained crude 5-amino-3-(N, N-dipropylamino) 2,3-dihydrobenzofuran in toluene (50 ml) was added 98% formic acid (20 ml). Toluene/formic acid was gradually dispersed, until there was obtained a temperature of 130 - 140oC. the mixture is Then poured into dilute aqueous NH4OH (250 ml) and added ethyl acetate (100 ml). The organic phase is separated and processed. Specified in the title compound 5A was purified column chromatography on silica gel (elwira 3% triethylamine in a mixture of dichloromethane and ethyl acetate 1:1). Crystalline oxalate salt was obtained from a 15% solution of ethanol in acetone. Yield 2.4 G. of melting point 135 - 136oC.

Similar were obtained by the following N,N-bisamidines 3-aminomethyl-2,3-dihydrobenzofuran:

3-[N-(2-phenylethyl)-N(1-piperidinomethyl)indan, oxalate 5s, melting point 158 - 160oC.

Example 6.

1-(N, N-dipropylamino)-6-(4-foraminiferida)indan, oxalate 6A (method e).

To a solution of 6-amino-N,N-dipropyl-1-indocarbocyanine (10 g), obtained as in example 1, and triethylamine (4.2 g) in dichloromethane (75 ml) which was kept at -5oC, was added dropwise a solution of 4-tormentilla (6 g) in dichloromethane (30 ml). The weakly temperature was raised to room. Added water (200 ml), the organic phase is processed, received 15 g of crude-derived 4-perbenzoate in the form of oil. A small sample was purified and was led. Melting point 135oC. To a suspension of LiAlH4(1 g) in dry tetrahydrofuran was added purified 4-perbenzoate derivative (3 g) and the mixture is gently heated in a flask under reflux for 1 hour. After cooling, the excess LiAlH4destroyed, carefully adding a 10% solution of water in tetrahydrofuran (15 ml) at 20oC. Inorganic salt was filtered, the filtrate was thoroughly washed with dichloromethane (2 x 50 ml), the solvent was boiled away, getting the crude product 6A, indicated in the title, in the form of oil. Oxalate salt (1.5 mol oxalic acid/mol of compound indicated in the title) Krista is amino-3-(1-piperidinomethyl)-2,3-dihydrobenzofuran, oxalate 7a (method a).

3-benzofurokaina acid: To a solution of benzofuran (75 g) in chloroform (600 ml) was added dropwise a solution of bromine (41 ml) in chloroform (150 ml) at -10oC. the Temperature is slightly increased, until they reached the room, and then the chloroform is evaporated in vacuum, obtaining the crude 2,3-dibromo-2,3-dihydrobenzofuran in the form of a crystalline product which was used without further purification. Exit 171, dibromopropionate (147 g) in ethanol (600 ml) was added a solution of KOH (59 g) in ethanol (200 ml). The mixture was heated in a flask under reflux for 2.5 hours. After cooling to room temperature the mixture was poured into water and was extracted with ethyl acetate (2 x 300 ml). Mixed organic phase was treated, and 3-bromobenzophenone then purified by washing through silica gel, using as eluent used n-heptane. The result was 51 g semi-crystalline product. The only solution thus obtained 3-bromobenzophenone and CuCN (33 g) in N-methyl-2-pyrrolidone (350 ml) was heated at 190oC under N2. At hourly intervals was added CuCN (3 x 4.5 g). The mixture is poured into a solution of FeCl3x 6N2About in the water (610 ml) and concentrated hydrochloric acid (156 ml) while it was still hot. Overovania diethyl ether (3 x 300 ml) and processing of mixed organic phases obtained crude crystalline 3-cyanobenzoate, melting at 76 - 82oC. Yield 34 g of the Obtained 3-cyanobenzoate dissolved in 660 ml of a mixture of acetic acid - sulfuric acid - water 1:1:1 and heated in a flask under reflux for 3 hours. After cooling, added water and made the final extraction of the 3-benzofuranol acid diethyl ether (3 x 200 ml) and processing it. Exit 37, melting point 152 - 156oC.

3-(1-piperidinylcarbonyl)benzofuran:

A mixture of 3-benzofuranol acid (15 g), N,N-dimethylformamide (2 ml) and thionyl chloride (25 ml) in dichloromethane (200 ml) was heated for 5 hours in a flask with reflux condenser. Volatile compounds were removed by evaporation under vacuum and the excess thionyl chloride was removed by conducting double-evaporation with toluene. Then thus obtained acid chloride 3-benzofuranol acid was dissolved in dichloromethane (100 ml) and added dropwise to a solution of piperidine (21.4 g) in methylene chloride (100 ml) at 0 - 5oC. and Then for one hour the mixture was stirred at room temperature. After washing with water and with brine the organic phase was treated as described above. Raw piperidine derived then was purified column chromatography is about in the title, in the form of butter.

3-(1-piperidinylcarbonyl)-2,3-dihydrobenzofuran:

To a solution of 3-(1-piperidinylcarbonyl)benzofuran (6.7 g) in methanol (150 ml) maintained at 35 - 50oC, in small portions over 5 hours was added Mg (3 g). After stirring for a further hour at 50oC the mixture was poured into an aqueous solution of NH4Cl. The aqueous solution was extracted with dichloromethane (2 x 200 ml). Mixed organic phase was processed, receiving 6.7 g of 2,3-dihydrobenzofuran derived in the form of butter.

5-nitro-3-(1-piperidinylcarbonyl)-2,3-dihydrobenzofuran:

All previously obtained 2,3-dihydrobenzofuran derived dissolved in triperoxonane acid (35 ml) and cooled to 10oC. the Solution became black, immediately poured on ice and extracted with ethyl acetate (2 x 50 ml). Mixed organic phase was thoroughly washed first with an aqueous solution of Na2CO3(2 x 25 ml), and finally - salt solution. After processing the organic phase was obtained 6.4 g of crude 5-nitro-derivatives in the form of oil. Further purification of column chromatography on silica gel (elwira with ethyl acetate - heptane 3:1) gave 3.2 g of pure 5-nitro-3-(1-piperidinylcarbonyl)- 2,3-dihydrobenzofuran to bonyl)-2,3-dihydrobenzofuran:

The solution is just a 5-nitrobenzophenone in 90% ethanol (50 ml) which is maintained by heating in a flask with reflux condenser, small portions over 10 min was added Fe powder (only 2.5 g) and concentrated HCl (just 0.1 ml). The mixture was heated in a flask under reflux for 1 hour. Inorganic precipitation was filtered, and the mixture was poured into brine and ethyl acetate (250 ml). After processing the organic phase was obtained 1 g of crystalline derivative of 5-aminobenzophenone.

5-acetylamino-3-(1-piperidinomethyl)-2,3-dihydrobenzofuran, oxalate 7a:

Derived 5-aminobenzophenone (1 g) dissolved in dry tetrahydrofuran, was added dropwise to a solution of LiAlH4(0.5 g) in dry tetrahydrofuran (30 ml). The mixture was heated for 2 hours in a flask with reflux condenser. After cooling in a water bath, the excess LiAlH4hydrolyzed by addition of an aqueous NaOH solution (0.5 ml 15%). The inorganic salt was filtered. The tetrahydrofuran is evaporated in vacuo, and the remaining viscous oil was dissolved in dichloromethane (100 ml). After drying (anhydrous MgSO4) dichloromethane boiled away, when this happened 0.7 g of crude 5-amino-3-(1-piperidinomethyl)-2,3-dihydrobenzofuran used bvii, was led from acetone in the form of the oxalate salt. The output of 0.15 G. of melting point 144 - 150oC.

Example 8.

Separation of compounds

(-)-6-acetylamino-1-(N,N-dipropylamino)indan, hydrochloride 8A.

To a solution of 6-atsetamino-1-(N,N-dipropylamino)indane (36.5 g), obtained as in example 2, in acetone was added (S)-(+)-binaphthyl-2,2'-diulgheroff ((+)-BNP) (21.2 g) when heated in a flask with reflux condenser. The mixture is cooled and at night left in the fridge. Usageprice crystalline product was filtered, and the solution used to obtain the other enantiomer 8b. By recrystallization from a mixture of 2:3 methanol and ethanol received 30 g of (+)-BNP salt. Melting point 257 - 260oC []D= +293.1o. Allocated free base of the compound indicated in the title 8A ([]D= -84.9o), and then bicrystalline in the form of cleaners containing hydrochloride salt from acetone. Melting point 236 - 238oC []D= -51.3o.

(+)-6-acetylamino-1-(N,N-dipropylamino)indan, hydrochloride 8b.

The acetone solution obtained above was poured into water (300 ml) and parselocale, adding water diluted NaOH. Were extracted with ethyl acetate (2 x 150 ml) and then crystal.

Compound 2b was divided in a similar way, using O,O-dichlorphenol acid as a decomposing agent:

(-)-6-acetylamino-1-(N, N-dimethylaminomethyl)indan allocated in the form of oil, 8s;

(+)-6-acetylamino-1-(N, N-dimethylaminomethyl)indan allocated in the form of oil, 8d.

Compound 2i was divided in a similar way, using O,O-dichlorphenol acid as a decomposing agent:

(-)-6-acetylamino-1-(1-piperidinomethyl)indan;

(+)-O, O-di-(4-toluyl)-D-tartrate 8E. Melting point 144 - 147oC []D= +59.2o(free base was isolated as described above []D= -46.8o).

(+)-6 - acetylamino-1-(1-piperidinomethyl)indan;

(-)-O, O-di-(4-toluyl)-L-tartrate 8f. Melting point 141 - 146oC []D= -56.3o(free base was isolated as described above []D= +50.7o).

Example 9.

(-)- and (+) 6-amino-1-(N,N-dipropylamino)indan 9a and 9b.

Compounds 8A and 8b hydrolyzed to the corresponding stereoisomers of 6-aminoindane, respectively:

A solution of (-) -6-acetamido-1-(N,N-dipropylamino)indane (8,4 g) in 10% concentrated hydrochloric acid in methanol (100 ml) was heated in a flask with reflux condenser is above 9) and was extracted with ethyl acetate (2 x 100 ml). The organic phase was treated, obtaining (-)-compound 9a in the form of oil. Yield 6.5 g []D= -81.3o.

A similar way of 8b was obtained:

(+)-6-amino-1-(N,N-dipropylamino)indan 9b; []D= +81.4o.

Similar by connecting 8C, 8d, and 8f 9e hydrolyzed to:

(-)-6-amino-1-(1-piperidinomethyl)indane 9d allocated in the form of butter;

(-)-6-amino-1-(N, N-dimethylaminomethyl)indane 9c allocated in the form of butter;

(-)-6-amino-1-(1-piperidinomethyl)indane 9d allocated in the form of butter;

(+)-6-amino-1-(1-piperidinomethyl)indane 9f allocated in the form of butter.

Example 10.

The following separated derivatives were obtained from compounds 9a - 9f using conventional acetylation process described above:

(-)-1-(N, N-dipropylamino)-6-formylamino, oxalate 10A. Melting point 149 - 151oC []D= -44o;

(+)-1-(N, N-dipropylamino)-6-formylamino, oxalate 10b. Melting point 152 - 154oC []D= +43.9o;

(-)-6-(3,3-dimethyl-1-ureido)-1-(N, N-dipropylamino)indan, hydrochloride 10C. Melting point 180 - 182oC []D= -49.2o;

(+)-6-(3,3-dimethyl-1-ureido)-1-(N,N-dipropylamine)indan, hydrochloride 10d. Teniendo, 10th. Melting point 200oC []D= -68.5o;

(+)-6-[3(4-forfinal)-1-ureido] -1-(N, N - dipropylamine)indan, 10f. Melting point 200oC []D= +69.8o;

(-)-1-(N,N-dimethylaminomethyl)-6-formylamino, oxalate 10g. Melting point 167 - 175oC []D= -57.4o;

(+)-1-(N,N-dimethylaminomethyl)-6-formylamino, oxalate 10h. Melting point 161 - 171oC []D= +59.5o;

(-)-6-formylamino-1-(1-piperidinomethyl)indan, oxalate 10i. Melting point 153 - 160oC []D= -47.3o;

(+)-6-formylamino-1-(1-piperidinomethyl)indan, oxalate 10j. Melting point 161 - 164oC []D= +47.4o.

Example 11.

(i) 6-acetylamino-5-chloro-1-(N, N-dipropylamino)indan oxalate 11a (method f).

To a solution of 6-acetylamino-1-(N,N-dipropylamino)indane 2A (3.0 g) in acetic acid (15 ml) was added in one portion SO2Cl2(1.5 g). The temperature rose to 65oC. After stirring for 2 hours at room temperature

the mixture was poured into dilute aqueous NH4OH and was extracted with diethyl ether (2 x 50 ml). Mixed organic phase was processed, and the connection 11a specified in the title, was purified in a column of crip who was litovali from acetone. Output 1.3, melting point 172 and 174oC.

The enantiomers of compound 11a was obtained from acetyl derivatives 8A and 8b, respectively, by chlorination, as described above:

(-)6-acetylamino-5-chloro-1-(N, N-dipropylamino)indan oxalate 11b. The melting point of 188 - 194oC []D= -35.4o;

(+)6-acetylamino-5-chloro-1-(N, N-dipropylamino)indan oxalate 11c. The melting point of 190 - 195oC []D= +39.7o.

(ii) 6-acetylamino-5-bromo-1-(N,N-dipropylamino)indan oxalate 11d.

To a solution of 6-acetylamino-1-(N, N-dipropylamino)indane 2A (5.0 g) in acetic acid (50 ml) was added dropwise a solution of Br2(1.2 ml) in acetic acid at 50-55oC. the Mixture was stirred over night at room temperature. Then it was poured into water/ethyl acetate, the organic phase is separated and washed Na2SO3(1% aqueous solution). After treatment of the organic phase, the remaining oil was contained quite a significant amount of unreacted educt and the connection specified in the title, was isolated from the mixture column chromatography on silica gel (elwira with ethyl acetate - heptane - triethylamine 40:60:3). Salt of oxalic acid compounds specified in

6-acetylamino-1-(N-methylaminomethyl)indan, fumarate 12A (method g).

To a solution of 6-acetylamino-1-(N, N-dimethylaminomethyl)indane 2b (54 g) in dioxane (1 l) is added dropwise at 50oC was added a solution of 2,2,2-trichlorethyl of chloroformiate (48.7 g) in dioxane (200 ml). Then the mixture was stirred for 0.5 hours at 50 - 60oC. the Solvent is boiled away, and the carbamate was purified by filtration through silica gel (elwira with ethyl acetate). Output of crude carbamate in the form of oil amounted to 89.7, To the solution thus obtained carbamate (45 g) in 90% aqueous acetic acid (575 ml) in small portions was added zinc (84 g) at 30 - 40oC. After stirring for 3 hours the excess zinc and zinc salts were filtered. Added water (2 l) and extragere diethyl ether (2 x 200 ml), removed the neutral products. Ice the aqueous phase was parselocale (pH above 10), carefully adding NaOH. As a result of extraction with dichloromethane (4 x 150 ml) and subsequent processing was obtained 14 g of compound 12A specified in the title, in the form of oil. Fumarate salt was led from ethanol. The melting point of 176 178oC.

Example 13

6-acetylamino-1-[N - (- 4-cyclohexylmethyl-1-yl)-N-methylaminomethyl] indan, sesquioxides 13A (method d).

Secretary of potassium iodide in MIBK (80 ml) was heated in a flask under reflux for 5 hours. After cooling, the inorganic salts were filtered, and the solvent was boiled away into the vacuum. The remaining oil was treated with column chromatography on SiO2(elwira with ethyl acetate - heptane - triethylamine 80: 20:4). The free base of the compound indicated in the title, provided in the form of oil. Sesquioxide 13A was led from acetone. Yield 1.6 G. of melting point 145 - 155oC.

In a similar way we have received the following N,N-bisamidines derivatives:

6-acetylamino-1-[N-methyl-N-4-phenylbutane-1-yl)-aminomethyl]indan, sesquioxides 13b. Melting point 121 - 123oC;

6-acetylamino-1-[N-4-(indol-3-yl)butane-1-yl)-N-methylaminomethyl] indan, oxalate 13C. The melting point of 111 - 113oC;

6-acetylamino-1-[N-2-(2-imidazoline-1-yl)-ethyl] -N - methylaminomethyl] indan, sesquioxides 13d. The melting point of 154 - 158oC:

6-acetylamino-1-[N-2-[3-(4-forfinal)-2-imidazoline-1-yl] - ethyl]-N-methylaminomethyl]indan, sesquioxides 13th. The melting point of 109 - 114oC;

6-acetylamino-1-[N-[4-(3-cyclohexyl-2-imidazoline-1-yl] -1-butyl]-N-methylaminomethyl]indan, sesquioxides 13f. Melting point 98 - 101oC;

6-acetylamino-1-[N-methyl-N-[3-(3-phenyl-2-imidazoline-1-yl] - 1-prop is midsolenon-1-yl] -1 - butyl]-N-methylaminomethyl]indan, oxalate 13h. The melting point of 102 - 106oC;

6-acetylamino-1-[N-[3-(3-cyclohexyl-2-imidazoline-1-yl] -1-propyl]-N-methylaminomethyl] indan, sesquioxides, hemihydrate 13i. The melting point of 108 - 115oC;

6-acetylamino-1-[N-[6-(3-cyclohexyl-2-imidazoline-1-yl] -1-hexyl]-N-methylaminomethyl] indan, sesquioxides, hemihydrate 13j. The melting point of 87 - 93oC;

6-acetylamino-1-[N-[4-(2-imidazoline-1-yl]-1-butyl]-N - methylaminomethyl] indan, profumata 13k. Amorphous freeze dried powder;

6-acetylamino-1-[N-[2-(3-(2-propyl)-2-imidazoline-1-yl]-1-propyl]-N-methylaminomethyl]indan, sesquioxides 13l. Melting point 151 - 154oC.

Example 14.

6-(N-acetyl-N-ethylamino)-1-(N, N-dipropylamino)indan, oxalate 14a (method a).

A solution of free base of compound 2A (5.0 g) in dry tetrahydrofuran was added dropwise to a suspension of 1 g of LiAlH4in 50 ml of dry tetrahydrofuran at 20 - 25oC. the Mixture was heated in a flask under reflux for 2 hours, the excess LiAlH4was destroyed by cautiously adding 2 ml of a diluted aqueous solution of NaOH. The inorganic salt was filtered, and the crude 6-ethylamino-1-(N,N-dipropylamino)-indan identified as a viscous oil at uparivaniya and added 2.3 ml of triethylamine. The mixture was cooled to 0oC and then added dropwise at 5 to 10oC solution of 1 ml of acetylchloride in 10 ml of dichloromethane. The mixture for 1 hour and stirred at room temperature. Added water (100 ml) and the organic phase is separated and processed. The remaining oil was dissolved in acetone and added oxalic acid. Crystalline oxalate salt of the connection specified in title 14 and was filtered and dried in vacuum. Yield 2.5 G. of melting point 129 - 130oC.

The following compound was obtained in a similar way, using compound 1A as the source:

6-(N-acetyl-N-methylamino)-1-(N, N-dipropylamino)indan, oxalate 14b. The melting point of 126 - 129oC.

Pharmacology

The compounds of formula I were tested according to reliable and generally accepted pharmacological methods to determine their affinity for the receptor 5-HT1Aand to determine In vivo agonistic effects of these compounds relative to a specific receptor. These tests were as follows.

The weakening of bonds3H-8-OH-DPAT with receptors 5-HT1Aserotonin in the brain of rats in vitro

Using this method were determined in vitro weakening drugs link 31Athe receptor.

Procedure

Male rats were wordplays, and their brains were dissected and weighed. Fabric cerebellum was homogenized in 10 ml having the temperature of the ice 50 nM Tris-buffer (pH 8.0. 25oC) containing 120 nM NaCl, 4 nM CaCl2and 4 nM MgCl2. The homogenate was centrifuged at 20000g and 4oC for 10 minutes Pill homogenized in 10 ml of buffer and incubated for 10 min at 37oC. the Homogenate was centrifuged as described above, while the tablet homogenized in 100 volumes of buffer, temperature and ice containing 10 m of pargyline.

Tubes for incubation were kept on ice in 100 m drug solution in water (or just water for General communication) and 1000 m of the suspension fabric (final fabric content corresponds to 10 mg of original tissue). The experiment was initiated by adding 100 m3H-8-OH-DPAT (final concentration 1 nM) and place the tubes in a water bath with a temperature of 37oC. After incubation for 15 min, the samples were filtered under vacuum (0.50 mbar) through a 25 mm filter from Whatman. Tubes were washed in 5 ml of 0.9% NaCl, with the temperature of the ice, and then placed on the filters. Then the filters were washed in 0.9% NaCl (2 x 5 ml). The filters were placed in a counting vial and added to 4 ml of the rise 2 hours in a dark place using a liquid scintillation counter was determined by radioactive concentration. Specific binding was obtained when reducing non-specific communication in the presence of 10 m 5-HT1A.

To determine the attenuation of binding were used five concentrations of drugs within 3 decades.

The measured values of concentrations and concentrations of drugs were pending on semi-log paper, and then built a curve that best corresponded to the S-form. The value of the IC50is defined as the concentration at which the binding is 50% of the total binding in the control samples minus the nonspecific binding in the presence of 10 m 5-HT.3H-8-OH-DPAT were obtained from Amersham international plc., England. The specific activity was approximately 200 Ci/mmol.

8-HE DPAT Stimulator agonism in rats

This model tests used to determine the agonistic effect of the test compounds on 5-HT1Areceptors in vivo. The appropriate method described in Tricklrbank, M. D., et al, Eur. J. Pharmacol., 1987, 133, 47 - 56; Arnt, J. Pharmacology & Toxicology, 1989, 64, 165.

Procedure

Male rats were trained to recognize 8-HE DPAT (0.4 mg/kg, such as 15-minute pre-treatment) and saline solution in the cells, which as a reward was placed in the water (0.1 ml). Rats were not allowed to water for at least 24 hours, they worked in the fixed mode.

The introduction of 8-HE DPAT was only intended for this purpose ("drug") arm, while the action on the opposite arm remained without consequences. The physiological solution was ruled by the arm, opposite the "drug" arm. Trials with medication and saline solution were followed by days. The level of recognition accuracy is expressed as a percentage of the response to the drug and is calculated as the number of correct responses, multiplied by 100 and divided by the sum of correct and incorrect responses until the first award. Time to first award also record as a measure of reaction time. Upon reaching a stable accuracy (average correct responses 90% individual response rate of at least 75% of its value) tests are conducted between days of training. Supervisory experience complete when made a total of 32 response on each arm, or after 20 minutes No reward now rats are not, and they have free access to water for 20 to 30 minutes after ulitity, obtained from rats given at least 10 "answers" on each arm. Moreover, included only those trials in which at least half of the rats gave an answer.

The weakening of the percentage of drug response received from each dose of the test compounds is used to calculate the value of the ED50.

The results are shown in the table below. Known ligands of the receptor 5-HT1A8-OH-DPAT and buspirone also included in the tests for comparison.

From the table below it is evident that the compounds of the present invention are ligands of the receptor 5-HT1A, any abscopal linking titiraupenga 8-hydroxy-2-dipropylenetriamine (8-OH-DPAT) receptors 5-HT1Ain vitro, many of which have the potential of more than 50 nM, and even in the range of from 0.5 to 10 nM. We also see that generally these compounds and in vivo have properties agonists 5-HT1A.

Furthermore, the authors investigated the affinity of the compounds of the present invention to the receptor of dopamine D2by determining its ability to reduce binding3H-spiroperidol with receptors D2method Hyttel et al, J. Neurochem., 1985, 44, 1615.

Compounds were also tested Methylphenidate according to which avedano according to Sanchez, C. et al.; Drug Dev.Res. 1991, 22, 239 - 250.

Tested compounds of the present invention, as has been shown, do not have significant affinity for the receptors of dopamine D2and have no kataleptogennoe effects at the highest dose, while many of them to be effective in Methylphenidate test, when values of the ED50in the range of mol/kg the Results of these tests show that the compounds of the present invention possess antipsychotic properties and do not exhibit extrapyramidal side effects.

In conclusion, the compounds of the present invention were tested for the presence of anxiolytic properties when measuring their ability to attenuate ultrasonic signals caused by the sound of footsteps. Adult rats emit ultrasonic distress as a response to the calling disgust stimulus, which can't be avoided, such as the shock of steps. It serves as a testbed anxiety (Tonoue T. et al. , Psychoneuroendocrinology. 1986. 11, N2, 177 - 184).

Tested compounds showed potential anxiolytic effects, and the magnitude of the ED50usually was in the range of from 0.03 to 1.0 mol/kg

Examples propisanymi in this area.

For example, tablets can be obtained by mixing the active ingredient with ordinary adjuvants and/or diluents and then extruding the mixture in a conventional tablet press machine. Examples of adjuvants or solvents include potato starch, corn starch, talc, magnesium stearate, gelatin, lactose, resin and the like. Any other adjuvants or additives commonly used for these purposes, such as dyes, corrigentov, preservatives, etc. can be used, provided that they are compatible with the active ingredients.

Injectable solutions can be obtained by dissolving the active ingredient and possible additives in a part of the solvent used for injection, preferably sterile water, bringing the solution to the desired volume, its sterilization and filling in suitable vials or flasks. Can be added to any suitable commonly used in this field additive, such as toning agents, preservatives, antioxidants, etc.

Typical examples of pharmaceutical formulations according to the present invention are the following:

1) Tablets containing 5.0 mg of compound 1A in the calculation of the free base:

Compound 1A - 5.0 mg

Lacquer is llulose 19.2 mg

Croscarmellose sodium type A - 2.4 mg

Magnesium stearate - 0.84 mg

2) Tablets containing 0.5 mg of compound 2b in the calculation of the free base:

Compound 2b 0.5 mg

Lactose - 46.9 mg

Corn starch - 23,5 mg

Povidone - 1.8 mg

Microcrystalline cellulose is 14.4 mg

Croscarmellose sodium type A - 1.8 mg

Magnesium stearate - 0,63 mg

3) Syrup, containing in 1 ml:

Compound 1C - 2.5 mg

Sorbitol 500 mg

Hydroxypropylcellulose 15 mg

Glycerol 50 mg

Methyl paraben 1 mg

Propyl-paraben 0.1 mg

Ethanol - 0,005 ml

Flavor - 0.05 mg

Saccharin 0.5 mg

Water Up to 1 ml

4) Solution for injection containing 1 ml:

Connection 10j - 0.5 mg

Sorbitol - 5.1 mg

Acetic acid - 0.08 mg

Water for injection To 1 ml

The tests of the claimed substance in a therapeutically acceptable amounts showed no harmful effects of substances on the patient.

1. Aminomethane - benzofuranyl, benzothiophene having a General formula I

< / BR>
where one of the radicals X or Y is CH2and the other is selected from the group consisting of CH2, O, S;

R1represents lower alkyl, phenyl - lower alkyl, hydrogen, lower alkyl, C3-C8-cycloalkyl, phenyl, possibly substituted with halogen;

R2represents hydrogen or lower alkyl;

R3- R5independently selected from the group consisting of hydrogen or halogen;

R6, R7is hydrogen;

R8, R9independently represents hydrogen, lower alkyl, C3-C8-cycloalkyl-lower alkyl, phenyl - lower alkyl, indolyl - lower alkali or group;

< / BR>
where R13represents hydrogen, lower alkyl, C3-C8-cycloalkyl, phenyl, forfinal;

r = 2-6;

w = 0,

or R8, R9linked together with the formation of a 3-7-membered ring containing one nitrogen atom, and their pharmaceutically acceptable salts.

2. Connection on p. 1, characterized in that X represents CH2, O, S, and Y is CH2.

3. Connection on p. 1, wherein R1represents phenyl-lower alkyl, acyl, lower alkylsulfonyl or a group R11R12-N-C(O)-, where

R11represents hydrogen, lower alkyl, and R12represents hydrogen, lower alkyl, phenyl, possibly substituted by halogen or C3-C8-cycloalkyl.

4. carbonyl or a group of the formula R11R12-N-C(O)-, where R11represents hydrogen, lower alkyl, R12represents hydrogen, lower alkyl, phenyl, possibly substituted with halogen, C5-C6-cycloalkyl.

5. Connection on p. 1, wherein R8represents hydrogen, lower alkyl, R9represents lower alkyl, phenyl-lower alkyl, C3-C8-cycloalkyl - lower alkyl, indolyl-lower alkyl or a group of the formula

< / BR>
where w represents O;

R13represents hydrogen, lower alkyl, C3-C8-cycloalkyl, phenyl or forfinal.

6. Connection on p. 5, wherein R9represents cyclohexyl-lower alkyl, phenyl-lower alkyl, indolyl-lower alkyl or a group

< / BR>
where w means ABOUT;

R13means hydrogen, lower alkyl, C3-C8-cycloalkyl, phenyl or forfinal.

7. Pharmaceutical composition having anxiolytic effect, containing one or more pharmaceutically acceptable carrier or diluent in combination with an active compound, characterized in that the active compounds it contains a therapeutically effective amount of the compounds on p. 1 Il

 

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