8-substituted-2-aminotetraline derivatives and methods of obtaining

 

(57) Abstract:

The proposed compound of formula I, where Z denotes hydrogen or halogen, Q means COR1or 5 - or 6-membered aryl which may contain 1 or 2 heteroatoms of N, O or S maybe substituted or condensed, where R is hydrogen or C1-methyl (CIS-configuration), R1means C1-6-alkyl or aromatic ring which may contain heteroatoms O or S and may be substituted or condensed with a substituted benzene ring, R2means a hydrogen atom or a C1-6-alkyl, and R3can have different values referred to in paragraph 1 of the formula and its enantiomers or salts, methods for obtaining such compounds, pharmaceutical preparations on their basis, as well as a method of treatment of diseases of the Central nervous system when using these compounds. 3 S. and 12 C.p. f-crystals, 1 table.

The invention relates to new 8-carbonylation 2-aminotetraline, their enantiomers and salts, processes for their preparation, pharmaceutical preparations on their basis and use of such compounds in therapy.

The purpose of the present invention to produce compounds for therapeutic use sobienie compounds with selective action on 5-hydroxytryptamine receptors in mammals, including man.

Therapeutically useful derivatives of tetralin, affect 5-hydroxytryptamine neurons in mammals, described in EP N 41488, 270947 and 272534.

The purpose of the present invention to obtain new compounds with high affinity for the 5-hydroxytryptamine receptors of the Central nervous system with their simultaneous action as agonists, partial agonists or antagonists to serotonin receptors.

Thus, the new compounds of formula I of the present invention, as well as their enantiomers and salts are useful for therapeutic treatment mediated 5-hydroxytryptamine conditions and disorders, such as depression, anxiety, anorexia, senile dementia, Alzheimer's disease, migraine, disorders of thermoregulation and sexual functions. Additional aspects of the invention relate to the use of these compounds and their enantiomers and salts to relieve pain and modulation of the cardiovascular system.

Thus, the present invention provides compounds of formula:

< / BR>
in which R denotes hydrogen or methyl, provided that C1- methyl Deputy is in CIS-configuration is poured, thiazolyl, pyridyl, hinely, indicazioni, indolyl, benzofuranyl, not necessarily substituted with halogen, lower alkyl, or lower alkoxy;

R1represents C1-6-alkyl, C3-6-cycloalkyl or phenyl, does not necessarily substituted with halogen or lower alkoxy;

R2represents hydrogen or C1-6-alkyl;

R3represents a group C1-6-alkyl or -(CH2)a-R4in which

a is 4;

R4is-NR11R12;

R11and R12together with the nitrogen atom form a ring:

< / BR>
where n represents 1 or 2,

and their enantiomers and physiologically acceptable salts.

C1-C6the alkyl in the formula I denotes unbranched or branched alkyl groups with 1-6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, C3-C6-cycloalkyl means a cyclic alkyl group with 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopropyl, ethylcyclopropane, methylcyclobutane. As preferred alkyl groups use C1-4-alkili.

Lowest alkoxygroup in the formula (I predstateli, ethoxy.

Halogen in formula I is fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine and bromine, especially fluorine.

Compounds of the invention contain one or two asymmetric carbon atoms. When R is hydrogen, the compounds contain an asymmetric carbon atom at the nitrogen, that is, C2and when R is methyl, the compounds contain an asymmetric carbon atom at the nitrogen and the asymmetric carbon atom in the methyl group, that is, C1and C2. Thus, the proposed compounds exist in the form of two or four stereoisomers, that is, enantiomers and/or diastereoisomers. In the scope of the present invention includes both the pure enantiomers and racemic mixtures. therapeutic properties of the claimed compounds to a greater or lesser extent can be attributed and the racemate and enantiomers.

It was found that C1-methylated derivatives of the formula I, in which methyl Deputy is in CIS-configuration relative to the 2-amino substituent with C2are strong agonists 5-hydroxytryptamine receptor. Preferred compounds have the 1S, 2R-configuration.

To obtain non-toxic physiologically p. the organic acid. As an example, sulfuric, nitric, phosphoric, oxalic, hydrochloric, Hydrobromic, citric, acetic, lactic, tartaric, pambou acid, econsultation, sulfamic, amber, cyclohexylsulfamic, fumaric, maleic and benzoic acid. These salts can easily get the well known ways.

For preferred compounds include those in which Q is phenyl, forfinal, thienyl or furanyl or group COR1in which R1means CH3C2H5C3H7C4H9C5H11cyclopropyl, methylcyclopropyl, methylcyclobutane, and R2means C1-6-alkyl, and R is hydrogen.

Compounds of the invention can be obtained in one of the following methods, which constitute another aspect of the invention.

a) Make the connection formulas II

< / BR>
where X represents a leaving group, for example triftormetilfosfinov (TF), phosphonate, halide, for example Br or J, and R, R2and R3have the above values,

by substitution of the group X is a carboxyl group COR1obtaining the compounds of formula IA.

Compound II can be converted into sedentexct M0such as Pd or Ni, which is able to undergo oxidative connection to the aryl-X-relations, for example arylalkenes relations. M0can be obtained in situ by treating M11carbon monoxide (CO). M1must be a metal, such as Sn, Mg, Zn, Zr, B, Al, Li which is able to transmetallation originally educated carbonyliron-aryl-metal-X-complex (for example, s-aryl-metallogenesis complex).

< / BR>
Additional reagents are carbon monoxide, amine, such as triethylamine, in an inert organic solvent, preferably a polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetone, acetonitrile, and so on, the Reaction is usually carried out at a temperature in the range from 40 to 120oC and a pressure of from 1 to 5 bar.

b) Compound IA can be obtained using the reverse process.

The reaction is carried out in the form of a catalytic cycle using transition metal zero valency M0such as Pd or Ni, with the ability oxidative addition to the group R1-X, where R1have the above in formula IA values, and X is a leaving group such as halide, ASU is SUP>-CO-M11-X can also be obtained directly from R1-COCl. Reaction conditions and reagents similar to those used in the above method.

C) make the connection formulas II

< / BR>
where X represents a leaving group, such as triftoratsetata (TF), phosphate, halide, for example Br or J, and R, R2and R3have the above meanings, by substitution group X 5 - or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S, and is either substituted or fused at two adjacent carbon atoms with an aryl ring, as described above, with the formation of the compounds of formula IB.

The compound of formula II can turn into the Ib connection through reaction with the transition metal with zero valency of M0such as Pd or Ni, with the ability to oxidative join aryl-X-communication. Suitable aryl-Deputy can be entered when using trialkyl-aristanemi.

Additional reagents are amine, for example triethylamine, and a lithium salt such as lithium chloride. The reaction is preferably carried out in polar aprotic solvent, such as dimethylformamide, dioxane, acetonitrile >,

where X represents a leaving group, such as triftormetilfosfinov, Z means a halogen, and R, R2, R3have the above values,

using the substitution group X group Q, which means the group COR1or 5 - or 6-membered aryl, as defined above.

e) turn the compound of formula IV (described in EP N 272534)

,

where R2and R3have the above meanings, by substitution of the nitrile carboxypropyl COR1with the formation of compounds of formula IA. The reaction is carried out by processing the appropriate ORGANOMETALLIC reagent, preferably organolithium compound or a Grignard reagent in an inert organic solvent, preferably a non-polar aprotic solvent, such as ethers, for example diethyl ether, tetrahydrofuran, benzene, followed by hydrolysis of the intermediate complex compounds with the formation of the target product.

Pharmaceutical

In accordance with the present invention the compounds of formula I are introduced, usually orally, rectally or by injection in the form of pharmaceutical preparations comprising the active substance or in the form of free osnovnata, acetate, phosphate, sulfate, sulpham, citrate, tartrate, oxalate and similar, in a pharmaceutically acceptable dosage form. Dosage form can be represented in the form of liquid, semi-liquid or solid preparation. The active ingredient is usually from 0.1 to 99 wt. drug, more specifically from 0.5 to 20 wt. for preparations intended for injection and between 0.2 and 50 wt. for preparations intended for oral administration.

For the preparation of pharmaceutical preparations containing a compound of formula I in the form of a unit dose for oral administration, the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches, such as potato, corn starch or amylopectin, cellulose derivatives, a binder such as gelatinous or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, etc., and then pressoffice in tablets. To obtain tablets coated core obtained in the above manner, can be coated with a concentrated sugar solution which may include, for example, the Arabian resin, gelatin, dioxi is solved in a volatile organic solvent or mixture of organic solvents. Can be added to these coatings colorants to simplify distinguish between tablets containing different active substances or different number of active connections.

To obtain capsules soft gelatin active substance can be mixed, for example, with vegetable oil or polyethylene glycol. Capsules on the basis of solid gelatin may contain granules of the active substance using the above-mentioned excipients for tablets, for example lactose, saccharose, sorbitol, mannitol, starches (potato, corn or amylopectin), cellulose derivatives or gelatin. Hard gelatin capsules can also fill out a medical product in a liquid or semi-liquid forms.

Single dose for rectal application can be in the form of solutions or suspensions, or they can be obtained in the form of suppositories containing the active substance in a mixture with a neutral fat base, or gelatin capsules containing the active substance in a mixture with vegetable or paraffin oil.

Liquid preparations for oral use may be in the form of syrups or suspensions, for example solutions containing from about 0.2 to 20 wt. active substances is their drugs may not necessarily include colorants, perfuming or flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other known in the field fillers.

Solutions for parenteral administration by injection can be obtained in the form of an aqueous solution of water-soluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of from about 0.5 to 10 wt. These solutions may also contain stabilizers and/or buffering agents. For convenience, these solutions can be produced in capsules with different dose.

A suitable daily dose of the proposed connection with therapeutic use for humans is approximately from 0.01 to 100 mg/kg body weight by oral administration and from about 0.001 to 100 mg/kg of body weight at parenteral administration.

Example 1. (+/-)-2-(Dipropylamino)-8-[(trifloromethyl)oxy]tetralin

A solution of the anhydride of triftoratsetata (7.0 g, 24,8 mmol) in dichloromethane (20 ml) is added to a mixture of potassium carbonate (3.4 g, 24,8 mmol) and 8-hydroxy-2- (dipropylamino)tetralin (a 3.06 g, 12.4 mmol) in dichloromethane (300 ml), incubated the mixture at -70oC. the cold bath is removed and stirring is continued over night. The mixture ekstragiruyut and concentrate. After purification of the residue on a column of alumina with elution with a mixture of simple ether/petroleum ether (1:8), get free 5.01 g of oil, which is converted into the hydrochloride. After recrystallization from a mixture of ethanol/simple ether get free 5.01 g (97%) of purified hydrochloric 2-(dipropylamino)-8-[(trifloromethyl)oxy] tetralin. (+)-(R)-2-(dipropylamino)-8-(tripterocalyx)tetralin and (-)-(S)-2-(dipropylamino)-8-(tripterocalyx)tetralin get a similar manner from the corresponding enantiomers of 8-hydroxy-2-(dipropylamino)tetralin that can be obtained with high yield and optical purity.

Example 2. Hydrochloride (+/-)-8-acetyl-2-(dipropylamino)tetralin

A mixture of 2-(dipropylamino)-8-[(trifloromethyl)oxy]tetralin (455 mg, 1.2 mmol), tetramethylurea (257 mg, 1.44 mmol), lithium chloride (158 mg, 3.7 mmol), dichloro-[1,1-bis(diphenylphosphino)ferrocene]palladium (II) (PdCl2) (dfff); 61 mg, 0.07 mmol), molecular sieves (4; 120 mg) and dimethylformamide (10 ml), stirred in an atmosphere of carbon monoxide for 14 hours at 90oC. the Catalyst is filtered off and the filtrate, partitioned between water and ether. The organic layer is dried (sodium sulfate) and concentrated in vacuo. Statestie faction merge and concentrate, and after processing the obtained essential oils chloride hydrogen obtain 158 mg (70%) of the pure hydrochloride of 8-acetyl-2-(dipropylamino)tetralin, which can precrystallization of CHCl3diethyl ether. So pl. - 125-127oC.

Example 3. Hydrochloride (+/-)-methyl-2-(dipropylamino)tetralin-8-carboxylate

A mixture of 2-(dipropylamino)-8-[(trifloromethyl)oxy] tetralin (3.5 g, 9.2 mmol), triethylamine (1.86 g, 18.4 mmol), palladium acetate (11) (62 mg, 0.28 mmol), 1,11bis(diphenylphosphino)ferrocene (306 mg, 0.55 mmol), methanol (5.7 g, 184 mmol) and dimethyl sulfoxide (70 ml), stirred overnight under a positive pressure of carbon monoxide. The reaction mixture was partitioned between saturated aqueous sodium chloride and ether. The organic layer is dried (using sodium sulfate) and concentrated. The residue is purified by chromatography on a column of alumina with elution with a mixture of simple ether/petroleum ether (1:16). Purified fractions merge and concentrate. The remaining oil is converted into hydrochloric salt. By recrystallization of the product from a mixture of diethyl ether/chloroform gain of 2.08 g (92%) of the hydrochloride of methyl 2-(dipropylamino)-tetralin-8-carboxylate. So pl. 136-137oC.

oC, it can be precrystallization from methanol/diethyl ether.

Example 5. Hydrochloride (+/-)-8-acetyl-2-(dipropylamino)tetralin

5% solution metallice simple ether (0.6 ml, 0.96 mmol) are added to sharply cooled suspension of hydrochloride (+/-)-carboxy-2-(dipropylamino)tetralin (100 mg, 0.32 mmol) in a simple ether. The mixture is stirred at room temperature under nitrogen atmosphere for 3 days. Carefully add water and the mixture extracted with simple ether. The organic layer is dried (potassium carbonate) and concentrated. The residue is purified by chromatography on a column of alumina with elution with a mixture of simple ether/petroleum ether (1: 4). The purified fraction is drained, concentrated and converted into the hydrochloride. Recrystallization from a mixture of acetonitrile/simple broadcast network is about)tetralin

A mixture of (+)-2-(propylamino)-8-[(trifloromethyl)oxy]tetralin (300 mg, 0.79, which mmol), tetramethylsilane (167 mg, 0.95 mmol), lithium chloride (104 mg, 2.5 mmol), dichloro[1,11bis(diphenylphosphino)ferrocene]palladium (II) (PdCl2) (dfff) (40 mg, 0,047 mmol), molecular sieves (4, 120 mg), 2,6-ditretbutyl-4-METHYLPHENOL (catalytic amount) in dimethylformamide (6 ml) is stirred under an atmosphere of carbon monoxide for 20 hours at 90oC. the Catalyst is filtered off and the filtrate is partitioned between water and ether. The organic layer is dried (sodium sulfate) and concentrated in vacuo. The residue is purified by chromatography on a column of alumina with elution with a mixture of simple ether/petroleum ether (1:16). The purified fraction is drained, and after concentrating obtain 120 mg (42%) of (+)-acetyl-2-(dipropylamino)tetralin in the form of butter.

Example 7. Hydrochloride (-)-8-acetyl-2-(dipropylamino)tetralin

A mixture of (-)-2-(dipropylamino)-8-[(trifloromethyl)oxy] tetralin (910 mg, 2.4 mmol), tetramethylsilane (514 mg, is 2.88 mmol), lithium chloride (315 g, 7,44 mmol), dichloro-[1,11bis-(diphenylphosphino)ferrocene]palladium (II) (12 mg, 0.144 mmol), molecular sieves (4 240 mg), 2,6-decret-butyl-4-METHYLPHENOL (catalyst) in dimethylformamide (20 ml) PE is t divided into aquatic and terrestrial layers. The organic layer is dried (sodium sulfate) and concentrated. The residue is purified by chromatography on a column of alumina with elution with a mixture of simple ether/petroleum ether (1: 16). Purified fractions merge and concentrate. The oil obtained is transformed into the hydrochloride, by recrystallization from a mixture of chloroform/simple broadcast receive 323 mg (44%) of pure (-)-8-acetyl-2-(dipropylamino)tetralin hydrochloride. So pl. 114-116oC []D: -123,2oC (with 1.0, MeOH).

Example 8. Hydrochloride (+/-)-8-benzoyl-2-(dipropylamino)tetralin

A mixture of racemate of 2-(dipropylamino)-8-[(trifluoromethyl)oxy] tetralin (200 mg, 0.52 mmol), vinyltrimethylsilane (154 mg, 0.64 mmol), lithium chloride (69 mg, 1.6 mmol), dichloro[1,11bis- (diphenylphosphino)ferrocene]palladium (II) (26 mg, of 0.332 mmol), 2,6-decret-butyl-4-METHYLPHENOL (as catalyst) and molecular sieves (4, 40 mg) in dimethylformamide is stirred at a temperature of 110oC in an atmosphere of carbon monoxide for 15 hours. The mixture was separated into aqueous and ether layers. The organic layer is dried (sodium sulfate) and concentrated in vacuo. The residue is purified by chromatography on a column of alumina with elution with a mixture of simple ether/petroleum ether, 1:16. Purified fractions drained and code (+/-)-8-benzoyl-2-(dipropylamino)tetralin.

Example 9. (+/-)-8-(1-Oxobutyl)-2-(dipropylamino)tetralin

A mixture of the hydrochloride of 2-(dipropylamino)-8-[(trifloromethyl)oxy] tetralin (216 mg, 0.52 mmol), tetrabutyltin (218 mg, 0.64 mmol), triethylamine (105 mg, 1.04 mmol), lithium chloride (68 mg, 1.6 mmol), dichloro-[1,11bis-(diphenylphosphino)ferrocene] palladium (26 mg, 0.03 mmol), 2,6-decret-butyl-4-METHYLPHENOL (catalytic amount) and molecular sieves (4, 40 mg) in dimethylformamide (5 ml) stirred in an atmosphere of carbon monoxide for 20 hours at 120oC. the Mixture is filtered and the resulting filtrate is separated into aqueous and ether layers. The organic layer is dried (sodium sulfate) and concentrated in vacuo. The residue is purified by chromatography on a column of alumina with elution with a mixture of simple ether/petroleum ether (1:16). Purified fractions merge and concentrate. The oil obtained handles ethereal oxalic acid, yielding 150 mg (71%) of the oxalate in the form of butter.

Example 10. Oxalate (+/-)-8-phenyl-2-(dipropylamino)tetralin

A mixture of racemic 2-(dipropylamino)-8-(tripterocalyx)tetralin (450 mg, 1.2 mmol), trimethylpentane (433 mg, 1.8 mmol), tetrakis(triphenylphosphine)palladium (0) (69 mg, 0.06 mmol), lithium chloride (153 mg, 3.6 mmol) is> in the flask with a glass stopper for 3 days. The resulting mixture was filtered (celite), concentrated and separated by a layer of saturated solution of potassium bicarbonate and ether layer. The organic layer is dried over potassium carbonate and concentrated in vacuo. The remainder chromatographic on a column of alumina with elution first with petroleum ether, and then with a mixture of simple ether/petroleum ether (1:40), and then a simple ether/petroleum ether (1: 20). Pure fractions are collected and treated with ethereal oxalic acid, getting 232 mg (48%) oxalate (+/-)-8-phenyl-2-(dipropylamino)tetralin. So pl. 162-163oC. (+)-(R)-8-phenyl(dipropylamino)tetralin and (-)-(S)-8-phenyl-2-(dipropylamino)tetralin receive similarly, from (R)- and (S)-2-(dipropylamino)-8-(tripterocalyx)tetraline, respectively.

Example 11. Oxalate(+/-)-8-(2-furanyl)-2-(dipropylamino)tetralin

A mixture of racemate of 2-(dipropylamino)-8-(tripterocalyx)tetralin (100 mg, 0.26 mmol), furan-2-yl-trimethylstyrene (75 mg, 0.32 mmol), dichloro[1,1-bis(diphenylphosphino)ferrocene] palladium (II) (12 mg, 0.014 mmol), lithium chloride (69 mg, 1.6 mmol), molecular sieves (60 mg) and 2,6-decret-butyl-4-METHYLPHENOL (catalyst) in 3 ml of dimethylformamide is stirred at a temperature of 90er sodium bicarbonate and ether. The ether layer is dried (potassium carbonate), filtered and concentrated in vacuo. The remainder chromatographic on a column of alumina using a mixture of simple ether/petroleum ether as eluent. Pure fractions are collected, treated with ethereal oxalic acid, obtaining a white powder after recrystallization from a mixture of MeOH/simple ether obtain 36 mg (36%) oxalate (+/-)-8-(furan-2-yl)-2-(dipropylamino) tetralin. So pl. 113-114oC.

Example 12. Oxalate (+/-)-8-(benzofuran-2-yl)-2-(dipropylamino)tetralin

A mixture of racemic 2-dipropylamino-8-(tripterocalyx)tetralin (400 mg, 1.04 mmol), benzofuran-2-ultimateinstance (444 mg, 1.6 mmol), tetrakis(triphenylphosphine)palladium (0) (60 mg, 0.52 mmol), lithium chloride (140 mg, 3,24 mmol) and 266-decret-butyl-4-METHYLPHENOL (catalyst) in 12 ml of 1,4-dioxane and 1.2 ml of dimethylformamide was stirred at 105oC in a sealed flask for 3 days. The mixture is filtered through celite), concentrated and partitioned between a saturated solution of potassium bicarbonate and simple ether. The ether layer is dried (potassium carbonate), filtered and evaporated. The remainder chromatographic on a column of alumina with elution with petroleum ether, then with a mixture of simple ether/petroleum EB and after processing the ethereal oxalic acid to obtain 220 mg (48%) oxalate (+/-)-8-(benzofuran-2-yl)-2-(dipropylamino)tetralin. So pl. - 168-170oC.

Example 13. (1S,2R)-1-Methyl-2-(dipropylamino)-8- (tripterocalyx)tetralin

A solution of hydrochloride (1S,2R)-1-methyl-8-methoxy-2-(dipropylamino)tetralin (J. Med. Chem. 1987, 30, 2105-2109) in freshly 48% solution of HBr was stirred at 120oC for 3 hours. The reaction mixture was concentrated and partitioned between ice saturated sodium bicarbonate solution and dichloromethane. The organic layer is dried over sodium sulfate, filtered and concentrated. The remainder of the crude (1S,2R)-8-hydroxy-1-methyl-2-(dipropylamino)tetralin used directly in the next stage. To the mixture demetilirovannogo source material and potassium carbonate (1.0 g, 6.6 mmol) in 20 ml of dichloromethane add a solution of the anhydride teflonovoy (triftormetilfullerenov) acid (1.3 g, 4.4 mmol) in 10 ml of dichloromethane at -78oC for 15 minutes in nitrogen atmosphere. The reaction mixture was kept at room temperature overnight with stirring. The reaction mixture was concentrated and partitioned between saturated potassium carbonate solution and ether. Organic saitua as eluent a mixture of simple ether/petroleum ether (1:8). Purified fractions are collected and concentrated, getting 744 mg (86%) of free base of the triflate.

Example 14. (1S,2R)-8-Benzoyl-1-methyl(dipropylamino)tetralin hydrochloride

A mixture of (1S,2R)-1-methyl-2-(dipropylamino)-8-(tripterocalyx)tetralin (100 mg, 0.25 mmol) (example 13), vinyltrimethylsilane (80 mg, 0.33 mmol), lithium chloride (33 mg, 0.77 mmol), dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) (13 mg, 0.015 mmol), 2,2-decret-butyl-4-METHYLPHENOL (catalyst) and molecular sieves (4, 40 mg) in 3 ml of dimethylformamide, stirred at 90oC in an atmosphere of carbon monoxide during the night. The reaction mixture was filtered through celite), concentrated and chromatographic on a column of alumina with elution with a mixture of simple ether/petroleum ether (1:16). Purified fractions are collected, and after processing the ethereal HCl get white powder after recrystallization which chloroform and simple ether obtain 45 mg (47%) of hydrochloride (1S, 2R)-8-benzoyl-1-methyl-2-(dipropylamino)tetralin So pl. - is 147.5-150oC.

Example 15. Getting oxalate salt of 2-di-p-propylamino-8-propionyl 1,2,3,4-tetrahydronaphthalene

2-Di-p-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalen (8.5 g, a 27.4 mmol) was dissolved in 80 ml tetrahedrite at -78oC for one hour, after which was added 2.4 ml (from 32.9 mmol) Propionaldehyde. The mixture was warmed to room temperature, then poured into water and was extracted with methylene chloride. The extract was dried over sodium sulfate and supariwala, giving of 9.1 g of yellow oil.

The oil was placed on silicagel column and loirevalley a mixture of 3% methanol in methylene chloride containing a trace of ammonium hydroxide. The appropriate fractions were combined, giving a 6.5 (82,0%) of 2-di-n-propylamino-8-(1'-hydroxypropyl)-1,2,3,4-tetrahydronaphthalene in the form of a light oil.

The above product was dissolved in 250 ml of methylene chloride, was added 17 g (to 78.7 mmol) of pyridinesulfonamide (PCC) along with 30 g of molecular sieves 4

The mixture is stirred for 3 hours at room temperature, after which was added 250 ml of a simple ester and Celica. The mixture was poured on short silicagel column and lirowaus simple ether. To dissolve the brown suspension was added methanol, and after adding a simple ether to the reaction mixture was deposited sediment. This substance was added to the column and was loirevalley 10% methanol in methylene chloride. Eluent was concentrated, giving a brown oil, which the ZAT as solvent. The fractions containing the product were combined and concentrated, giving 4.7 g of product. Formed oxalate salt 2.5 g of the substance and precrystallization three times from a mixture of ethanol/simple ether, giving the product as a white solid (1.5 g). So pl. - of 114.5-115oC.

Elemental analysis:

calculated: C 66,82, H 8,29, N 3,71;

found: C 67,07, H 8,20, N 4,00.

Example 16. Getting hydrobromide salt 2-di-n-propylamino-8-butanoyl - 1,2,3,4-tetrahydronaphthalene

2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalen (5.0 g, 16,1 mmol) was dissolved in 50 ml of tetrahydrofuran, and the mixture was cooled to -78oC, after which was added 21 ml of n-utility (0.92 M in hexane). The mixture was mixed for 30 minutes and was added 1.85 ml (21,0 mmol) Butyraldehyde. The mixture was left to warm to room temperature and stirred overnight, after which it was poured into water and was extracted with methylene chloride. The extract was dried over sodium sulfate and supariwala, giving 6.4 g of residue. The residue was placed on silicagel column and elyuirovaniya a mixture of 2% methanol in methylene chloride containing a trace of gidroksilamina. The appropriate fractions were combined, giving 4.8 g of 2-di-n-propylamino-8-(1'-hydroxyethylamide and added 4 a molecular sieves (30 g). The mixture was mixed, and was added 10.0 g (46.2 mmol ) of PCC. Stirring is continued for 3 hours at room temperature, after which the mixture was poured on silicagel column and loirevalley consistently simple ether and 3% methanol in methylene chloride containing a trace of ammonium hydroxide, giving the product as a brown oil.

The oil was placed on silicagel column and lirowaus a mixture of 3% methanol and methylene chloride containing a trace of ammonium hydroxide.

The appropriate fractions were combined, giving an oil, which was dissolved in ordinary air, causing the formation of a brown precipitate. The precipitate was removed by filtration, the filtrate was supariwala, giving 3.0 g of light brown oil in the form of the free base of the target compound.

One gram of the oil turned into hydrobromide salt and precrystallization from a mixture of methanol and ethyl acetate, giving 0.9 g of target compound in the form of reddish-brown crystals. So pl. 122-123oC. After the second recrystallization was received 750 mg So pl. 125-126,5oC.

Elemental analysis:

calculated C 62,82, H 8,43, N 3,66;

found: C 63,09, H by 8.22, N 3,66.

Example 17. Getting hydrobromide salt 2-di-p-PR1,0 g, 3.2 mmol) was dissolved in 10 ml of tetrahydrofuran and cooled to -78oC, after which was added 3.5 ml (1.0 M in hexane) n-utillity. After 30 minutes, to the mixture was added 0,41 ml (3.5 mmol) of methylisobutyl, and the mixture was mixed for 30 minutes at -10oC and then poured into 10% aqueous hydrochloric acid solution, was filtered by a simple ether, and the pH was brought to 10. The mixture was then extracted with methylene chloride, and the extract was dried over sodium sulfate and supariwala, giving 0,72 g of residue.

The residue was placed on silicagel column and elyuirovaniya successively with a mixture of hexane and simple ether (4:1), containing a trace of ammonium hydroxide, and then with a mixture of hexane and simple ether (3:1) containing a trace of ammonium hydroxide. The appropriate fractions were combined, yielding 190 mg of the free base of the target compound.

The connection turned in his hydrobromide salt and precrystallization from ethyl acetate, yielding 80 mg of target compound in the form of reddish-brown crystals. So pl.-175-176,5oC.

Elemental analysis:

calculated C 62,82, H 8,43, N 3,66;

found: C 62,54, H 8,53, N 3,44.

Example 18. Getting hydrobromide salt 2-di-n-propylamino-8-(b-methylb is the very in 10 ml of tetrahydrofuran and cooled to -78oC, after which was added 3.5 n-utility (1.0 M in hexane). After 20 minutes was added to 0.53 ml (3.5 mmol) of utilizability, and the mixture was heated to -10oC and left to stand for 30 minutes. The mixture was then poured into a dilute acid, was filtered by a simple ether, and the pH was brought to 10. The mixture was extracted with methylene chloride, and the extract was dried over sodium sulfate and supariwala, giving 0,83 g of residue.

The residue was placed on a column of silica gel and elyuirovaniya successively with a mixture of hexane and simple ether (4:1), containing a trace of ammonium hydroxide, and then with a mixture of hexane and simple ether (3:1) containing a trace of ammonium hydroxide. The appropriate fractions were combined, giving 50 mg of the free base of the target compound.

The free base was turned into hydrobromide salt, which was precrystallization from a mixture of ethyl acetate and hexane, yielding 30 mg of target compound in the form of a reddish-brown powder. So pl. 131-132oC.

Elemental analysis:

calculated C 63,63, H 8,64, N 3,53;

found: C 63,35, H 8,42, N 3,83.

Example 19. Getting hydrobromide salt 2-di-n-propylamino-8 - dimethylpropionic-1,2,3,4-tetrahydronaphthalene

2-Di-n-propylamino-8-b which was added to 4.7 ml of n-utility (0,82 M in hexane). The mixture was mixed for 30 minutes at -78oC, after which was added to 0.56 ml (4.2 mmol) of methyltrimethoxysilane. The mixture was left to warm to room temperature and then poured into water and was extracted with methylene chloride. The extract was dried over sodium sulfate and supariwala, giving 1.6 g of residue.

The residue was placed on silicagel column and elyuirovaniya with a mixture of hexane and simple ether (3:1) containing a trace of ammonium hydroxide. The appropriate fractions were combined, giving 140 mg of the free base of the target compound.

The free base was turned into hydrobromide salt and precrystallization from methanol/ethyl acetate, yielding 80 mg of target compound. So pl. 157-158oC.

Elemental analysis:

calculated C 63,63, H 8,65, N 3,53;

found C 63,39, H 8,46, N 3,43.

Example 20. Getting oxalate salt of 2-di-n-propylamino-8 - cyclohexanecarbonyl-1,2,3,4-tetrahydronaphthalene

Method A: 2-di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g, 3.2 mmol) was dissolved in 10 ml of tetrahydrofuran and cooled to -78oC, after which was added to 2.8 ml of n-utility (1.27 M in hexane). The mixture is stirred at -78oC for 45 minutes, after which was added 0,59 intelligent solution of hydrochloric acid, was filtered by a simple ether, the pH was brought to 10 with ammonium hydroxide, and the mixture was extracted with methylene chloride. The extract was dried over sodium sulfate and supariwala, giving 0.8 g of residue.

The residue was placed on silicagel column and elyuirovaniya with a mixture of hexane and simple ether (3:1) containing a trace of ammonium hydroxide. The appropriate fractions were combined, yielding 0.36 g of the target compound.

Method B: To a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (1.0 g, 3.2 mmol) in tetrahydrofuran (10 ml) was added utility (1.2 M in hexane (3.0 ml, 3.5 mmol) at a temperature of -78oC, and the mixture is stirred for 45 minutes. Added cyclohexanecarboxaldehyde (of 0.47 ml, 3.9 mmol). The reaction mixture was stirred at -78oC for 5 minutes, warmed to room temperature, poured into dilute hydrochloric acid and was filtered by a simple ether. The aqueous layer was podslushivaet NH4OH and extracted with methylene chloride. The extract was dried (sodium sulfate) and concentrated, giving 1.1 g of the unpurified crude product. The crude product was dissolved in methylene chloride (50 ml) was added molecular sieves and pyridineboronic (1.4 g, 6.4 mmol). The reaction is I, and the mixture was concentrated, giving sludge. The slurry was dissolved in methylene chloride (50 ml), was added a sufficient number of ordinary ether, giving a cloudy solution. This substance was added on a column of silica gel and loirevalley simple ether.

Silikagelya column was lirowaus 10% methanol in methylene chloride, and the eluent was concentrated, giving an oily residue. This substance was pulverized with methanol and filtered through celite. The filtrate was combined with the ether solution obtained above, and concentrated. The substance was dissolved in methylene chloride. Added a simple ether until then, until the solution became turbid, and then the solution was filtered through Florisil. The filtrate was concentrated, giving 560 ml of oil, which was purified instant chromatography on silica gel using mixtures of hexane/simple ether (3:1) containing traces of NH4OH, as a solvent. The appropriate fractions were combined and concentrated, yielding 350 mg of the desired compound. Formed oxalate salt crystallizability from a mixture of ethyl acetate/hexane, yielding 370 mg of a white solid. So pl. is to 98.5-100oC.

Elemental analysis:

calculated C 69,58, H 8,64, N 3,35;

found C 69,28, H 8,86, N 3,00.

Example traditonally (1.0 g, 3.2 mmol) was dissolved in 10 ml of THF and cooled to -78oC, after which was added 3.5 ml of n-utility (1.0 M in hexane). The mixture was mixed for one hour at -78oC, and then added with 680 mg (1.5 equivalents) of 4-chlorobenzaldehyde in THF. The mixture was mixed for 15 minutes at -78oC, and then were left to warmed to room temperature. The mixture was poured into 10% aqueous hydrochloric acid solution, rinsed with ether, the pH was brought to 10 with ammonium hydroxide, and the solution was extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated, yielding 1.5 g of residue.

The residue was placed on silicagel column and elyuirovaniya with a mixture of hexane and ethyl acetate(1: 1) containing a trace of ammonium hydroxide. The appropriate fractions were combined, giving 1.3 g of essentially pure 2-di-p-propylamino-8-(alpha-methyl-4'-Chlorobenzyl)-1,2,3,4-tetrahydronaphthalene.

The above product (3.2 mmol) was dissolved in 50 ml of methylene chloride, was added 30 g of 4 a molecular sieves followed by the addition of 1.4 g (6.4 mmol) of PCC. The mixture was mixed for one hour and then was diluted simple ether and poured through a layer of silica gel, and silica gel was propulsively ether the t was evaporated, and the residue was dissolved in methanol and filtered twice. This filtrate was combined with the ether filtrate, and the resulting mixture was placed on silicagel column and swerves with a mixture of hexane and ether (2:1), containing a trace of ammonium hydroxide. The appropriate fractions were combined, giving 0.3 g of the target compound.

MS (FD) m/e 369.

Example 22. Obtaining p-toluensulfonate salt 2-di-n-propylamino-8-(o-perbenzoic)-1,2,3,4-tetrahydronaphthalene

2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g, up 3.22 mmol) was dissolved in THF (25 ml) and cooled to -78oC and was added to 2.5 ml of n-utility (1.27 M in hexane). One hour later, was added o-perbenzoate (0,38 g, up 3.22 mmol). The mixture was mixed for 10 minutes at -78oC, after which the reaction was slaked by adding water at -78oC. the Reaction mixture was poured into dilute HCl solution and was extracted with methylene chloride. The aqueous layer was podslushivaet sodium hydroxide and was extracted with methylene chloride. The basic extract was dried (sodium sulfate) and concentrated, giving 200 mg of residue, which according to NMR data did not contain product. Extract from the acidic material was dried (sodium sulfate) and concentrated, giving 2.0 g Osan (1:1), containing a trace of ammonium hydroxide as solvent, gave the free base of the target compound (340 mg). Sol 130 mg of the substance with p-toluensulfonate were prepared and crystallized from a mixture of ethyl acetate/ether, yielding 118 mg of the target compound. So pl. 107-109oC.

Elemental analysis:

calculated C 68,55, H 6,90, N 2,66;

found: C 68,41, H 7,02, N 2,65.

Example 23. Getting 2 di cyclopropanemethylamine-8-acetyl-1,2,3,4-tetrahydronaphthalene

A. 2 Di cyclopropanemethylamine-8-bromo-1,2,3,4-tetrahydronaphthalen

A solution of 8-bromo-2-tetralone (9.0 g, 40 mmol), Dicyclopentadiene (10 g, 80 mmol) and toluensulfonate acid (0.1 EQ. 4 mmol, 760 mg) in toluene (200 ml) was heated to the temperature of reflux distilled for 5 hours while water was collected in the trap Dean-stark. The reaction solution is then concentrated in vacuo and the resulting residue was taken in tetrahydrofuran (200 ml), and added cyanoborohydride sodium NaCNBH3(50 mmol, 3 g). Added gaseous HCl until then, while the reaction solution is not saturated. The solution is then stirred at room temperature overnight, poured into ice-cold water and podslushivaet solution of sodium hydroxide. The floor is the very vacuum, giving a brown oil. This oil was dissolved in tetrahydrofuran (200 ml), was added triethylamine (25 ml). The resulting solution was heated to reflux distilled and filtered through a layer of the primary oxide ammonium. The alumina was propulsives with methylene chloride. The combined filtrates were concentrated, giving 11.8 g of the crude compound in the form of oil. Purification of this crude substances by means of flash chromatography (ether/hexane (2:1), ammonium hydroxide) to give 8.6 g of the desired product as a yellow oil.

1NMR (CDCl3): 7,4 (d, 1 H), 7,03 (d, 1 H), 6,98 (t, 1 H), 3,42 be 3.29 (m, 1 H), 3,16-3,00 (m, 1 H), 3.00 and-2,78 (m, 2 H), 2,78 is 2.44 (m, 5 H), 2,15-of 1.97 (m, 1 H), 1,67-of 1.45 (m, 1 H), 10,4-0.87 (m, 2 H), 0,64-of 0.48 (m, 4 H), 0,28-0,10 (m, 4 H).

MC (FD) m /e 333 (100, M+), 355 (97, M+).

Elemental analysis for C18H24Br:

calculated C 64,67, H 7,24, N 4,19;

found C 64,47, H 7,32, N 4,28.

b. 2 Dicyclopentadiene-8-(1-hydroxyethyl)-1,2,3,4 - tetrahydronaphthalen

A solution of n-utility in hexane (1.37 M, 5,65 ml, 7.7 mmol) was added to a solution of 2.0 g (6,45 mmol) of the compound obtained in stage a, in tetrahydrofuran at -78oC. the Resulting solution is then stirred at -78oC for 20 minutes, and was added acetaldehyde (12 mmol, 530 mg). After what was mostly due to the water, and then was extracted with methylene chloride. The extract was dried (sodium sulfate) and concentrated in vacuo, giving 2.3 g of orange oil. Purification of this oil by flash chromatography (ether/hexane (2:1), ammonium hydroxide) gave 1,53 g of the target product.

1H NMR (CDCl3): d 7,40 (t, 1 H), 7,20 (m, 1 H),? 7.04 baby mortality (d, 1 H), 5,24-5,10 (m, 1 H), 3,55-3,30 (m, 1 H), 3,20-to 2.40 (m, 7 H), 2,18-2,03 (m, 1 H), 1,80-of 1.40 (m, 5 H), 1,30 (Shir.s, 1 H), 1.18 to to 0.80 (m, 2 H), 0,65-of 0.48 (m, 4 H), 0,27-0,10 (m, 4 H).

C. 2-Dicyclopentadiene-8-acetyl-1,2,3,4-tetrahydronaphthalen

The Jones reagent (1.9 ml) was added to a solution of 1.5 g (4,36 mmol) of the compound obtained in stage "b", in a mixture of acetone (50 ml) and 2 M sulfuric acid (16 ml) at a speed slow enough to maintain the temperature of the reaction solution below 30oC. the Resulting solution stirred at room temperature for 20 minutes, and then slowly extinguished by the addition of isopropanol (0.5 ml). The precipitate was filtered, and the filtrate was added to water. The aqueous solution was extracted mixed solution of isopropanol/chloroform (1: 3), podslushivaet solution of sodium hydroxide, and then extracted with methylene chloride. The combined organic layers were filtered through celite, rinsed E via flash chromatography (5% methanol in methylene chloride,ammonium hydroxide), giving 1.2 g of a yellow oil. Additional purification using flash chromatography (ether/hexane (4:1), ammonium hydroxide) gave 1.0 g of the target product.

1H NMR (CDCl3): d of 7.48 (d, 1 H), 7.24 to 7,16 (m, 2 H), 3,35-3,18 (m, 1 H), 3,16-3,03 (m, 1 H), 3,03-2,84 (m, 3 H), 2,64 is 2.46 (m, 3 H), 2.57 m (s, 3 H), 2,16-of 1.95 (m, 1 H), 1,75-of 1.55 (m, 2 H), 1,02-0,88 (m, 2 H), 0,57 of 0.47 (m, 4 H), is 0.22 to 0.08 (m, 4 H).

Example 24. Obtaining hydrochloride dimethyl-8-(o-methoxybenzoyl)-1,2,3,4-tetrahydronaphthalene

a. 2-Dimethyl-8-(-hydroxy-2-methoxybenzyl)-1,2,3,4 - tetrahydronaphthalen

A solution of n-utility in hexane (1.42 M, 14,54 ml, 20,65 mmol) was added to a solution of 3.5 g (13,77 mmol) 2-dimethyl-8-bromo-1,2,3,4-tetrahydronaphthalene in tetrahydrofuran (300 ml) at -78oC. the Resulting solution is then stirred at -78oC for 10 minutes, and added on-anisaldehyde (27,54 mmol, 3.75 g). After stirring at -78oC for 60 minutes the reaction solution was warmed up to room temperature, poured into water and then extracted with a mixture of chloroform/isopropanol (3:1). The extract was dried (sodium sulfate) and concentrated in vacuo, giving 7,83 g of yellowish white solids. Purification of this solid by using flash chromatography (10% methanol in methylene chloride (ammonium hydroxide)) gave 2 is draftologist

The Jones reagent (3.0 ml) was added to a solution of 2.54 g of the compound obtained above in a mixture of acetone (100 ml) and 2 M sulfuric acid (24,48 ml) at a speed slow enough to maintain the temperature of the reaction solution below 30oC. the Resulting solution was mixed at room temperature until until thin layer chromatography indicated that the reaction was completed, and then it was extinguished by the addition of isopropanol (2 ml). The resulting solution was poured into water, and then podslushivaet solution of sodium hydroxide. The basic solution was extracted with a mixture of isopropanol/chloroform (1:3) solution, dried over sodium sulfate, and then concentrated in vacuo, giving 2,599 g target untreated connection. This crude product was purified using flash chromatography (5% methanol in methylene chloride, sodium hydroxide), giving 1,781 g target oil. This oil was dissolved in methanol, and then with stirring was added 5.8 ml of 1 n hydrochloric acid. The resulting solution is then concentrated in vacuo, giving a white foam. This foam was re-dissolved in hexane. After the foam was completely dissolved, was added ethyl acetate slowly, causing deposition (after obbl. 170-172oC.

Analysis calculated for C20H23NO2HCl:

calculated: C 69,45, H 6,99, N 4,05;

found: C 69,20, H 7,08, N 4,07.

Example 25. 2-Di-n-propylamino-8-(1-methylpyrazole-3-yl)-1,2,3,4 - tetrahydronaphthalen, Malatya salt and 2-di-n-propylamino-8-(1-methylpyrazole-5-yl)-1,2,3,4 - tetrahydronaphthalen, pagedata salt

A solution of n-utility (1.6 M in hexane to 15.1 ml, and 24.2 mmol) was added to a solution of 8-bromo-2-di-n-propylamino-1, 2,3,4-tetrahydronaphthalene (5.0 g, 16,1 mmol) in THF (50 ml) at -48oC, and the reaction mixture was Persepolis at -78oC for one hour. After the reaction mixture was barotraumas gaseous carbon dioxide at -78oC as long, until he disappeared a dark purple color, which is formed. Added motility (1.4 M in ether, 23 ml). The reaction mixture was stirred at -78oC for 30 minutes and heated to room temperature. The reaction mixture was mixed for an additional ten minutes at room temperature, during this time, the pink color was lost. Added an additional 10 ml metallice, and the reaction mixture again became pink. 15 minutes later the pink color was lost, and added an additional 10 ml metallice who was otshelushivatsya and was extracted with methylene chloride. The basic extracts were dried (sodium sulfate) and concentrated, giving 3.8 g of the crude product. Cleaning with silicagel flash chromatography using a mixture of hexane/ether (2:1), containing a trace of ammonium hydroxide, gave 2-di-n-propylamino-8-acetyl-1,2,3,4-tetrahydronaphthalen in the form of a yellow oil (2.7 g, 61%).

2-Di-n-propylamino-8-acetyl-1,2,3,4-tetrahydronaphthalen (3.0 g, 11.0 mmol) was dissolved in 125 ml of toluene, after which was added 4.6 ml (27.5 mmol) of Tris(dimethylamino)methane. The mixture was heated up to 80oC overnight, after which it was evaporated, and the residue was dissolved in 100 ml of methanol. Added methylhydrazine (2,9 ml, 54,9 mmol). The mixture was heated under reflux for six hours, and then stirred at room temperature over night. The mixture was then poured into water and the aqueous mixture was extracted with methylene chloride. Methylenchloride the extract was dried over sodium sulfate and evaporated, giving 3.7 g of residue, which contained both target compounds.

The residue was placed on silicagel column and elyuirovaniya a mixture of 2% methanol in methylene chloride containing a trace of ammonium hydroxide. The appropriate fractions were combined, giving 2.1 g of the basics is telecharge, containing a trace of ammonium hydroxide). This substance is turned into maleato salt, and the salt was precrystallization from a mixture of ethanol and ether, giving 2.3 g of white crystals. So pl. 139,5-to 140.5oC. MC(FD) 311 (100).

Analysis:

calculated: C 67,42, H 7,78, N 9,83;

found: C 67,62, H 7,81, N 9,80.

The appropriate fractions were combined, giving 165 mg of the minor isomer.

2-DIN-n-propylamino-8-(1-methylpyrazol-5-yl)-1,2,3,4 - tetrahydronaphthalen (Rf0.27 in 2% methanol in methylene chloride containing a trace of ammonium hydroxide). Formed pagedata salt of the substance and precrystallization from a mixture of methanol and ethyl acetate, yielding 30 mg of a solid product. So pl. 203-204oC. MC(FD) 311 (100).

Analysis:

calculated: C 50,76, H 6,60, N 8,88;

found: C 50,09, H is 6.61, N 8,65.

Example 26. Getting 2-di-n-propylamino-8-(5-methoxypyrazine-3-yl)-1,2,3,4-tetrahydronaphthalene

A solution of 20 mmol of diazomethane was obtained by adding 4,29 (29 mmol) of 1-methyl-3-nitro-1-nitrosoguanidine to 25% of the resultant solution of KOH (10 ml) and Et2O in an ice bath. The ether phase was decentralise in a solution of 25 ml of methanol containing 400 mg (1.28 mmol) of 2-di-n-propylamino-8-(5-hydroxypyrazol-3-yl)-1,2,3,4-thereafter.in. The target connection is matography on column elution with a mixture of methylene chloride in methanol (9:1).

Example 27. Getting chlorhydrate salt 2-di-p-propylamino-8-(thiazol-2-yl)-1,2,3,4-tetrahydronaphthalene

The thiazole (0,46, 6.5 mmol) was dissolved in 10 ml of tetrahydrofuran, and the mixture was cooled to -78oC, after which was added n-utility (6.5 mmol, 1.0 M in hexane). The mixture was warmed to -20oC and then cooled again to -78oC. the resulting mixture was slowly added to deleverage a mixture of 1.0 g (3.2 mmol) of 2-di-p-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene and 370 mg (0.3 mmol) of Pd (Ph3P)4in 50 ml of toluene. To the mixture was added an additional 10 ml of tetrahydrofuran to achieve the full transition of the substances in the reaction mixture. If the response was noticeable, very slightly. It was felt that the anion of the thiazole or not formed or decomposed. Two equivalent thiazole was treated with N-butyllithium in 20 ml of THF at -78oC for 30 minutes. The resulting mixture is light yellow suspension was added to deleverage the reaction mixture, and the mixture was heated under reflux for 45 minutes and stirred over night at room temperature. The reaction mixture was now black, resulted in a 10% Viy and was extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated, giving 1.6 g of dark brown oil.

The oil was placed on silicagel column and loirevalley gradient mixture of 3:1 to 1:1 hexane and ether containing a trace of ammonium hydroxide. Fractions 12 to 16 were combined, giving 120 mg of brown oil.

The oil was turned into bromperidol salt, and the salt was precrystallization from a mixture of methanol and ethyl acetate, yielding 45 mg of target compound in the form of reddish-brown crystals.

Analysis:

calculated: C 47,91, H 5,93, N 5,88;

found: C 47,62, H 6,10, N 6,15.

Example 28. Getting 2-di-n-propylamino-8-(thiazol-4-yl)-1,2,3,4 - tetrahydronaphthalen, p-toluensulfonate salt

To 5 ml of 85% phosphoric acid was added 0.87 g (2.6 mmol) of 2-di-p-propylamino-8-(2-aminothiazol-4-yl)-1,2,3,4-tetrahydronaphthalene (very slightly dissolved). The solvent is then changed by adding 20 ml of 35% sulfuric acid. The mixture was cooled to 0oC, and with a syringe below the surface of the reaction mixture was added concentrated aqueous solution of 460 mg (6.6 mmol) of sodium nitrite. The mixture was slowly added to 20 ml of 50% hypophosphorous acid at 0oC, and the reaction mixture then was warmed up to room demonia. The mixture was extracted with methylene chloride, and the extract was dried over sodium sulfate and evaporated, giving 0.7 g of residue.

The residue was placed on silicagel column and elyuirovaniya with a mixture of hexane and ether (2:1), containing a trace of ammonium hydroxide. The appropriate fractions were combined, yielding 350 mg of oil. This substance is turned into p-toluensulfonate salt and precrystallization from a mixture of ethyl acetate and hexane, yielding 220 mg reddish-brown solid. So pl. - 143-144oC. (FD) 315 (100).

Analysis (1/3 H2O):

calculated: C 63,38, H 7,09, N 5,69;

found: C 63,29, H 7,01, N 5,67.

Example 29. Getting 2-di-n-propylamino-8-(China-2-yl)-1,2,3,4 - tetrahydronaphthalene

2-Di-n-propylamino-8-bromo-1, 2, 3, 4 tetrahydronaphthalen (1 g, up 3.22 mmol) was added to deleverage a mixture of magnesium turnings (120 mg, 4.9 mmol) in 50 ml of THF. The formation of the Grignard reagent was initiated by adding 0.2 ml of 1,2-dibromethane (0.002 mmol). After 1.5 hours was added 220 mg (0.33 mmol) of Ni(PPh3)2Cl2in 10 ml of THF followed by the addition of 800 mg (4,89 mmol) of 2-chlorhydrin. The solution was continued to be heated under reflux for 15 minutes, after which it was cooled, poured into water and was extracted three times the e substance was purified using two columns for flash chromatography. The first was lirowaus a mixture of hexane/simple ether (1:1) and the second a mixture of methylene chloride/methanol (20:1). The quality of the product was about 130 mg of the target compound. After crystallization in ethanol and water was allocated 66 mg of a solid product. So pl. 82oC.

Analysis (1/3 H2O):

calculated: C 82,37, H 8,48, N 7,68;

found: C 82,33, H 8,44, N 7,73.

Example 30. Getting 2-di-n-propylamino-8-(China-3-yl)-1,2,3,4 - tetrahydronaphthalene, bromhidrosis salt

To deleverage mixture of 520 mg (21 mmol) of magnesium in 50 ml of THF was added 5 g (16,13 mmol) of 2-di-n-propylamino-8 - bromo-1,2,3,4-tetrahydronaphthalene. The Grignard reagent was formed after 2 hours after heating under reflux, and then a syringe was added to 1.05 g (1.6 mmol) of Ni(PPh3)2Cl2in 25 ml of THF. After 5 minutes was added 3-bromination (3 ml, 21 mmol) in 25 ml THF. The reaction mixture continued to be heated under reflux for one hour.

After cooling, the solution was poured into aqueous sodium bicarbonate solution and was extracted three times with methylene chloride. After drying with sodium sulfate and concentration was obtained 7.2 g of black oil. This substance was purified using flash chromatography on a column with elution of smali from methanol and ether were allocated 423 mg So pl. 200oC.

Analysis for 2 HBr salt:

calculated: C 57,71, H 6,23, N 5,38;

found: C 57,75, H 6,27, N 5,34.

Example 31. Getting 2-di-n-propylamino-8-(peril-3-yl)-1,2,3,4 - tetrahydronaphthalene, oxalate salt

2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalen (5 g, 16,12 mmol) in 50 ml THF was slowly added to deleverage a mixture of 500 mg (20 mmol) of magnesium in 50 ml of THF. Initiating formation of the Grignard reagent was provided by adding drops of 1,2-dibromoethane. The reflux was continued for 2 hours before addition of 1.05 g (1.6 mmol) of Ni(PPh3)2Cl2in 25 ml of THF and 3 ml (31,7 mmol) 3-bromopyridine in 25 ml of THF. After heating under reflux for an additional 15 minutes, the mixture was cooled, poured into sodium bicarbonate and was extracted with methylene chloride. The extracts were dried with magnesium sulfate and concentrated, yielding 10.2 g of black oil.

The crude product was purified using flash chromatography on a column using a mixture of ether/hexane (1:1) as solvent, giving of 1.05 g of the free base of the target compound.

Formed salt of oxalic acid and crystallized from a mixture of acetone/ether, yielding 173 mg of the product. So PR 32. Getting 2-di-n-propylamino-8-(peril-2-yl)-1,2,3,4 - tetrahydronaphthalene, oxalate salt

2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalen (5 g, 16,72 mmol) in 50 ml THF was slowly added to deleverage a mixture of 500 mg (20 mmol) of magnesium turnings in 50 ml THF. Initiating formation of the Grignard reagent was made by adding drops of 1,2-dibromoethane. The reflux was continued for 2 hours before addition of 1.05 g (1.6 mmol) of Ni(PPh3)2Cl2THF and 3 ml (at 31.7 mmol) of 2-bromopyridine in 25 ml of THF. The reaction mixture was heated under reflux for an additional 15 minutes before it was poured upon cooling in water, and was extracted with methylene chloride. The extracts were dried with sodium sulfate and concentrated, giving a 10.5 g of black oil.

Purification was performed using flash chromatography on a column with elution by the mixture hexane/ether (1: 1), giving 1.5 g of the free base of the target compound. Formed salt of oxalic acid and crystallized from a mixture of acetone/ether, giving 215 mg of brown powder. So pl. 135oC.

Analysis:

calculated C 69,32, H to 7.59, N 7,03;

found: C 69,12, H of 7.64, N 6,88.

Example 33. Getting 2-di-n-propylamino- (5 g, 16,12 mmol) in 50 ml THF was slowly added to deleverage a mixture of 500 mg (20 mmol) of magnesium turnings in 50 ml of THF. Initiating formation of the Grignard reagent was caused by a drop of 1,2-dibromoethane. The reflux was continued for 2 hours before adding 105 g (1.6 mmol) of Ni(PPh3)2Cl2in 25 ml of THF and 3 ml (% 31.2 mmol) of 4-chloropyridine in 25 ml of THF. The reaction mixture was heated under reflux for an additional 1.5 hours before cooling, pouring into water and extracting with methylene chloride. The extracts were dried with magnesium sulfate and concentrated, yielding 9.7 g of black oil.

Purification was performed using flash chromatography on a column with elution by the mixture hexane/ether (1:1). The free base of the desired product (850 g) was allocated. Could salt of oxalic acid and crystallized in a mixture of methanol/ether. So pl. 191oC.

Analysis:

calculated: C 69,32, H to 7.59, N 7,03;

found: C 69,47, H of 7.55, N 6,99.

Example 34. Getting 2-di-n-propylamino-8-(indexation-3-yl)-1,2,3,4 - tetrahydronaphthalene, chlorhydrate salt

2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g, up 3.22 mmol) dissolved in THF (25 ml), cooled to -78oC, and added 2 sevalas for 10 minutes at -78oC, after which the reaction mixture was slaked by adding water at -78oC. the Reaction mixture was podslushivaet sodium hydroxide and was extracted three times with methylene chloride. The basic extract was dried (sodium sulfate) and concentrated, giving 2.0 g of crude residue. Purification of this material with the help of a flash chromatography on silica gel using a mixture of ether and hexane (1: 1) containing a trace of ammonium hydroxide, the solvent gave 2-di-n-propylamino-8-(2-perbenzoic)-1,2,3,4-tetrahydronaphthalen (340 ml).

To 47,5 mg acetone-oxime (of 0.65 mmol) in 25 ml THF was added 73 mg (0.66 mmol) of potassium tert-butylate. The mixture is stirred at room temperature for one hour, after which the syringe was added 210 mg of 2-di-n-propylamino-8-(2'-perbenzoic)-1,2,3,4-tetrahydronaphthalene in THF. The resulting mixture was heated under reflux for 3 hours, after which it was cooled and poured into an aqueous solution of ammonium chloride. The mixture then was extracted with ether, and the extract was dried and concentrated, giving 343 mg of 2-di-n-propylamino-8-[2-[(isopropylamino)oxy]benzene]- 1,2,3,4-tetrahydronaphthalene.

The previous connection was mixed while heating with skim milk is alas at room temperature over night. The mixture was then poured into water, podslushivaet sodium bicarbonate and was extracted with methylene chloride. The extract was dried over magnesium sulfate and concentrated, yielding 219 mg of impure product.

The residue was purified using flash chromatography on a column using a mixture of methylene chloride and methanol (10:1) as eluent, giving 121 mg of the free base of the target compound.

The free base was turned into chlorhydrate salt, which was precrystallization from a mixture of ethyl acetate and ether, yielding 65 mg solids. So pl. 186oC.

Example 35. Getting 2-di-n-propylamino-8-(pyrazole-8-yl)-1,2,3,4 - tetrahydronaphthalene, oxalate salt

2-Di-n-propylamino-8-(1-oxo-3-dimethylamino)-propenyl)-1,2,3,4-tetrahydronaphthalen, obtained as described in example 8, (0.75 g, to 2.29 mmol) was dissolved in 10 ml of methanol. To the mixture was added 0.16 ml of hydrazine, and the mixture is stirred at room temperature under nitrogen atmosphere for 18 hours, after which volatiles were removed in vacuo, giving a dark orange residue. The residue was dissolved in ether and was placed on a flash column of silica. The column was lirowaus ether containing a trace of ammonium hydroxide.

Freetramadol in oxalate salt, which is crystallized from a mixture of ethanol and ether, yielding 0.26 g of the target compound as colorless crystals. So pl.-143-150oC.

Analysis:

calculated: C 65,10, H rate of 7.54, N 10,84;

found: C 65,33, H 7,44, N 10,83.

Example 36. Getting 8-(indol-3-yl)-2-dipropylamino-tetralysal

A. 1-Phenylsulfonyl

Sodium hydroxide (50 g, 1.25 mmol), acid tetrabutylammonium sulfate (3.5 g, or 10.3 mmol) and indole (46,75 g, 0.4 mmol) was dissolved in 500 ml of chilled (0oC) methylene chloride. Then was added slowly a solution of phenylsulfonylacetate (63,8 ml, 0.5 mmol), dissolved in 300 ml of methylene chloride. The resulting solution was left to warmed to room temperature and then stirred for 4 hours. After 4 hours sediments that formed during the reaction was removed by filtration and the resulting filtrate was concentrated in vacuo, giving an orange oil. This oil was dissolved in hot methanol, and the resulting solution was left to cool to room temperature over night. The next morning orange solids that have precipitated from the methanol solution was removed by filtration. Data solid was again dissolved in hot precipitated white solid. These substances were separated by filtration, yielding 50 g of the desired product as white crystals.

B. 1-Phenylsulfonyl-C-bromoindole

Part of the compound obtained above (14,77 g, to 57.1 mmol) was dissolved in 150 ml of methylene chloride. Then was added to the indole solution for 15 minutes, bromine (8,2 g, 51,38 mmol), dissolved in 50 ml of methylene chloride. The resulting solution was mixed for 4 hours after treatment was 17.3 g of white powder. This white powder was analyzed as the target connection. So pl. 120oC.

C. 8-(1-Phenylsulfonyl-3-yl)-2-dipropylenetriamine

The Grignard reaction was started by adding a solution of 8-bromo-2-dipropylenetriamine (5.0 g, 16,13 mmol) in 50 ml of tetrahydrofuran to a solution of deleverage tetrahydrofuran (50 ml) containing magnesium. After 2 hours stirring the resulting solution at reflux for delegateuser solution was added a solution of NiCl2(PPh3)2tetrahydrofuran (THF) followed by a solution of 10.8 g (32,26 mmol) of the compound obtained in stage B in 15 ml of tetrahydrofuran. The resulting solution is then stirred at reflux for dopolnitelbnogo solution in water, and the resulting aqueous solution was extracted with methylene chloride. The organic extract was washed with saturated saline solution, dried over sodium sulfate, and then concentrated to dryness in vacuo, giving 13 g of solid material, which according to the analysis represented the crude target compound. This crude material was purified via chromatography using 3% methanol in methylene chloride as eluent, yielding 1.35 g of the target compound as a brown oil.

D. 8-(Indol-3-yl)-2-dipropylenetriamine

The oil obtained in stage C was dissolved in 100 ml of methanol and 40 ml of 1 n sodium hydroxide solution. The resulting solution was then heated to reflux distilled and mixed under conditions of reflux distilled for 6 hours. After 6 hours the reaction solution was cooled to room temperature and poured into water. The resulting aqueous solution was extracted with methylene chloride. The organic extract was dried over sodium sulfate, and then concentrated to dryness in vacuo, giving 1.2 g of a yellow oil, which was analyzed as the crude target compound. This crude substance was purified using flash chromatography with ispolzovaniya pure form of the free base of the desired product.

Oxalate salt of the free base of the target compound was obtained by dissolving the oil obtained above in oxalic acid. The solids that precipitated were separated by filtration, then purified through recrystallization from methanol/titilating solution, giving 174 mg of the target compound. So pl. 144oC.

Analysis for C24H30N2C2H2O4:

calculated: 71,54, H 7,39, N 6.42 PER;

found: 71,79, H 7,43, N 6,736.

Example 37. Getting dichlorhydrate 8-(indol-2-yl)-2-dipropylenetriamine

A. 8-(1-Phenylsulfonyl-2-yl)-2-dipropylenetriamine

A solution of 1-phenylsulfonyl-2-bromoindole (1.7 g, of 6.45 mmol) obtained by the method basically similar to that described in example 36, A and B, in 30 ml of tetrahydrofuran was cooled to -78oC. After cooling, was added to 5.7 mg of 1.13 M solution of n-utility (6,45 mmol). The resulting solution is then heated to -20oC after stirring at -78oC for 15 minutes. After stirring the reaction solution at -20oC for 30 minutes was added a cold solution of indole to deleverage a mixture of 8-bromo-2 - dipropylenetriamine (2.0 g, of 6.45 mmol) and 7,44 mg (to 0.645 mmol) of Pd(PPh3)4 is of the hours, and then was left to cool to room temperature. Stirring of the reaction mixture is continued at room temperature over night. The next morning the reaction mixture was cooled by pouring the reaction solution into water. The resulting aqueous solution was extracted with methylene chloride. The organic extract was washed with saturated saline solution, dried over sodium sulfate, and then concentrated in vacuo, giving b mg brown oil, which according to the analysis presented crude target compound. This oil was purified using flash chromatography on a column using 3% methanol in methylene chloride as eluent, yielding 230 mg of the substance, which according to the analysis was essentially pure target compound.

B. 8-(Indol-2-yl)-2-dipropylenetriamine-dichlorhydrate the Compound obtained in stage A is dissolved in a solution of 20 ml of 10% potassium hydroxide in methanol. The resulting solution was heated to the temperature of reflux distilled, and then stirred at this temperature over night. The next morning the reaction mixture was extinguished by pouring the reaction solution into water. The resulting aqueous solution of extragonadal what Ulfat sodium, and then was concentrated in vacuo, giving crude target compound. This crude substance was purified using flash chromatography on a column (3% methanol and methylene chloride as eluent) to give 126 mg of purified target compound (free base) as a yellow oil.

Dichlorhydrate salt of the free base of the target compound was obtained by dissolving the oil obtained above, in hydrochloric acid. The solids that precipitated were separated by filtration, and then purified through recrystallization from a mixed ethyl acetate/hexane solution, followed by recrystallization from ethyl acetate/hexane solution containing a small amount of methanol, yielding 23 mg of the target compound. So pl. more than 160oC.

Analysis for C24H30N2HCl:

calculated: C 75,27, H 8,16, N 7,31;

found: C 74,98, H 8,10, N 7,29.

Example 38. The hydrochloride of (-)-5-fluoro-8-(trifloromethyl)oxide-2-(dipropylamino)tetralin

To a solution of (-)-6-F-8-OH-2-(dipropylamino)tetralin (500 mg, 1.88 mmol) and 2,4,6-trimethylpyridine (912 mg, 7.5 mmol) in dichloromethane (10 ml) was added to the anhydride of triftoratsetata (849 mg, 3 mmol) in diha bath was then removed, and was added diethyl ether. The ether solution was washed with saturated potassium carbonate solution and then with water, was dried (potassium carbonate) and was evaporated. Chromatography of the residue on alumina using E/PE (1:20) as eluent gave the target compound. The purified base was transformed into the hydrochloride (580 mg, 71% yield). So pl.-145-146oC.

Example 39. The hydrochloride of (-)-5-fluoro-8-(2-furyl)-2-(dipropylamino)tetralin

Method 1

To a mixture of the hydrochloride of (-)-5-fluoro-8-(triftormetilfullerenov)oxide-2-(dipropylamino)tetralin (400 mg, 1 mmol), (Ph3P)4Pd (23.1 mg, 0.02 mmol), lithium chloride (127 mg, 3 mmol) in DMF (10 ml) was added tributyl (2-furyl) stannane (428,5 mg, 1.2 mmol) in DMF (6 ml). The flask was filled with nitrogen and germetizirovany. The flask was immersed in an oil bath at 120oC. the Reaction was terminated when the mixture became black after about 5 minutes. The catalyst was filtered off through celite, the solvent was evaporated and the crude residue was dissolved in ether, the ethereal solution was washed with a saturated solution of potassium carbonate, dried (potassium carbonate) and was evaporated. Chromatography of the residue on alumina using E/PE (1:20) as eluent gave the target compound in the form of net is. the HP 159-160oC. (MeOH/ether).

Method 2

A mixture of (-)-5-fluoro-8-(triftormetilfullerenov)oxide-2-(dipropylamino)tetralin, hydrochloride (100 mg, 0.25 mmol) (Ph3P)4Pd (7,28 mg, 6,310-3mmol), lithium chloride (21,36 mg, 0,504 mmol), 2 M sodium carbonate solution (0,38 ml) in DMA (3 ml) and EtOHabc(0.75 ml) and 2-Farnborough acid (36.2 mg, 0.38 mmol) was heated under reflux for 3 hours. The solvent was evaporated, and the residue was dissolved in ether, the solution was washed with saturated potassium carbonate solution and brine, was dried (potassium carbonate) and was evaporated. Chromatography on aluminum oxide using E/PE (1:30) as eluent allowed to obtain the target compound in the form of pure reason, which turns into a hydrochloride (57 mg, 65% yield). So pl.-160-161oC (MeOH/ether).

Example 40. The hydrochloride of (-)-5-fluoro-8-(2-acetyl)-2-(dipropylamino)tetralin

A solution of triethylamine (20,37 mg, 2,013 mmol), Pd(OAc)2(5,65 mg of 0.025 mmol) and oppp (diphenylphosphino) (11,42 mg, or 0.027 mmol) in DMF (1.3 ml) was added to (-) 1 C 20 (200 mg, 0,503 mmol). To the resulting solution were added butylvinyl ether (504 mg, of 5.03 mmol). The reaction flask was filled with nitrogen, was germetizirovany and immersed in an oil bath, portals (absence of starting substances according to TLC). Then to the reaction mixture was added 5% HCl (2 ml) and the mixture was left to stand at room temperature for 15 minutes, then it was podslushivaet sodium bicarbonate, the aqueous solution was extracted with ether, the organic matter was washed with water to neutral pH, dried (potassium carbonate) and was evaporated. The crude residue was purified using flash chromatography on aluminium oxide using E/PE (1:8) as eluent. The target compound in the form of net Foundation, was transformed into the hydrochloride and precrystallization from a mixture of ethyl acetate/ether (140 mg, 85% yield). So pl. 106-107oC (AcOEt/ether).

Example 41. The hydrochloride of (-)-5-[fluoro-8-](2-thienyl)-2-(dipropylamino)tetralin

Triphenylphosphorane (13,78 mg, 0,0119 mmol) and lithium chloride (50,55 mg, 1,19 mmol) in DMF (1.5 ml) was added to the hydrochloride of (-)-5-fluoro-8-(triftormetilfullerenov)oxide, 2-(dipropylamino)tetralin (158 mg, 0,397 mmol), this mixture was added tributyl-(2-thienyl)stannane (222,5 mg, 0,596 mmol) in DMF (1.5 ml). The reaction flask was placed in a bath preheated to 120oC in nitrogen atmosphere. After 10 minutes the mixture became black, and according to TLC the original substance remained. The reaction mixture razbavlyalo and was evaporated. Instant (flash) chromatography using alumina and a mixture of ether/petroleum ether (1:20) as eluent gave the target compound in the form of pure reason, which was transformed into the hydrochloride and precrystallization from a mixture of MeOH/ether (106 mg, 73% yield). So pl.-157-159oC.

Example 42. Hydrochloride (+/-)-8-acetyl-2-N-cyclopropylacetylene

(+/-)-2-N-cyclopropylamino-8-[(trifloromethyl)oxide]tetralin (0.4 g, 1.3 mmol), lithium chloride (0.2 g, 4.7 mmol) and DMF (6 ml) were mixed in a three-neck round-bottom flask. The flask was akoumianakis putting carbon monoxide (procedure was repeated 5 times, the CO gas in the burette with water). Were added tetramethylsilane (0.3 ml, 2.2 mmol), dichloro [1,1-bis (diphenylphosphino)ferrocen] palladium (II) (PdCl2) dppf (40 mg, catalytic amount) and 2,6-di-tertbutyl-4-METHYLPHENOL (catalytic amount), and the reaction mixture was then stirred in an atmosphere of CO at 100oC for 3 hours before dilution with diethyl ether and filtered through celite. The filtrate was washed with sodium bicarbonate and dried (magnesium sulfate). The solvent was removed in vacuo, giving crude oil residue, which was purified using instant chromatography /dioxide to the camping in hydrochloride, then precrystallization from a mixture of ethanol/diethyl ether, yielding 60 mg (20%) of pure hydrochloride (1/-)-8-acetyl-2-N-cyclopropylacetylene. So pl.-196-198oC.

Example 43. Hydrochloride (+/-)-2-(N-isopropyl-N-n-propylamino-8-tert - BUTYLCARBAMATE

(+/-)-2-(N-isopropyl-N-n-propylamino)-8-(2,2'-dimethyl-1 - propanol)tetralin (0.6 g, 1.9 mmol) was dissolved in methylene chloride (dried with molecular sieves, 3) in nitrogen atmosphere. Added chlorproma pyridinium (0.6 g, 2.8 mmol) and the mixture is stirred for 3 hours at room temperature (20oC) before dilution with diethyl ether, washed with sodium bicarbonate and dried (magnesium sulfate). The solvent was removed in vacuo, and the crude residue was purified using instant chromatography /silicon dioxide, a mixture of methylene chloride/ethyl acetate (10:1) (+0.5% ammonia)/. Pure fractions were merged and concentrated. The resulting oil was transformed into the hydrochloride by precipitation from diethyl ether at 0oC, giving 320 mg (48%) of hydrochloride (+/-)-2-(N-isopropyl-N-n-propylamino)-8-tert-BUTYLCARBAMATE. So pl. - 197-199oC.

Example 44. Hydrochloride (+/-)-8-acetyl-2-(N-cyclopropyl-N-n-propylamino)tetralin

(+/-)-2-(N-cyclopropyl-N-n-prop is s), dichloro-[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) [PdCl2(dppf)] (0.2 g, catalytic amount), 2,6-decret-butyl-4-METHYLPHENOL (catalytic amount) and tetramethylsilane (0.8 g, 4.6 mmol) were mixed in an atmosphere of carbon monoxide for 7 hours at 110oC. the Solvent was removed in vacuo, and the residue was dissolved in a mixture of diethyl ether/ammonia. The layers were separated, and the product (ether phase is then subjected to an acid-base treatment and were dried (magnesium sulfate). The solvent was removed in vacuo, giving crude oily residue, which was purified instant chromatography (SiO2CH2Cl2/EtOAc, 4:1). Pure fractions were combined and concentrated. The resulting oil was transformed into the hydrochloride, which was then precrystallization from a mixture of EtOAc/diethyl ether, yielding 140 mg 12% hydrochloride (+/-)-8-acetyl-2-(N-cyclopropyl-N-n-propylamino)tetralin. So pl. - 126-128oC.

Example 45. Hydrochloride (+/-)-8-acetyl-2-(N-isopropyl-N-n-propylamino)tetralin

(+/-)-2-(N-isopropyl-N-n-propylamino)-8-[(trifloromethyl)oxide] tetralin of 0.85 g, 2.2 mmol), tetramethylsilane (of 0.48 g, 2.7 mmol), lithium chloride (0,38 g, 9.0 mmol), dichloro-[1,1'-(biphenylphosphine)ferrocene]palladium (II) [PdCl2(dpp 1% water) were mixed in an atmosphere of carbon monoxide (2 bar) for 6 hours at 110oC. the Solvent was removed in vacuo, and the residue was dissolved in diethyl ether, was filtered ammonia and dried (magnesium sulfate). The solvent was removed in vacuo, yielding oily residue which was purified instant chromatography (SiO2, EtOAc). Pure fractions were combined and concentrated. The hydrochloride was precipitated from diethyl ether (0oC) and precrystallization from a mixture EtAOc/diethyl ether, yielding 130 mg (19%) of hydrochloride (+/-)-8-acetyl-2-(N-isopropyl-N-n-propylamino)tetralin. So pl. 154-156oC.

Example 46. Hydrochloride (+/-)-8-cyclopentanecarbonyl-2-(N-isopropyl-N-n-propylamino)tetralin

(+/-)-8-(1-Cyclopentylmethyl)-2-(N-isopropyl-N-n-propylamino)tetralin (of 0.44 g, 1.3 mmol) was dissolved in methylene chloride (dried with molecular sieves, 3) in nitrogen atmosphere. Added pyridine-chloroformate (of 0.44 g, 2.0 mmol) and the resulting mixture stirred 3 hours at room temperature (20oC) before it was diluted in diethyl ether, was filtered sodium hydroxide (0.5 M) and dried (magnesium sulfate). The solvent was removed in vacuo, giving crude oil, which was purified instant chromatography /SiO2CH2Cl2/EtAOc (5:2)/, giving the base with 70% yield (ylcarbonyl-2-(N-isopropyl-N-n-propylamino) -tetralin, so pl. 140 142o.

Example 47

Hydrochloride (+/-)-8-acetyl-2-N-isopropylaminomethyl

(+/-)-2-N-isopropylamino-8-[(trifloromethyl)oxide] tetralin (1.0 g, 3.0 mmol), tetramethylsilane (0.6 g, 3.6 mmol), lithium chloride (0.5 g, to 11.8 mmol), dichloro-[1,1'-bis(diphenylphosphino)ferrocene] palladium (II) [PdCl2(dppf)] (150 mg), 2,6-decret-butyl-4-METHYLPHENOL (catalytic amount) in DMF (30 ml, containing 1% water) were mixed in an atmosphere of carbon monoxide (2 bar) at 110oC for 5 hours. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate, was washed with ammonia and dried (magnesium sulfate). The solvent was removed in vacuo, yielding oily residue which was purified instant chromatography [SiO2, EtOAc/EtOH (10:1) (+0.5% of NH3)] Pure fractions were combined and concentrated. The resulting oil was transformed into the hydrochloride (precipitated from diethyl ether) to give 100 mg of the hydrochloride of (+/-)-8-acetyl-2-N-isopropylaminomethyl. So pl. 241 to 243oC.

Example 48. Hydrochloride (S)-8-(2-furyl)-2-[N - [4-(8-azaspiro[4,5] decane-7,9-Dion-8-yl)butyl]Propylamine]tetralin

a) Hydrochloride (S)-8-methoxy-2-[N - [4-(8-azaspiro[4,5] decane-7,9-Dion-8-yl)butyl]propylamino]tetralin

A solution of (S)-8-methoxy-2-(impregnated mg, 4,11 mmol) in 20 ml of acetonitrile were mixed at 85oC in nitrogen atmosphere for 6 days. The reaction mixture was diluted simple with ether, and filtered to remove solid potassium carbonate. The filtrate was concentrated, and the residue was chromatographically on a column of aluminum oxide, elyuirovaniya a mixture of simple ether/light petroleum ether (2:1). Pure fractions were combined, concentrated and processed ethereal hydrochloric acid, giving 440 mg (67% yield) of the target compound (48, a).

Hydrochloride (R)-8-methoxy-2-[N-[4(8 azaspiro[4,5] decane-7,9-Dion-8-yl)butyl] propylamino] tetralin was obtained in accordance with the method described in example 48, a.

(b) Hydrochloride (S)-8-hydroxy-2-[N - [4(8 azaspiro[4,5] decane-7,9-Dion-8-yl)butyl]propylamino]tetralin

To a solution of tribromide boron (from 2.445 g, 9,76 mmol) in 15 ml of chloroform was added a solution of compound of example 48 a (538 mg, 1,22 mmol) in 10 ml of chloroform at room temperature in a nitrogen atmosphere for 10 minutes. The reaction was completed after stirring at room temperature for 1.5 hours and was terminated by adding saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with 3 portions of 30 ml of chloroform, and the organic layer sobi was chromatographically on silica gel, was elyuirovaniya a mixture of chloroform/methanol (30:1). Pure fractions were combined and processed ethereal hydrochloric acid, giving 550 mg (97% yield) of target compound 48, b.

Hydrochloride (R)-8-hydroxy-2-[N - [4(8 azaspiro[4,5] decane-7,9-Dion-8-yl)butyl]propylamino]tetralin was obtained in accordance with the method described in example 48, b.

c) Hydrochloride (S)-8-(trifloromethyl)hydroxy-2-[N - [4-(8-azaspiro[4,5] decane-7,9-Dion-8-yl)butyl]propylamino]tetralin

The solution triftormetilfullerenov anhydride (410 mg, of 1.46 mmol) in 20 ml of dichloromethane was added dropwise to a mixture of compound 48, b (413 mg, 0.97 mmol), collidine (176 mg, of 1.46 mmol) and potassium carbonate (199 mg, of 1.46 mmol) in 10 ml of dichloromethane at -78oC in nitrogen atmosphere for 10 minutes. The reaction was completed after stirring for 2 hours and was terminated by adding a saturated aqueous solution of potassium carbonate. The reaction mixture was distributed between CH2Cl2and the solution of K2CO3. The organic layer was dried (K2CO3), filtered and concentrated. The resulting residue was chromatographically on a column of aluminum oxide, elyuirovaniya a mixture of simple ether/light petroleum ether (1:1) and then a simple ether. Net fra) of target compound 48, c.

Hydrochloride (S)-8-(trifloromethyl)oxy-2-1[N[4(8 azaspiro[4, 5] decane-7,9-Dion-8-yl)butyl] propylamino]tetralin was obtained in accordance with the method of 48, c.

d) Hydrochloride (S)-8-(2-furyl)-2-[N - [4(8 azaspiro[4,5]decane-7,9-Dion-8-yl)butyl]propylamino]tetralin

In a round bottom flask filled with a mixture of compounds 48, c (100 ml, 0.18 mmol), aqueous lithium chloride (61 mg, 1.44 mmol), triphenylphosphine (19 mg, 0,072 mmol) and chloride bis-(triphenylphosphine)palladium in dimethylformamide, was added (2-furyl)tributylstannyl (129 mg, 0.36 mmol) and a crystal radical inhibitor (2,6-decret-butyl-4-METHYLPHENOL). The flask was filled with a stream of nitrogen, was germetizirovany and was heated at 120oC for 20 hours. DMF was removed in vacuo and the resulting residue was distributed between the simple ether and water. The ether layer was dried (K2CO3), filtered and concentrated. The residue was chromatographically on a column of alumina using a mixture of simple ether/light petroleum ether (2:1) as eluent. Pure fractions were combined and processed ethereal hydrochloric acid, yielding 70 mg (76% yield) of target compound 48, d. []022- 36,8oC

Hydrochloride (R)-8-(2-furyl)-2-[N - [4 (8-azamar 49. Hydrochloride CIS-1S,2R-methyl-8-acetyl-2-[N - [4(8 azaspiro[4,5]decane-7,9-Dion-8-yl)butyl]propylamino]tetralin

a) Hydrochloride CIS-1S,2R-1-methyl-8-methoxy-2-[N - [4(8 azaspiro[4,5]decane-7,9-Dion-8-yl)butyl]propylamino]tetralin

A solution of CIS-1S, 2R-1-methyl-8-methoxy-2-(propylamino)tetralin (300 mg, 1.28 mmol), 8-(4-bromobutyl)-8-azaspiro[4,5] decane-7,9-dione (427 mg, of 1.42 mmol) and potassium carbonate (263 mg, 1.92 mmol) in 10 ml of acetonitrile was heated under reflux at 85oC in nitrogen atmosphere for 5 days. The reaction mixture was diluted simple ether, filtered and concentrated. The residue was chromatographically on silica gel, elyuirovaniya a mixture of chloroform/methanol (15:1). Pure fractions were combined and processed ethereal hydrochloric acid, yielding 591 mg (9% yield) of target compound 49, a.

(b) Hydrochloride CIS-1S, 2R-1-methyl-8-hydroxy-2-[N - [4(8 azaspiro[4,5] decane-7,9-Dion-8-yl)butyl]propylamino]tetralin

To a solution of trichromate boron (1.63 g, of 6.52 mmol) in 15 ml of chloroform was added a solution of compound 49, a (370 mg, 0.81 mmol) in 10 ml of CHCl3. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 10 hours. The reaction was completed and was terminated by adding 10% aqueous solution of NaHCO3Was organisovalsa and concentrated. The residue was chromatographically on silica gel, elyuirovaniya a mixture of chloroform/methanol (15:1). Pure fractions were combined and processed ethereal hydrochloric acid, yielding 370 mg (95% yield) of target compound 49, b.

c) Hydrochloride CIS-1S, 2R-1-methyl-8-[trifloromethyl(oxy)] -2-[N - [4-(8-azaspiro[4,5]decane-7,9-Dion-8-yl)butyl]propylamino]tetralin

The solution trifluoro anhydride (178 mg, to 0.63 mmol) in 5 ml of dichloromethane was added to a mixture of the product of example 49, b (185 mg, 0.42 mmol), collidine (76 mg, 0,63 mmol) and potassium carbonate (86 mg, to 0.63 mmol) in 10 ml of CH2Cl2. The reaction was completed after stirring at -78oC for 2 hours and was terminated by adding a saturated aqueous solution of K2CO3. Extraction with three portions of 30 ml dichloromethane gave the organic layer was dried over potassium carbonate), filtered and concentrated. The residue was chromatographically on aluminium oxide, elyuirovaniya a mixture of simple ether/light petroleum (1:1), then a simple ether. Pure fractions were combined and processed ethereal hydrochloric acid, yielding 217 mg (84% yield) of target compound 49, c.

d) Hydrochloride CIS-1S,2R-1-methyl-8-acetyl-2-[N - [4(8 azaspiro[4,5]decane-7,9-Dion-8-yl)butyl]propylamino]tetralin2
(Ph3P)2) (18 mg, of 0.025 mmol), triphenylphosphine (22 mg, 0,084 mmol), lithium chloride (71 mg, 1.88 mmol) and crystal radical inhibitor (2,6-3-tert-butyl-4-METHYLPHENOL) were mixed at 120oC for 18 hours in a sealed flask, filled in advance with nitrogen. The mixture was concentrated in vacuo to remove DMF and stirred with 10% aqueous solution of hydrochloric acid at room temperature for 15 minutes. The solution was podslushivaet 1 M NaOH and was extracted with three portions of simple ether and 30 ml each. The ether phase was dried (K2CO3_ filtered and concentrated. The residue was chromatographically on a column of alumina using a mixture of simple ether/light petroleum (2:1) as eluent. Pure fractions were combined and processed ethereal hydrochloric acid, yielding 80 mg (76% yield) of target compound 49, d. []022+2,2oC.

Example 50. N-cyclopropyl-N-propyl-8-phenyl-2-aminotetralin

N-cyclopropyl-N-propyl-8-tripterocalyx-2-aminotetralin (2.50 g, 6,35 mmol), phenylboronic acid (0,90 g, 7,30 mmol), lithium chloride (0.54 g, 12.7 mmol), Na2CO3(2 M 9 ml), ethanol (29 ml) and toluene (63 ml) were mixed in a 250 ml three-neck to3)4(240 mg, 0.2 mmol). The reaction mixture was heated at 95oC for 12 hours. The solvent was then supariwala up to a volume of 70 ml, the Residue was diluted with ethyl acetate and washed twice in 1 M NaOH, processed salt solution and dried (magnesium sulfate). The solvent was removed in vacuo, yielding oily yellow-brown residue, which was purified instant chromatography (SiO2CH2Cl2the ethyl acetate 100:2 --> 10:1).

N-cyclopropyl-N-propyl-8-phenyl-2-aminotetralin stood out with the release of 72% (1.4 g) as a colourless oil. The oil was dissolved in ether. The solution was cooled in an ice bath, was added dropwise hydrochloric acid (2 M in a simple ether). Filtration and recrystallization from a mixture of ethyl acetate/simple ether gave colorless crystals of the target compound. So pl. 153-156oC.

Example 51. Oxalate (+/-)-2-(dipropylamino)-8-(4'-forfinal)tetralin

A mixture of 2-(dipropylamino)-8-((trifloromethyl)oxy)tetralin (200 mg, 0.51 mmol), tetrakis(triphenylphosphine)palladium (0)(30 mg, was 0.026 mmol), 4-tortenelmietlen (232 mg, 0.6 mmol, see example 53), lithium chloride (67 mg, 1.6 mmol) in dimethylformamide (3 ml) and 1,4-dioxane (3 ml) was heated at the temperature of reflux distilled during the night. Prov.and aluminum, was elyuirovaniya a mixture of simple ether/light petroleum (1:20). Pure fractions were combined and processed ethereal oxalic acid, giving 145 mg (68% yield) of the target compound. So pl.-197-199oC.

Both enantiomers of oxalate ()-2- (dipropylamino)-8-(4'- forfinal)tetralin was synthesized in the same way, but using source separated materials:

oxalate (+)-2-(dipropylamino)-8-(4'-forfinal)tetralin. Yield: 59% () 136,8oC.

oxalate (-)-2-(dipropylamino)-8-(4'-forfinal) tetralin. Yield: 65% (a) -27,2oC.

Example 52. Hydrochloride ()-2-(dipropylamino)-8-(4'-methoxyphenyl)tetralin

A mixture of 2-(dipropylamino)-8-(tripterocalyx)tetralin (1 g, 2.5 mmol), tri-n-butyl-(4-methoxyphenyl)stannane (1.2 g, to 3.02 mmol, prepared as described in: Wardell I. Ahmed S. I. //were obtained. Chem. 1971, 78, 395), tetrakis(triphenylphosphine)palladium (0), (87 mg, of 0.075 mmol), lithium chloride (330 mg, of 7.75 mmol) in 1,4-dioxane (15 ml) and dimethylformamide (2 ml) was stirred at 120oC in a sealed flask for 20 hours. The catalyst was hoteltravel (celite) and the filtrate was concentrated. The resulting residue was purified by chromatography on a column of alumina using a mixture of simple ether/light was Amityville ethereal HCl and left to stand at room temperature overnight, giving 793 mg (85% yield) of the target compound as a white solid.

Example 53. Tri-n-butyl-(4-forfinal)stannane

A solution of n-ferramenta (5 g, 28.6 mmol) in ether (15 ml) was added to the newly powdered magnesium with stirring in nitrogen atmosphere. The reaction mixture was heated to the temperature of reflux distilled until until dissolved magnesium. To the Grignard reagent was added a solution of tributyltinchloride (7,8 g, 2.4 mmol) in a simple ether (10 ml) and the reaction was stopped after three days of heating under reflux. The reaction mixture was diluted aqueous saturated solution of ammonium chloride and was distributed between the simple ether and water. The organic layer was dried (magnesium sulfate), filtered and concentrated. The residue was converted into the vacuum, giving 7,1 g (68%) of tri-n-butyl-(4-forfinal)stannane in liquid form (117-134oC) 1 mm Hg.

Check pharmacological action

Treatment of depression in humans

There are reports that patients with depression the transmission of nerve signals through the Central nervous system (CNS) can be interrupted. Apparently, these disorders are associated with the neurotransmitters noradrenaline (NA) and 5-hydroxytryptamine (5-HT). Lekarstvennyie transmission of nerve impulses in any or both of these physiological agonists. The results indicate that with increased 5-hydroxytryptamine of neurosecretion, in essence, eliminates depression and psychosis, while at enhancing noradrenergic of neurosecretion is rather relieving symptoms appear in patients with depression. In recent years there have been a lot of attempts to create new drugs with high selectivity to improve 5-HT-conducting nerve signals to the Central nervous system.

The mechanism of action of drugs, currently used in the treatment of depression is not related to direct their action, that is, they have an effect when blocking high content of neurotransmitters (NA and/or 5-HT) released from nerve endings in the Central nervous system, thereby increasing the concentration of these neurotransmitters in the synaptic cleft, resulting in restoring the proper transmission of nerve impulses.

Fundamentally different way of regulation of nerve impulses in 5-HT neurons of the CNS is to use a direct 5-HT-receptor agonists/antagonists. To minimize side effects in this case, preferably selective effect for such is inym, direct stimulating effect on the Central nervous system or blocks a subset of 5-HT receptors. It was also established that some of these compounds have excellent bioavailability after oral administration. To assess the means specified subgroup 5-HT - receptor study in vitro effects on different receptors in rat brain using analysis of binding to receptors (nm).

in vitro test. Analysis of the receptor binding

Test the binding of 5-HT1A. The cerebral cortex with the hippocampus of each rat was separated and homogenized in 15 ml ice 50 mm Tris-HCl buffer, 4.0 mm CaCl2and 5.7 mm ascorbic acid, pH 7.5, homogenizer Ultra Turrax (Janke and Kunkel, Staufen, Germany) for 10 seconds. After centrifugation for 12.5 minutes at a speed of 17,000 rpm (39800 about. in the centrifuge Beckman with rotor A-17) Bechman, Paolo Alto, CA, USA, pellets re-suspended in the same buffer and homogenized, and centrifuged again. To each pellet add 5 ml ice of 0.32 M sucrose solution and homogenized for 5 seconds. These samples are kept in a frozen state at a temperature of -79oC. When used diluted with the buffer solution in the payment of the nut at a temperature of 37oC, then enter 10 μm of parylene then re-incubation for 10 minutes.

Conducted further analysis on the binding of the receptor described in: J. Peroutka //Neurochem, 1986, 47, 529-540. The incubation mixture (2 ml), contains3H-8-OH-PAT (from 0.25 to 8 nm), 5 mg/ml of tissue homogenate in 50 mm Tris-HCl buffer containing 4.0 mm CaCl2and 5.7 mm ascorbic acid, pH 7.5. Analyzed 6 different concentrations3H-8-OH-PAT. Test linking, beginning with the introduction of tissue homogenate, followed by incubation for 10 minutes at a temperature of 37oC. the Incubation mixture was filtered through glass filters Whatman type IB when using a cell harvester, Brandel (Gaithersburg, MD, USA). The filters are washed twice with 5 ml ice 50 mm Tris-HCl buffer solution, pH 7.5, and count the cells using 5 ml of this solution HP (Beckman) in a scintillation counter Beckman model LS 3801. Nonspecific binding is determined by adding 10 μm of 5-HT to the reaction mixture. Test results linking processed by the analysis on the mainframe using the method of nonlinear ordinary least squares (Munson and Rodbard Anal. Biochem, 1980, 107, 220-239).

The results of the evaluation of the various compounds of the present invention placed in a table. who are the salt of the investigated compounds, and the last column gives the concentration of the compound in nanomolar required for 50% suppression binding 3H-8-OH-DPAT in figure 1C50.

1. 1,8-Zameshannye-2-aminotetraline derivatives of General formula

< / BR>
where R is hydrogen or methyl, provided that C1-methyl Deputy is in the CIS configuration;

Z is hydrogen or halogen;

Q COR', or phenyl, furyl, thienyl, pyrazolyl, thiazolyl, pyridyl, hinely, indicazioni, indolyl, benzofuranyl, optionally substituted with halogen or lower alkoxy;

R1C1C6-alkyl or phenyl, optionally substituted with halogen or lower alkoxy, or C3-C6-cycloalkyl;

R2hydrogen or C1C6-alkyl;

R3group C1C6-alkyl or -(CH2)a-R4where a 4, R4- -NR11R12, R11and R12together with the nitrogen atom form a ring

< / BR>
n is 1 or 2,

or their enantiomers and physiologically acceptable salts.

2. Connection on p. 1, in which Q COR1where R1methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutane.

3. Connection on p. 1, in which Q is phenyl, forfinal, Tieni"ptx2">

5. Connection on p. 1, representing 8-acetyl-2-di-n-propylaminoethyl.

6. Connection on p. 1, representing 8-phenyl-2-di-n-propylaminoethyl.

7. Connection on p. 1, representing 8-(2-furanyl)-2-di-n-propylaminoethyl.

8. Connection on p. 1, representing the (1S, 2R)-8-benzoyl-1-methyl-2-di-n-propylaminoethyl.

9. The compound according to any one of paragraphs.1 8 active Central 5-HT receptor.

10. The way to obtain 8-substituted-2-aminotetraline derivatives of General formula I

< / BR>
in which R is hydrogen or methyl, provided that C1-methyl Deputy is in the CIS configuration;

Z is hydrogen or halogen;

Q COR1;

R1C1C6-alkyl or phenyl, optionally substituted with halogen or lower alkoxy, or C3C6-cycloalkyl;

R2hydrogen or C1C6-alkyl;

R3group C1C6-alkyl or -(CH2)a-R4where a 4, R4- -NR11R12, R11and R12together with the nitrogen atom form a ring;

< / BR>
n is 1 or 2,

or their enantiomers and physiologically acceptable salts, characterized in that soedineniya above for the compounds of formula I, subjected to transformation through the catalytic cycle using a transition metal with zero valency of M0that is oxidation join aryl-X-communication, the processing of carbon monoxide followed by transmetilirovanie between R1M1where M1metal and R1has the values defined for the compounds of formula I, and originally formed carbonyliron o-aryl-metal-X complex with the formation of the compounds of formula I, and then, if necessary, the compound obtained in the form of the base is converted into a physiologically acceptable acid additive salt or compound, obtained as a salt, is converted into a base or another physiologically acceptable acid additive salt obtained isomeric mixture, if necessary, separated into the pure isomers.

11. The method according to p. 10, characterized in that Q COR1where R1methyl, ethyl, propyl, butyl, pentylcyclohexyl, methylcyclopropyl, cyclobutyl, methylcyclobutane.

12. The method according to any of paragraphs. 10 and 11, characterized in that R3- C1C6is an alkyl group.

13. The way to obtain 8-substituted-2-aminotetraline derivatives of General formula

Z is hydrogen or halogen;

Q is phenyl, furyl, thienyl, pyrazolyl, thiazolyl, pyridyl, hinely, indicazioni, indolyl, benzofuranyl, optionally substituted with halogen or lower alkoxy;

R2hydrogen or C1C6-alkyl;

R3group C1C6-alkyl or -(CH2)a-R4where a 4, R4-NR11R12, R11and R12together with the nitrogen atom form a ring

< / BR>
n is 1 or 2,

or their enantiomers and physiologically acceptable salts, characterized in that the compound of formula II

< / BR>
where X represents a leaving group, and R, R2and R3have the values defined above for the compounds of formula I, is subjected to the conversion by using the reaction using a transition metal with zero valency of M0and a suitable aryl-substituent, such as trialkyl-allscanner with the formation of the compounds of formula I, and then, if necessary, the compound obtained in the form of the base is converted into a physiologically acceptable acid additive salt or compound, obtained as a salt, is converted into a base or another physiologically acceptable acid additive salt obtained isomeric mixture in the case of high q is l or furanyl.

15. The method according to p. 13, wherein R3C1- C6is an alkyl group.

 

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2 ex

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