The method of obtaining derivatives of 1,2,3,4-tetrahydronaphthalene or their pharmaceutically acceptable acid salt additive

 

(57) Abstract:

The inventive product of General formula I, where R is H, CH3; R1-H, CH3; X-CH2CH2- or-CH2-CH2-CH2; R2-H , Hal, C1-C3-alkoxy, C1-C3-alkyl; R3-H , Hal; R4-H , Hal, C1-C3-alkyl, C1-C3-alkoxy; R5-H , C1-C3-alkyl, C1-C3-alkoxy. Reagent 1: the corresponding tetralone 2. Reagent 2: the corresponding piperazine or homopiperazine 3. Reaction conditions: obtained by the reaction of compounds 2 and 3 product restore. New connections - selective inhibitors of absorption of serotonin, which do not have a direct effect on neural receptors. table 1. Formula I:

In the past decade has been noticed and investigated the relationship between absorption (consumption) of monoamines and many different diseases and conditions. For example, chlorhydrate salt of fluoxetine (dl-N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy] propanamine) is a selective inhibitor of overconsumption of serotonin (5-hydroxytryptamine), useful for the treatment of depression and, possibly, for treatment of disorders in feeding, alcoholin-hydrochloride] is a selective inhibitor of the uptake of norepinephrine, studied in a clinical setting on his protivoleprosnoe activity. These compounds along with many are described in the U.S. patents as being strong absorption blockers variety of physiologically active monoamines, including serotonin, norepinephrine, and dopamine.

The present invention provides a method of obtaining new substituted in the ring 2-piperazinil - or 2-homopiperazin-1,2,3,4-tetrahydronaphthalene, which are selective inhibitors of the uptake of serotonin and have no direct effects on neural receptors. Consequently, there is reason to expect that these compounds will give less side effects, because they do not effectively block monoamine receptors and does not inhibit the absorption of other monoamines.

More specifically this invention relates to a method for producing derivatives of tetrahydronaphthalene, compounds of General formula

where R is hydrogen or methyl;

R1is hydrogen or methyl;

X - CH2CH2- or-CH2CH2CH2-;

R2is hydrogen, halogen, C1-C3-alkoxy or C1-C3-alkyl;

R3is hydrogen, halogen;

R4is hydrogen, CH or C1-C3-alkoxy;

Under the following conditions:

(a) if R1is stands, R2and R4can be simultaneously hydrogen;

(b) if R1is hydrogen, one of R2and R4is not hydrogen;

(C) R5may be other than hydrogen only when R2is other than hydrogen;

(d) R3may be a halogen only when R4is not hydrogen,

and their pharmaceutically acceptable acid additive salts.

Although all of the compounds of the present invention are useful for treating a variety of disorders that are associated with reduced neurotransmission serotonin in mammals (or as intermediates for such compounds), some of the compounds are preferred. So, X preferably represents-CH2-CH2-. Also, when R4is other than hydrogen, R1represents preferably methyl, and when R2is other than hydrogen, R1preferably represents hydrogen.

When R2is other than hydrogen, it preferably represents alkoxy or halogen, and more prefer the et a methoxy. Preferably also, when R2is other than hydrogen, to R5also was other than hydrogen. In particular, when R5is other than hydrogen, it preferably represents a halogen, and most preferably bromine.

When R4is other than hydrogen, it preferably represents halogen, and, most preferably, chlorine.

Compounds of the present invention have asymmetric carbon represented by the carbon atom marked with an asterisk in the following formula:

Thus, each of the compounds exist in the form of its individual d - and l-stereoisomers, as well as racemic mixtures of such isomers. Accordingly, the compounds of the present invention include not only the dl-racemates, but also their corresponding optically active d - and l-isomers.

In addition, when R1represents methyl, there is one more asymmetric carbon, located at R1the Deputy, which gives the possibility of the existence of an additional class of stereoisomers.

As mentioned above, the invention includes pharmaceutically acceptable acid additive salts of the compounds defined and in nature and accordingly interact with any of a number of inorganic and organic acids, forming a pharmaceutically acceptable acid salt additive. Since the free amines of the compounds of this invention are typically oils at room temperature, it is preferable to make available amines to their corresponding pharmaceutically acceptable acid salt additive for ease in handling them and the appointment for the reception, since the latter are usually solid at room temperature. Acids commonly used for the formation of such salts are inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena, sulfuric, phosphoric acid and similar, and organic acids such as p-toluensulfonate, methanesulfonate, oxalic acid, p-bromophenylacetate, carbonic, succinic, citric acid, benzoic acid, acetic acid and similar. Examples of such pharmaceutically acceptable salts are sulfate, persulfate, bisulfate, sulfite, bisulfite, phosphate, secondary acid phosphate, monopotassium phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, kaprilat, acrylate, format, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, who Insaat, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, ecological, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and similar. Preferred pharmaceutically acceptable acid additive salts are salts formed with mineral acids such as hydrochloric and Hydrobromic acid, and salts formed with organic acids such as maleic acid.

In addition, some of these salts may form a solvate with water or organic solvents, such as ethanol. Such a solvate is also included as the compounds of this invention.

The following connections are additionally illustrate the connections provided in the scope of this invention:

1-Methyl-2-pinoresinol-8 ethoxy-1,2,3,4-tetrahydronaphthalen

2-(N-methylpiperazine)-8-ethyl-1,2,3,4-tetrahydronaphthalen

2-Piperazinil-8-methylthio-1,2,3,4-tetrahydronaphthalen

2-Homopiperazin-8 ethylthio-1,2,3,4-tetrahydronaphthalen

1-Methyl-2-piperazinil-6-ethyl-1,2,3,4-tetrahydronaphthalen

1-Methyl-2-(N-methylpiperazine)-6-ethoxy-1,2,3,4-tetrahedral-1,2,3,4-tetrahydronaphthalen

2-Piperazinil-5-trifluoromethyl-8-iodine-1,2,3,4-tetrahydronaphthalen

2-(N-methylpiperazine)-5-acetyl-8-chloro-1,2,3,4-tetrahydronaphthalene, 2-Homopiperazin-5-peracetyl-8-methylthio-1,2,3,4-tetrahydronaphthalen

2-(N-methylpiperazin-(8-n-propyl-1,2,3,4-tetrahydronaphthalen

2-Piperazinil-6-ethylthio-1,2,3,4-tetrahydronaphthalen

2-(N-methylpiperazine)-6-isopropyl-1,2,3,4-tetrahydronaphthalen and similar.

Compounds of the present invention can be prepared using techniques well known to specialists in this field. These compounds preferably are synthesized by obtaining selected tetralone that restorative miniroot piperazine, N-methylpiperazine or relevant homopiperazine the homologues, giving selected compounds of the present invention. Other compounds of this invention are available by using a modification of the ring substituents stages after reductive amination.

Schemes of these reactions are the following:

A. Synthesis of tetralone

< / BR>
< / BR>
< / BR>
< / BR>
Century Vostanovlenie amination

< / BR>
PIP = unsubstituted or substituted piperazinilnom or

homopiperazine fragment

As ukases piperazine or homopiperazine connection result in the compounds of this invention or compounds that are in the core structure of the compounds of this invention.

Tetralone can be obtained using any of a wide variety of recognized methods. For example, they can be obtained by reaction of the Friedel-appropriate substituted in the ring phenylacetylide with ethylene in the presence of aluminum chloride.

1,7-Dilaksanakan can recover the sodium in the appropriate monoalkylation.

Another way of obtaining tetralone is carried out through 1,4-dilaksanakan. Naphthalene is recovered sodium 1,4-dihydronaphthalene, and the latter is oxidized to the corresponding epoxide m-chlormadinone acid. Epoxide is recovered by sociallyengaged (LiAH), and the resulting alcohol is oxidized to the desired product using chloramine pyridinium.

When R1in the compounds of the present invention is a methyl, methylseleninic the tetralone can be obtained from the corresponding unsubstituted tetralone. The tetralone is first processed by pyrrolidine to obtain the corresponding 1,2-what th 1-methyl-2-tetralone.

The tetralone can use a simple reductive amination using unsubstituted or substituted piperazine or homopiperazine (RR) to become a connection of the present invention or the compound useful as intermediate compounds of the present invention. The tetralone is first subjected to interaction with RR with the formation of the corresponding enamine, after which the enamine is reduced by sodium borohydride to obtain tetrahydronaphthalene.

Optically active isomer of the racemate of the invention are also considered part of this invention. Such optically active isomers can be obtained from their respective optically active precursors using the techniques described above, or by using the splitting of racemic mixtures. This splitting or separation may be carried out in the presence of a decomposing agent, using chromatography or re-crystallization. Especially useful splitting agents are d - or l-tartaric acid, d - and l-dichlorine acid and similar.

Compounds used as starting materials in the synthesis of compounds of this invention are well known and easily the Pharmaceutically acceptable acid salt additive of the present invention in a typical case are formed by the reaction of 1,2,3,4-tetrahydronaphthalene of the present invention with an equimolar or excess amount of acid. The reactants are typically combined at a mutually acceptable for both solvents, such as diethyl ether or benzene, and salt normally precipitates out of solution during a period in the range from about one hour to 10 days and can be separated by filtration.

The following examples further illustrate the compounds of the present invention and methods for their synthesis. The examples are not intended to limit this invention in any respect, and should not be construed as restrictive.

Unless otherwise stated, NMR data given in the examples refer to the free bases of the compounds discussed.

P R I m e R 1. Getting dichlorhydrate 2-(methylpiperazine)-8-methoxy-1,2,3,4-tetrahydronaphthalene.

A. 8-Methoxy-2-tetralone.

To 1 l of acetone added 50.0 g (0.31 mol) of 1,7-dihydronaphthalene. To the solution were then added 95,0 g (0.69 mol) of powdered potassium carbonate and 65 ml (0.69 mol) of dimethylsulfate. The mixture was stirred while heating under reflux in nitrogen atmosphere for about 18 hours the Mixture is then left to cool to room temperature and diluted with 2 l of water, after which it was extracted with methylene chloride. what about the sodium, was dried over sodium sulfate and evaporated in vacuo giving a brown oil.

The oil was distilled in vacuo, giving 52,51 g (90,1%) 1.7 dimethoxyaniline in the form of a light orange transparent oil; so bales. 155-157aboutC/4 mm RT. Art.

NMR (l3): of 7.6 to 6.9 (m, 5H), 6,7-6,6 (D., j = 7,2, 1H), 3,88 (C., 3H), 3,84 (C., 3H).

The above product (52,5 g, 0,279 mol) was dissolved in 450 ml of ethanol. To the solution were then added to 54.4 g (2,37 mol) of sodium at a rate sufficient to maintain gentle boiling under reflux. Through a mixture missed the nitrogen to remove hydrogen that has formed. The mixture was then heated under reflux until until the sodium is not consumed, after which it was cooled to room temperature, diluted with 300 ml of water followed by the addition of 350 ml of concentrated Hcl, and then was heated on a steam bath for 30 minutes the Mixture was diluted with water to until all remaining solid substance was not dissolved, and then cooled to room temperature and was extracted with simple ether. The organic extracts were combined, washed with water, and then saturated aqueous saturated sodium chloride, dried over sodium sulfate and evaporated in vacuo, giving a yellow oil. Matria. Two-phase system was stirred vigorously for 18 h

The resulting colorless suspension was filtered and the collected solid was washed with ether and dried in vacuum. The solid is then added to about 300 ml of 50% aqueous potassium carbonate. Added ether and the mixture is vigorously stirred until then, until all the solid did not dissolve. A two-phase mixture is then separated, and the aqueous portion was extracted with ether. The combined ether phases are washed successively with water and saturated aqueous sodium chloride, dried over sodium sulfate and evaporated in vacuo, giving 32,8 g (67%) of target compound in the form of colorless, crystalline mass.

NMR (l3): a 7.2-7.0 (triplet, j = 7,2, 1H), 6,8-6,6 (triplet, j = 7,2, 2H), 3,76 (singlet, 3H), 3,48 (singlet, 2H), 3,14-2,92 (triplet, j = 7,2, 2H), 2,62 is 2.46 (t, j = 7,2, 2H).

Century Dichlorhydrate 2-(N-methylpiperazine)-8-methoxy-1,2,3,4-tetrahydronaphthalene.

The tetralone (10 g, 56,8 mol) was dissolved in 200 ml of toluene. To the solution were then added at 13.0 ml (0,117 mol) of N-methylpiperazine followed by the addition of 25.1 g (0.13 mol) of p-toluenesulfonic acid. The mixture was stirred at reflux with continuous removal of water. After 2 h the mixture Oh,2-dihydronaphthalene in the form of reddish-orange pulp.

The slurry was dissolved in 200 ml of ethanol. To the solution was added 30 ml of acetic acid and then adding 10 g of sodium borohydride. The mixture was stirred for 2 h at room temperature, after which it was diluted with 200 ml of 10% Hcl, and then was stirred for an additional hour at room temperature. The mixture was diluted with water and was extracted with ether. The aqueous layer was then podslushivaet the addition of ammonium hydroxide and was extracted with methylene chloride. Methylenechloride extracts were combined, dried over sodium sulfate and evaporated under vacuum, yielding a red-brown oil. This oil was dissolved in methylene chloride and placed on a pillar instant chromatography of silica. The column was suirable with methylene chloride containing 3% Meon and traces of ammonium hydroxide, giving a light orange transparent oil. The oil is triturated with hexane. The resulting mixture was filtered, the filtrate was evaporated in vacuo, yielding 7.5 g of light yellow solid. 1 g of this solid was converted into diclorhidrato salt and was led from methanol, receiving 1.10 g of target compound in the form of colorless crystals; so pl. above 200aboutC.

WITH16H24N2O2HCl.

Vychisl., 2H), 3,76 (C., 3H), 3,20-of 2.36 (m, N), 2,31 (C., 3H), 2,22-of 1.92 (m, 2H), 1,8-1,2 (m, 1H).

MS: 260 (25), 216 (8), 202 (9), 189 (17), 188 (11), 174 (10), 162 (32), 160 (39), 100 (92), 70 (62), 53 (100).

P R I m m e R 2. Getting dichlorhydrate 2-piperazinil-8-methoxy-1,2,3,4-tetrahed-ronfalin.

The tetralone (1.0 g, of 5.68 mmol) obtained in example 1 was treated in accordance with the procedure described in example 1, using piperazine instead of N-methylpiperazine, obtaining 0,22 g of a yellow, viscous oil. This oil was treated with gaseous HCl for receipt of 0.13 g of the target compound as colorless crystals.

C15H22N2O 2HCl.

Calculated,%: 56,43; N 7,58; N 8,77.

Found,%: C 56,22; N 7,51; N 8,53.

NMR (l3): 7,22-7,00 (triplet, j = 7,2, 1H), 6,84-6,60 (multiplet, 2H), 3,91 (singlet, 3H), 3,28-2,5, (multiplet, N), 2,45 (singlet, 1H), 2,36-2.0 (multiplet, 2H), 1,96-1,40 (multiplet, 1H).

MS: 247 (23), 246 (100), 245 (8), 231 (5), 204 (65), 161 (78).

P R I m e R 3. Getting Dimineata 2-piperazinil-8-chloro-1,2,3,4-tetrahydro-naphthalene.

A. 8-Chloro-2-tetralone.

A mixture of 30.0 g (0,176 mol) o-chlorophenylalanine acid and 40 ml of thionyl chloride are stirred for 18 hours Volatiles were then removed in vacuo, giving 32.76ˆ g (99,0% ) o-LASS="ptx2">

AlCl3(46,5 g, 0,348 mol) is suspended in 400 ml of methylene chloride. The mixture then was cooled to -78aboutWith, and dropwise over 1 h solution was added 32.76ˆ g (0,174 mol) obtained previously chlorophenylacetyl in 100 ml of methylene chloride. Bath of a mixture of dry ice/acetone, and then was replaced by a bath of ice water. In the reaction mixture was barbotirovany ethylene, and during this period of time the temperature rose to 15aboutC. the Addition of ethylene was stopped and the mixture was left to mix with about a 5aboutC for 4 h and Then to the mixture was added ice to decompose any remaining aluminum complexes. After the exothermic reaction mixture was diluted with water (500 ml) and vigorously stirred until then, until all the solid did not dissolve. The aqueous and organic phases were separated, and the organic phase is washed 3 times with 400 ml portions of 1 N. Hcl and two times using each time with 400 ml of 10% aqueous sodium bicarbonate. The organic phase is then dried over sodium sulfate and evaporated in vacuo, yielding a pale orange residue. The residue was dissolved in a mixture of hexane and ether (1:1) and applied on a column of instant chartography of silica, which was then suirable with a mixture of hexane and ether (1:1) soedineniya.

NMR (l3): of 7.5 to 7.2 (m, 3H), 3,7 (S., 2H), 3,3-3,0 (t, j = 7, 2H), 2,8-2,4 (t, j = 7, 2H).

MS: 180 (60), 165 (9), 138 (100), 117 (52), 115 (50), 103 (48), 89 (20), 76 (25), 74 (18), 63 (30), 57 (9), 52 (28), 51 (20), 42 (6), 39 (32).

IR (nujol): 2950, 2927, 1708, 1464, 1450, 1169, 1141.

Century Demolet 2-piperazinil-8-chloro-1,2,3,4-tetrahydronaphthalene.

The above tetralone (0.5 g, 2,78 mmol) was treated with piperazine, and the resulting product was recovered by sodium borohydride according to the procedure described in example 1. The product was treated with maleic acid and was obtained 0.12 g of target compound; so pl. 180-181aboutC.

C14H19N2Cl 2C4H4O4.

Calculated,%: C 54,72; N 5,64; N 5,80.

Found,%: C 54,81; N 5,67; N Of 5.89.

NMR (l3): of 7.4 to 6.8 (m, 3H), 3,3-2,6 (m, 15 NM), 2,55 (S., 1H).

MS: 252 (10), 250 (35), 210 (28), 208 (100), 167 (17), 165 (39), 129 (40), 54 (68).

P R I m e R 4. Getting Dimineata 2-(N-methylpiperazine)-8-chloro-1,2,3,4-tet - raidernation.

Using the method of example 3, 0.5 g (2,78 mmol) of 8-chloro-2-tetralone was treated with N-methylpiperazine, and the resulting product was reduced by sodium borohydride, the product was treated with maleic acid, and received of 0.48 g of target compound is.

Calculated,%: C 55,59; N 5,88; N 5,64.

Found,%: C 55,81; N. Of 6.02; N 5,59.

NMR (l3): of 7.4 to 6.8 (m, 3H), 3,3-2,4 (m, 11N), 2,3 (C., 3H), 2,2-1,0 (m, -N).

MS: 266 (18), 264 (52), 222 (5), 224 (12), 193 (32), 129 (30), 45 (100).

P R I m e R 5. Getting Dimineata 2-(homopiperazine)-8-chloro-1,2,3,4-Tetra-gerenation.

Using the procedure of example 3, 2.0 g (11.1 mmol) of 8-chloro-2-tetralone was subjected to interaction with 2.2 g (22,2 mmol) homopiperazine, and the resulting product was recovered by sodium borohydride, and the recovered product was treated with maleic acid; received of 0.13 g of target compound in the form of colorless crystals; so pl. 146-148aboutC.

WITH15H21N2Cl 2C4H4O4.

Calculated,%: C 55,59; N 5,88; N 5,64.

Found,%: C 55,89; N. Of 6.02; N Lower Than The 5.37.

NMR (l3): 7,24-to 6.80 (m, 3H), 3,28-2,48 (m, 14N), 2,47 (S., 1H), 2,24-1,08 (m, 3H).

MS: 266 (17), 265 (12), 264 (49), 224 (5), 222 (20), 220 (15), 210 (18), 209 (21), 208 (55), 207 (48), 206 (16), 196 (19), 194 (22), 165 (48), 129 (24), 98 (42), 72 (75), 54 (100).

P R I m e R 6. Getting Dimineata 2-(N-methylpiperazine)-8-fluoro-1,2,3,4-tet - raidernation.

A. 8-fluoro-2-tetralone.

on-Ftorhinolona acid (35,9 g, 0,233 mmol) was stirred in 40 ml of thionyl chloride is dcost. The liquid was distilled in a vacuum, and received 27,45 g (68.5 per cent) o-perforazione in the form of a colourless liquid; so bales. 85aboutC/4 mm RT.article.

NMR (l3): of 7.6 to 6.9 (m, 4H), from 4.3 to 4.1 (D., j = 4, 2H).

Aluminium chloride (42.5 g (0.32 mol) was stirred in 400 ml of methylene chloride, and the resulting solution was cooled to -78aboutC. To the solution was then added dropwise a solution of 27,45 g (0.16 mol) of a previously received acylchlorides in 100 ml of methylene chloride for 1 h Bath of a mixture of dry ice/acetone was replaced by a bath of ice water, and the flask was vigorously barbotirovany ethylene, and the temperature was raised to -50aboutTo +17aboutC. After completion of the exothermic reaction of the addition of ethylene was stopped, and the reaction mixture was stirred for 2 hours at a temperature of about 5aboutWith and then for 2 h at room temperature.

To the reaction mixture was then carefully added to ice. After the resulting ectothermy the reaction mixture was diluted with 500 ml of cold water. The organic and aqueous phases were separated, and the organic phase is washed three times with 100 ml of 1 N. HCl and two times with 100 ml saturated aqueous sodium bicarbonate. The organic layer was then dried over sodium sulfate and aparience instant chromatography of silica. The column was suirable with a mixture of hexane and ether (1:1) yielding a yellow viscous residue. The residue is crystallized from a mixture of hexane and ether (4:1), and has received a total of 5.85 g tetralone in the form of a colorless solid.

NMR (l3): of 7.4 and 6.7 (m, 3H), 3,6 (S. 2N), of 3.2 and 2.9 (t, j = 6, 2H), 2,7-2,4 (t, j = 6, 2H).

MS: 164 (100), 149 (23), 140 (8), 138 (31), 136 (17), 135 (57), 134 (12), 133 (40), 123 (31), 122 (100), 120 (41), 115 (24), 109 (26), 107 (18), 101 (22), 96 (34), 89 (7), 83 (16), 75 (17), 63 (22), 57 (21), 51 (17), 39 (18).

IR (KBR, tablet): 3436, 3427, 3401, 1716, 1705, 1495, 1246, 886 cm-1.

Century Demolet 2-(N-methylpiperazine)-8-fluoro-1,2,3,4-tetrahydronaphthalene.

The above tetralone (1.0 g, 6.1 mmol) was dissolved in 30 ml of toluene. To the solution were then added to 1.4 ml (12.2 mmol) of N-methylpiperazine and 2,78 g (14.6 mmol) of p-toluenesulfonic acid. The mixture was heated at the boil under reflux for 18 h with continuous removal of water, after which the mixture was cooled to room temperature. The solvent was removed in vacuo, yielding 3-(N-methylpiperazine)-5-fluoro-1,2-dihydronaphthalene in the form of a reddish-orange solid. Dihydronaphthalene was dissolved in 20 ml of ethanol. To the solution was added 1.5 ml of acetic acid and then adding the total number of approximately 0.5 g of sodium borohydride in portions. The floor is whether 10% aqueous HCl and was stirred for an additional hour at room temperature. The reaction mixture was added water and was extracted with ether. The aqueous layer was poured into ice and podslushivaet the addition of ammonium hydroxide. Then it was extracted with methylene chloride. Methylenechloride extracts were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated in vacuo giving a brown viscous oil.

The oil was dissolved in methylene chloride and placed on a column of instant chromatography. The column was suirable 5% methanol in methylene chloride with traces of ammonium hydroxide, and the eluate was evaporated in vacuum, obtaining 0.25 g of product free base as a pale yellow, transparent, viscous residue.

The residue was dissolved in methanol, and the solution was heated to boiling. To the solution were then added two equivalents of maleic acid in methanol, and received the resulting mixture was heated to boiling. The solution was filtered and the filtrate was cooled to room temperature with the formation of crystals. The solution then was cooled to 0aboutWith, and the crystals were filtered and dried in vacuum, obtaining of 0.37 g of target compound in the form of colorless crystals; so pl. 204-205aboutC.

C15H21N2F 2C4H4O4.

the., N), 2,3 (C., 3H), 2,2-1,4 (m, 3H).

MS: 249 (17), 248 (100), 247 (13), 204 (27), 190 (14), 189 (11), 179 (21), 177 (68), 176 (22), 150 (51), 148 (58), 100 (76), 70 (83), 58 (93).

When applying the method described in detail in examples 3 and 6 were obtained compounds of examples 7-9.

P R I m e R 7. Getting dichlorhydrate 2-(N-methylpiperazine)-8-methyl-1,2,3,4-tet - raidernation.

C16H24N22HCl.

Calculated,%: C 60,57; H Compared To 8.26; N 8,83.

Found,%: C 60,31; N At 8.36; N 8,62.

NMR (l3): of 6.96 (C., 3H), 3,12-to 2.40 (m, N), 2,36 (C., 3H), 2,28-2,0 (m, 2H), 2,28 (C., 3H), 1,92-of 1.40 (m, 1H).

MS: 245 (15), 244 (81), 243 (8), 201 (10), 200 (20), 185 (19), 183 (10), 174 (17), 173 (51), 172 (23), 145 (63), 143 (63), 129 (58), 100 (88), 70 (62), 58 (100).

P R I m e R 8. Getting Dimineata 2-(N-methylpiperazine)-5,8-dimethyl-1,2,3,4-tetrahydronaphthalene.

C17H26N22C4H4C4.

Calculated,%: C 61,21; N. Of 6.99; N 5,71.

Found,%: C 61,06; N 6,85; N Of 5.84.

MS: 260 (18), 258 (94), 243 (6), 214 (14), 200 (12), 187 (28), 186 (13), 144 (15), 143 (31), 100 (62), 72 (60), 58 (100).

P R I m e R 9. Getting Dimineata 2-(N-methylpiperazine)-8-bromo-1,2,3,4-tet - raidernation.

C15H21N2Br 2C4H4ABOUT4.

Calculated,%: 51,03; N. Of 5.40; N 5,17.

Found,%: C 51,32; N 5,54; N 5,42.

MS: 310 (40), 308 (40), 266 (11), 264 (10), 252 (13), 250 (10), 239 (35), 237 (35), 224 (10), 210 (12), 208 (12), 130 (70), 129 (88), 128 (65), 115 (30), 100 (92), 99 (50), 72 (75), 70 (95), 58 (100), 56 (69), 54 (98).

P R I m e R 10. Getting dichlorhydrate 2-(N-methylpiperazine)-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene.

A. 5,8-Dimethoxy-2-tetralone.

To 1 l of acetone was added 50.0 g (0.31 mol) of 1,4-dihydroxynaphthalene. To the resulting solution were added 95,0 g (0.69 mol) of powdered potassium carbonate and 65 ml (0.69 mol) of dimethylsulfate. The resulting mixture was stirred at reflux for 18 h, after which they were diluted with 2 l of water, and then extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate and evaporated in vacuum, obtaining the black oil. The oil was distilled in vacuum, obtaining 12.5 g of 1,4-dimethoxyaniline in the form of an orange crystalline solid, so Kip. 155aboutC/5 mm RT.article.

Dimethoxyaniline connection to 66.5 mmol) was dissolved in 120 ml of ethanol. The resulting mixture was heated to boiling under reflux in an atmosphere of nitrogen was added in portions of 11.7 g (0.51 mol) of sodium. Mixing while heating under reflux in a nitrogen atmosphere prominately temperature, then carefully diluted with 50 ml water. The mixture is evaporated in vacuo to remove ethanol and the residue was diluted with water and was extracted with ether. The organic extracts were combined, dried over sodium sulfate and evaporated in vacuo, yielding 11.1 g of 5,8-dimethoxy-1,4-dihydronaphthalene in the form of a yellow oil.

Dihydronaphthalene (58,4 mmol) was dissolved in 80 ml of methylene chloride. To the solution was added 12.9 g (0,063 mol) of 85% m-chlormadinone acid (MSRA) in 140 ml of methylene chloride dropwise over 10 minutes while adding needed cooling to maintain the temperature at about 25aboutC. the Mixture was then stirred at room temperature for 45 min, after which it was washed with saturated aqueous sodium bicarbonate solution to remove any number of m-chlorbenzoyl acid. The organic phase was washed with water and then with saturated aqueous sodium bicarbonate, dried over sodium sulfate and evaporated in vacuum, obtaining a brown viscous resin. The resin was dissolved in ether and was placed on a silica column for instant chromatography. The column was suirable ether, and fractions 3-6 were combined and evaporated in vacuum, obtaining a transparent viscous orange oil. The oil was dissolved in a mixture of hexane and ether (2:1). Fractions 5-8 were combined and evaporated in a vacuum, getting to 2.35 g of 5,8-dimethoxy-2,3-oxo-1,2,3,4-tetrahydronaphthyl-Lin in the form of colorless needles; so pl. 128-129aboutC.

Exocoetidae (2.35 g, to 11.4 mmol) was dissolved in 50 ml of ether and the solution was added dropwise to boiling under reflux the suspension of 1.53 g of lithium aluminum hydride (Li an) in 100 ml of ether. The resulting mixture was heated under reflux for 5 h, then was cooled to 0aboutC. To the mixture was then added gradually and carefully 1,53 ml of water, 1,53 ml of 15% aqueous sodium hydroxide and 4.59 ml of water. The mixture was vigorously stirred for 18 h at room temperature, and then filtered through a layer of celite. The filter was washed with ether, and the filtrate was evaporated in vacuum, obtaining 2.1 g (88,6%) 2-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene as not quite white solid.

Tetrahydronaphthalen (2.1 g, 10.1 mmol) was dissolved in 20 ml of methylene chloride. The resulting solution was added to a solution of 3.27 g (15,2 mmol) Harrogate pyridinium in 60 ml of methylene chloride. The mixture was stirred for 7 h at room temperature, and then filtered through a layer of celite. The filtrate was evaporated in vacuo to a dark viscous residue. The residue was dissolved by oricom, and the eluate was evaporated in vacuum, obtaining 0.8 g (38,4%) 5,8-dimethoxy-2-tetralone in the form of a Golden crystalline solid.

Century Dichlorhydrate 2-(N-methylpiperazine)-5,8-dimethoxy-1,2,3,4-tetrahedronal-Talin.

Dimethoxyethane (0.4 g, 1.94 mmol) was dissolved in 10 ml of toluene. To the solution were added and 0.46 ml (4 mmol) of N-methylpiperazine followed by the addition of 0.91 g (4.8 mmol) of p-toluenesulfonic acid. The mixture was stirred for 3.5 h under reflux in a nitrogen atmosphere with continuous removal of water. The mixture was then cooled to room temperature, and the volatile matter was removed under vacuum, obtaining 3-(N-methylpiperazine)-5,8-dimethoxy-1,2-dihydronaphthalene in the form of an orange-brown residue.

Dihydronaphthalene was dissolved in 10 ml of ethanol. To the resulting solution was added 0.3 g of sodium borohydride in portions. The mixture was stirred for 18 h at room temperature, after which it was diluted with approximately 15 ml of 10% aqueous Hcl. The resulting mixture was stirred for 45 min at room temperature and then was diluted with water and was extracted with ether. The aqueous layer was podslushivaet with ammonium hydroxide and extracted with methylene chloride. Methylenechloride extracts the volume of astoral in methylene chloride and placed on a silica column instant chromatography. The column was suirable 3% methanol in methylene chloride with traces of ammonium hydroxide, and the eluate was evaporated in vacuum, obtaining 0.31 g of the free base of the target compound in the form of weakly-orange glazed solid.

The solid was dissolved in ethanol and the solution saturated with gaseous hydrogen chloride. As the cooling solution was gradually formed solid, yielding 0.14 g diclorhidrato salt of the target compound as colorless crystals; so pl. above 200aboutC.

C15H26N2O22HCl.

Calculated,%: C 56,20; N To 7.77; N 7,71.

Found,%: C 56,09; N. Of 7.65; N 7,78.

NMR (l3): 6,48 (singlet, 2H), 3,69 (singlet, 6N), 3,16-2,32 (multiplet, N), and 2.26 (singlet, 3H), 2,28-1,92 (multiplet, 2H), 1,72-1,20 (multiplet, 1H).

MS: 291 (11), 290 (50), 289 (8), 275 (8), 246 (10), 232 (10), 231 (13), 219 (16), 218 (12), 191 (53), 190 (100), 164 (36), 99 (48), 43 (88).

P R I m e R 11. Getting Dimineata 1-methyl-2-(N-methylpiperazine)-8-chloro-1,2,3,4-tetrahydronaphthalene.

A. 1-Methyl-8-chloro-2-tetralone.

To 100 ml of tololo was added 5.0 g (27.8 mmol) of 8-chloro-2-tetralone. To the resulting solution is then added 3.5 g of pyrrolidine and the mixture was heated to boiling under reflux for 3 is the asle (about 6 g).

Dihydronaphthalene was dissolved in 30 ml of p-dioxane. To the solution was added 10 ml under the conditions, and the mixture was heated to boiling under reflux for 18 h under nitrogen atmosphere. To the reaction mixture was then added 25 ml of water and 1 ml of acetic acid, and heating was continued for 4 h the Reaction mixture was then cooled to room temperature and the solvent was removed in vacuum. The resulting residue is suspended in water and the aqueous mixture was extracted with ether. The organic extracts were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated in vacuum, obtaining a dark oil. The oil was dissolved in ether and was placed on a silica column instant chromatography. The column was suirable with a mixture of hexane and ether (1:1) containing a trace of ammonium hydroxide. The eluate was evaporated in vacuum, obtaining of 3.14 g of 1-methyl-8-chloro-2-tetralone in the form of mobile-orange liquid.

NMR (l3): of 7.4-7.0 (multiplet, 3H), 4,40-3,70 (Quartet, j = 7,2, 1H), 3,32-2.0 (multiplet, 4H), 1,52-1,36 (doublet, j = 7,2, 3H).

Century 1-Methyl-2-(N-methylpiperazine)-8-chloro-1,2,3,4-tetrahydronaphthalen.

The above tetralone (1.0 g, 5.2 mmol) was dissolved in 30 ml of toluene. To the solution was added 1,1 (10,3 mmol) N-methylpiperazin the nitrogen with continuous removal of water. The reaction mixture was cooled to room temperature and the solvent was removed in vacuum, obtaining 3-(N-methylpiperazine)-4-methyl-5-chloro-1,2-dihydronaphthalene as an orange viscous residue.

Dihydronaphthalene (approximately 5.2 mmol) was dissolved in 25 ml of ethanol. To the resulting solution was then added 1.5 ml of acetic acid followed by the addition of approximately 0.5 g of sodium borohydride in portions. The reaction mixture was stirred for 2 h at room temperature, after which was added 30 ml of 10% aqueous HCl, and the mixture was stirred for additional 2 h at room temperature. The reaction mixture was diluted with 100 ml of water and was extracted once with ether. The water part was podslushivaet with ammonium hydroxide and extracted with methylene chloride. Methylenechloride extracts were combined, dried over sodium sulfate and evaporated in vacuum, obtaining a viscous orange oil.

The oil was dissolved in methylene chloride and placed on a silica column instant chromatography. The column was suirable with methylene chloride containing 3% methanol and a trace of ammonium hydroxide, and the eluate was evaporated in vacuum, obtaining of 0.41 g of a yellow glass. The glass began to crystallize, and the mixture is triturated with hexane. Colorless solid is escoto solid is the desired product.

The filtrate is then evaporated in a vacuum, getting 0.21 g of a pale yellow, transparent glass. The glass was dissolved in methanol and was treated with two equivalents of maleic acid in methanol at reflux. The resulting mixture gave the opportunity to slowly cool to room temperature and was received of 0.30 g of the target compound as a colourless crystalline solid; T. pl. 174-175aboutC.

C16H23N2Cl 2C4H4O4.

Calculated,%: 56,41; N 6,12; N 5,48.

Found,%: C 56,63; N 6,01; N 5,49.

NMR (l3): 7,24-6,8 (multiplet, 3H), 3,68-3,32 (sq, j = 7, 1H), 3,0 of-2.32 (m , 10H), 2,30 (C., 3H), 2,10-1,20 (m, 3H), 1,24-1,08 (D., j = 7, 3H).

MS: 280 (8), 278 (28), 236 (4), 207 (20), 135 (100), 100 (31), 70 (58), 58 (59), 53 (54), 43 (62).

P R I m e R 12. Getting dichlorhydrate 1-methyl-2-piperazinil-8-chloro-1,2,3,4-tet-raidernation.

When using the method of example 11 of 1.94 g (10 mmol) of 1-methyl-8-chloro-2-tetralone were treated with piperazine, followed by reduction with sodium borohydride and treatment with HCl receipt of 0.67 g of the target compound as colorless crystals; so pl. above 200aboutC.

C15H21N2Cl 2HCl.

Calculated,%: C m, 10H), 2,24 (S., 1H), 2,15-of 1.44 (m, 3H), 1.18 to 1,04 (D., j = 7, 3H).

MS: 266 (6), 264 (18), 224 (19), 223 (10), 222 (59), 208 (14), 179 (31).

P R I m e p 13. Getting tosilata 1-methyl-2-piperazinil-8-methoxy-1,2,3,4-tetrahydronaphthalene.

A. 1-Methyl-8-methoxy-2-tetralone.

To 75 ml of toluene was added to 3.52 g (20 mmol) of 8-methoxy-2-tetralone and then adding 2.5 g of pyrrolidine. The mixture was heated to boiling under reflux for 3 h, after which the solvent is evaporated in vacuum, obtaining 3-pyrrolidino-5-methoxy-1,2-digitonal - Talin in the form of a dark oil.

The oil was dissolved in 25 ml of p-dioxane. To the solution were then added 7.5 ml of methyl iodide, and the mixture was stirred for 18 h under reflux in a nitrogen atmosphere. The mixture was then diluted with 25 ml water and 1 ml of glacial acetic acid, after which it is stirred for 3 h under reflux. The mixture was then cooled to room temperature, and volatiles were removed in vacuum. The resulting residue is suspended in water and the aqueous mixture was extracted with ether. The organic extracts were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated in vacuum, obtaining 3.5 g korichnevaya. The column was suirable with a mixture of hexane and ether (1:1), and the eluate was evaporated in vacuum, obtaining of 3.27 g (86,5%) target tetralone in the form of a light brown transparent oil.

Century 1-Methyl-2-piperazinil-8-methoxy-1,2,3,4-tetrahydronaphthalen.

The above tetralone (3,27 g, 17.3 mmol) was dissolved in 150 ml of toluene. To the solution were then added 3.04 from g (34.6 mmol) of piperazine followed by the addition of 7.2 g (38,2 mmol) p-toluenesulfonic acid. The mixture was stirred while heating under reflux in a nitrogen atmosphere with continuous removal of water. After 2 h the reaction mixture was cooled to room temperature, and volatiles were removed in vacuum to obtain tosilata 3-piperazinil-4-methyl-5-methoxy-1,2-di - gerenation in the form of a light yellow solid.

The solid is suspended in about 250 ml of ethanol. To the mixture was added portions of 2.4 g of sodium borohydride. The mixture was stirred for 18 h at room temperature. The reaction mixture was then diluted with 10% aqueous HCl, after which it was further diluted with water and then was extracted with ether. The aqueous layer was podslushivaet with ammonium hydroxide and was extracted with a mixture of chloroform and isopropyl alcohol (3:1). The organic layers were combined, suemori on a silica column instant chromatography. The column was suirable with methylene chloride containing 5% methanol and a trace of ammonium hydroxide. The eluate is evaporated in vacuum, obtaining 0.35 g of the target compound as a yellow glass.

NMR (l3): 7,2-6.42 per (m , 3H), 3,76 (C., 3H), 3,6-3,2 (m, 1H), 3.04 from-to 2.40 (m , 13H), a 2.0 of 1.40 (m, 1H), 1,28-1,16 (D., j = 7), 1,13-1,00 (D., j = 7).

P R I m e R 14. Getting dichlorhydrate 2-piperazinil-6-chloro-1,2,3,4-tetrahydro-naphthalene.

A mixture of 6-chloro-2-tetralone (5,41 g), piperazine (5,16 g) and 4A molecular sieves (8 g) in 100 ml dry toluene: was heated under reflux with stirring for a short period of time in an atmosphere of nitrogen. The toluene is evaporated and to the residue was added 100 ml THF and 10 ml of methanol. Added cyanoborohydride sodium (1.86 g), the solution was stirred in the cold under nitrogen atmosphere and portions periodically over the surface of the added gaseous HCl until then, while the reaction solution remained acidic. After stirring at room temperature overnight, the sieve was filtered, and the filtrate evaporated to dryness. The residue was distributed between 1 N. HCl and simple ether; the aqueous phase was separated and was extracted twice with ether. The solution was podslushivaet sodium hydroxide. The oil which formed was extracted into solids in ethanol was treated with an excess of gaseous HCl. After cooling for a certain period of time, the crystals which separated, was filtered and washed with ethanol. After recrystallization from methanol has received 2.64 g of target compound; so pl. 264-265aboutC.

C14H21Cl3N2.

Calculated,%: 51,95; N Is 6.54; N 8,65.

Found,%: C 52,17; N 6,60; N 8,71.

P R I m e R 15. Getting dichlorhydrate 2-piperazinil-6-bromo-1,2,3,4-tetrahydro-naphthalene.

Using the method described in example 14, the target compound were prepared from 6-bromo-2-tetralone; etc., 258-260aboutC (ethanol).

C14H21BrCl2N2.

Calculated,%: C 45,68; N. Of 5.75; N To 7.61.

Found,%: C 45,65; N 6,01; N A 7.85.

P R I m e R 16. Getting dichlorhydrate 2-piperazinil-6-fluoro-1,2,3,4-tetrahydro-naphthalene.

Using the method described in example 14, using molecular sieves 3A instead 4A, to prepare the target compound 6-fluoro-2-tetralone; so pl. 243-245aboutC (ethanol).

C14H21Cl2FN2.

Calculated,%: C 54,73; N 6,89; N 9,12.

Found,%: C 54,48; N 6,62; N Which 9.22.

P R I m e R 17. Getting dichlorhydrate 2-piperazinil-6-methyl-1,2,3,4-tetrahydro - naphthalene.

aboutC (methanol).

C15H23Cl2N2.

Calculated,%: 59,41; N 7,98; N 9,24.

Found,%: C 59,61; N 7,87; N 8,99.

P R I m e R 18. Getting dichlorhydrate 2-piperazinyl-6-methoxy-1,2,3,4-Tetra - gerenation.

Basically using the method described in example 14, the target compound was obtained from 6-methoxy-2-tetralone; so pl. 264-266aboutC (methanol).

C15H24Cl2N2O.

Calculated,%: 56,43; N 7,58; N 8,77.

Found,%: C 56.26 Vertical; N 7,42; N 8,50.

P R I m e R 19. Getting dichlorhydrate 2-piperazinil-6,7-dichloro-1,2,3,4-Tetra - gerenation.

A mixture of 6,7-dichloro-2-tetralone (4,30 g), piperazine (3,44 g) and molecular sieves 4A (4G) in 100 ml of toluene was stirred over night under nitrogen atmosphere and stirred briefly. Sieves was filtered, and the filtrate is freed from solvent on the evaporator. To the residue was added 75 ml of THF and 6 ml of methanol. The solution was cooled in an ice bath under nitrogen atmosphere, was added 1.24 g of cyanoborohydride sodium. Periodically added small amounts of gaseous HCl until then, until the solution remained acidic. The solution was stirred over night at a temperature surrounding the portions of ether, and then podslushivaet sodium hydroxide. The oil which separated was extracted with ether, and the ether solution was dried with sodium sulfate. The residue remaining after evaporation of the ether, was dissolved in ethanol, and added an excess of anhydrous HCl. The crystalline solid is separated from ethanol, melted at about 272-275aboutC. After recrystallization from ethanol was obtained 1.1 g of target compound; so pl. 278-282aboutC.

C14H20Cl4N2.

Calculated,%: C 46,95; N 5,63; N 7,84.

Found,%: C 47,22; N 5,54; N 7,74.

P R I m e R 20. Getting dichlorhydrate 2-(N-methylpiperazine)-6-bromo-1,2,3,4-tet - raidernation.

A mixture of 6-bromo-2-tetralone (4,50 g) N-methylpiperazine (4.0 g) and potassium carbonate (55,52 g) in 75 ml THF was stirred for about 1 h, the Solids were filtered and to the filtrate was added cyanoborohydride sodium (1.24 g). To stir the solution at room temperature was added in portions sufficient amount of ethereal HCl to acidify the solution. When NMR analysis of a sample of the reaction solution showed the absence of the vinyl proton of the intermediate enamine, the solvents were evaporated. The residue was distributed between ether and 1 N. HCl is ovale in a simple ether and ethyl acetate. The extracts were dried with sodium sulfate. The solvents are evaporated, and the residual base material in ethanol was treated with excess hydrochloric acid. Turned out to 4.41 g of the target compound, so pl. 270-272aboutC (decomp.).

C15H23N2BrCl2.

Calculated,%: C 47,14; N 6,07; N 7,33.

Found,%: C 46,99; N 5,95; N 7,54.

P R I m e R 21. Getting dichlorhydrate 2-(N-methylpiperazine)-6-chloro-1,2,3,4-tet - raidernation.

When used in the method, in General, described in example 20 6-chloro-2-tetralone instead of 6-bromo-2-tetralone, received the target connection; so pl. 269-271aboutC (ethanol).

C15H23N2Cl3.

Calculated,%: 53,35; N 6,86; N 8,29.

Found,%: C 53,11; N. Of 6.68; N 8,23.

P R I m e R 22. Getting dichlorhydrate CIS-1-methyl-2-piperazinil-6-chloro-1,2,3,4-tetrahydronaphthalene.

A solution of 13.7 g of 6-chloro-2-tetralone and 12.7 ml of pyrrolidine in 250 ml of dry benzene was heated under reflux using traps for water Dean-stark for 17 hours, the Benzene and excess pyrrolidine was removed on a rotary evaporator. To the residue was added dry toluene and then evaporated leaving a crystalline residue.

NMR (l3): 1,9 (m, 4H), dioxane, added 24 ml of methyliodide and the solution was heated under reflux for about 3.5 hours Approximately 0.5 h began to separate crystalline solid. A solution containing 1 ml of acetic acid in 50 ml of water was added to the reaction mixture and the whole mixture was heated under reflux for about 3.5 hours, the Solvent evaporated, and the residue was distributed between water and ether. The ether phase was separated, was extracted with a small amount of diluted hydrochloric acid and dried. Removal of solvent gave approximately 12 g of oil. Preparative HPZ C gave 9.3 g of 6-chloro-1-methyl-2-tetralone.

NMR (l3): 1,48 (D. , 3H), 2,28-to 2.67 (m, 2H), 2,78-3,2 (m, 2H), 3.25 to to 3.73 (m, 1H), 7,0-7,35 (m, 3H).

To 15 ml of 4A molecular sieves in 250 ml of dry tololo was added piperazine (6,37 g) and 6-chloro-1-methyl-2-tetralone (8.6 g). When using traps for water Dean-stark mixture was stirred and heated at boiling under reflux in a nitrogen atmosphere. After 23 h NMR analysis of a sample of the reaction solution showed the presence of tetralone. Added 500 mg of p-toluenesulfonic acid and the mixture was stirred and heated under reflux for an additional 26 hours was Added an additional 10 g of 4A sieves, and heating the C filtrate. The residue was dissolved in a mixture of 200 ml of THF and 20 ml of methanol. To the resulting solution stirred under nitrogen atmosphere while cooling in an ice bath, was added cyanoborohydride sodium (2,68 g). To the solution was added gaseous HCl portions until then, until the solution remained acidic. After stirring over night at room temperature the solvents were removed on a rotary evaporator, and the residue was distributed between ether and dilute hydrochloric acid. The acidic solution was separated and podslushivaet in the cold with sodium hydroxide. The oil which separated was extracted with ether and the ether solution was dried with magnesium sulfate. Removal of the ether gave 8.1 g butter. The oil was combined with 1 g of the product from the previous reaction conducted on a small scale. A solution of the product in ethanol was treated with excess gaseous hydrogen chloride. The crystals which separated, was filtered and was degidrirovanie on the steam bath with 100 ml of methanol. Several charges of crystals obtained from methanol, were combined and recrystallized from ethanol, yielding 6.3 g of the target compound. When drying at 120aboutWith the vacuum dichlorhydrate lost one mole of hydrogen chloride and gave the following:

C15
NMR (l3): 1,14 (D., j = 7, 3H), and 1.63 (m, j = 6,4, 12, 1H), 2.06 to (m , j = 3, 1, 1H), and 2.14 (broad m, 1H), 2,36 (m, j = 3, 4,4, 12, 1H), 2,48 of 2.68 (m , 4H), to 2.75 (m, 1H), 2,85 (m, 1H), 2,93 (t, j = 5,2, 4H), 3.14 (m, j = 7, 4.4, 1.1 km N), 6,97 for 7.12 (m, 3H).

After standing in a humid atmosphere for 60 h sample dichlorhydrate gave dehydrate dichlorhydrate; so pl. 244-246aboutC.

C15H27N2O2Cl3.

Calculated,%: C 48,21; N 7,28; N 7,50.

Found,%: C 48,30; N 7,05; N 7,35.

The free amine was obtained from () racemic crystal dichlorhydrate (32,7 g) with water, ether and 40 ml of 5 n sodium hydroxide. The basic aqueous portion was extracted three times with ether. The combined ether extracts were washed twice with water and once with saturated sodium chloride solution. The ether solution was dried over magnesium sulfate and evaporated, getting 24.8 g of the free amine.

A. Obtaining (+) CIS-1-methyl-2-piperazinil-6-chloro-1,2,3,4-tetrahydronaphthalene, salts of (-) di-p-toluene-L-tartaric acid (2:1).

(-) Di-p-toluene-L-tartaric acid (18,9 g) dissolved in 42 ml of methanol, was added to the free amine (24.8 g) in 100 ml of methanol under stirring. The residue was rubbed ten times with hot methane is P CLASS="ptx2">

The free amine was obtained from salt (21.1 g) with ether, water and 10 ml of 5 n sodium hydroxide. The combined ether extracts were washed four times with water and once with saturated sodium chloride. The ether solution was dried over magnesium sulfate, filtered and evaporated, receiving, 11,3

(-) Di-p-toluene-L-tartaric acid (8,64 g) dissolved in 60 ml of methanol, was added to the amine (11.3 g) in 1400 ml of methanol. The mixture was heated in a short period of time on the steam bath and left to stand at room temperature. The precipitate was filtered and washed with methanol, and then a simple ether, and dried in vacuum, obtaining of 19.2 g of salt (-) di-p-toluene)-L-tartaric acid; so pl. 250-251aboutC.

C50H60N4O8Cl2.

Calculated,%: C 65,57; N 6,60; N 6,12.

Found,%: C 65,61; N 6,50; N 6,15.

C. Obtaining (+) CIS-1-methyl-2-piperazinil-6-chloro-1,2,3,4-tetrahydronaphthalene, D(-)-winnability salt (1:1).

D(-)-tartaric acid (5,78 g), dissolved in 100 ml of methanol, was added to the free amine obtained from part a dissolved in 450 ml of methanol. The precipitate, which rapidly formed was left to stand overnight at room temperature. It was filtered and washed with methanol-tartaric acid was recrystallized by dissolving it in 4.5 l of methanol, containing 50 ml of water, while heating under reflux, after which the solution was concentrated to 2.5 liters

After standing over night at room temperature the precipitate was filtered and washed with methanol, and then a simple ether. After drying was obtained 11.3 g of the salt of D(-)-tartaric acid; so pl. 208-209aboutC.

C19H27N2O6Cl.

Calculated,%: 55,01; N 6,56; N 6,75.

Found,%: C 55,12; N. Of 6.71; N 6,68.

Specific rotation in DMSO at 25aboutWITH:

589 nm + 48,04 degrees,

365 nm + 176,94 degrees.

C. Dehydrate dichlorhydrate (+) CIS-1-methyl-2-piperazinil-6-chloro-1,2,3,4-Tetra - gerenation.

Free base were prepared from D - (-)-winnability salt using 50 ml of 1 n sodium hydroxide and ether. The ether extracts were washed two times with 25 ml of 1 n sodium hydroxide. These water-alkaline extracts were extracted three times with ether. The combined ether extracts were washed twice with water and once with saturated sodium chloride solution. The ether solution was dried over sodium sulfate, filtered and evaporated.

Diclorhidrato salt is prepared by adding a methanolic solution of hydrogen chloride to free the ptx2">

Specific rotation in water at 25aboutWITH:

589 nm + 47,72 degrees,

365 nm + 175,84 degrees.

Sample diclorhidrato salt was hydrational in a humid atmosphere for 40 h and received dehydrate dichlorhydrate; so pl. 225-230aboutC.

C15H27N2O2Cl3.

Calculated,%: C 48,21; N 7,28; N 7,50.

Found,%: C 48,17; N 7,01; N 7,58.

Specific rotation in water at 25aboutWITH:

589 nm + 45,83 degrees,

365 nm + 169,64 degrees

D. (-)CIS-1-Methyl-2-piperazinil-6-chloro-1,2,3,4-tetrahydronaphthalen, (+) di-p-toluene-D-minociclina salt (2:1).

The combined filtrates from rubbing (+)CIS-1-methyl-2-piperazinil-6-chloro-1,2,3,4-tetrahydronaphthalene, salts of (-)di-p-toluoyl-tartaric acid (2:1) were combined and converted into the free amine (11,8 g) using a mixture of air, water and sodium hydroxide.

(+)Di-p-toluoyl-D-tartaric acid (9.0 g), dissolved in 60 ml of methanol, was added to the amine in 1500 ml of methanol. The mixture was heated for a short period of time on the steam bath and left to stand at room temperature over night.

The precipitate was filtered and washed with methanol and then ether. After drying in vacuum was received of 23.5 g of salt (+)di-p

Calculated,%: C 65,57; N 6,60; N 6,12.

Found,%: C 65,41; N 6,41; N 6,12.

That is, (- ) CIS-1-Methyl-2-piperazinil-6-chloro-1,2,3,4-tetrahydronaphthalen, salt of L (+)-tartaric acid (1:1).

The free amine were prepared from this salt (23,5 g) ether and 1 N. sodium hydroxide. Water-alkaline portion was extracted three times with additional quantities of ether. The combined ether extracts were washed three times with water and once with saturated sodium chloride solution. The ether solution was dried over sodium sulfate, filtered and evaporated, receiving 9.7 g of the free amine.

L(+)-Tartaric acid (5.53 g), dissolved in 100 ml of methanol, was added to the free amine in 500 ml of methanol. The precipitate, which was formed after the addition of an acid, left to stand at room temperature over night. The precipitate was filtered and washed with methanol and then ether. After drying, the air got to 14.4 g of the salt of L(+)-tartaric acid; so pl. 204-206aboutC.

This salt was recrystallized by dissolving it in 4.5 l of methanol at reflux, after which the solution was concentrated to 2 liters, filtered and left to stand at room temperature over night.

The floor of the salt.

C19H27N2O6Cl.

Calculated,%: 55,01; N 6,56; N 6,75.

Found,%: C 55,18; N 6,79; N 6,76.

Specific rotation in DMSO at 25aboutFrom: 589 nm - 45,57 degrees,

365 nm - 169,75 degrees

F. Dehydrate dichlorhydrate (-)CIS-1-methyl-2-piperazinil-6-chloro-1,2,3,4-Tetra - gerenation.

The free amine product of the partition E (11.1 g) were prepared by processing the 55 ml of 1 n sodium hydroxide and ether. The ether extract was washed two times with 25 ml of 1 n sodium hydroxide. The combined ether extracts were washed twice with 25 ml water and once with saturated sodium chloride solution. The ether solution was dried over sodium sulfate, filtered and evaporated.

Diclorhidrato Sol was obtained by adding methanolic hydrogen chloride to the free amine in methanol. The resulting precipitate was filtered and washed with methanol, obtaining 7.5 g; so pl. 216-218aboutC.

Specific rotation in water at 25aboutWITH:

589 nm - 44,73 degrees.

365 nm - 166,11 degrees.

Sample diclorhidrato salt was hydrational to dehydrate, leaving her to stand in a humid atmosphere for 40 h, and was obtained 7.5 g; so pl. 230-235aboutC.

C15H27N2aboutWITH:

589 nm - 45,69 degrees.

365 nm - 167,63 degrees.

P R I m e R 23. Getting dichlorhydrate 1-methyl-2-piperazinil-1,2,3,4-tetrahydro - naphthalene.

Using 1-methyl-2-tetralone and piperazine in the same way as described in example 22, had been the target connection; so pl. 227-230aboutC (ethanol).

C15H24N2Cl2.

Calculated,%: 59,41; N 7,98; N 9,24.

Found,%: 59,37; N 7,73; N 9,52.

P R I m e R 24. Getting dichlorhydrate 1-methyl-2-(N-methylpiperazine)-1,2,3,4-tet-raidernation.

A solution of 1-methyl-2-tetralone (5.0 g) and N-methylpiperazine (6.25 g) in 140 ml of toluene was stirred and heated under reflux in nitrogen atmosphere with the use of traps Dean-stark for azeotropic removal of water. After 60 h, the toluene is evaporated, and the residue was dissolved in 90 ml of THF and 9 ml of methanol. The solution was cooled with stirring in an atmosphere of nitrogen, was added 2 g of cyanoborohydride sodium and periodically portions as needed added gaseous HCl until then, until the solution became acidic. Processing, selection and processing of crude basic product dry HCl as described in example 22, gave the target compound, so pl. 262-265aboutWith (once Found,%: C 60,84; N 8,10; N 8,96.

P R I m e R 25. Getting dichlorhydrate 2-homopiperazin-6-chloro-1,2,3,4-Tetra - gerenation.

To a solution of 6-chloro-2-tetralone (7,22 g) and homopiperazine (8.0 g) in 100 ml of toluene was added 10 g of 3A molecular sieves. The mixture was heated on the steam bath for 2 h, the sieves were filtered off and the toluene is evaporated from the filtrate. The residue was dissolved in a mixture of 100 ml of THF and 30 ml of methanol. The resulting solution was cooled in an ice bath under stirring in nitrogen atmosphere, was added of 2.51 g of cyanoborohydride sodium, and with stirring and cooling portions are periodically added gaseous hydrogen chloride until then, until the solution became acidic. After stirring over night at room temperature, the solvents evaporated and the residue was distributed between dilute hydrochloric acid and ether. The acidic aqueous layer was separated and was podslushivaet sodium hydroxide. The oil which formed was extracted with ether. The ether solution was dried with magnesium sulfate, and the ether was evaporated. The residue was dissolved in ethanol and to the solution was added an excess of gaseous HCl. The solvent is evaporated. The residue was led slowly from a mixture of ethanol and ether and received 3,22 g target LASS="ptx2">

Found,%: C 53,40; N 7,12; N 8,49.

P R I m e R 26. Getting dichlorhydrate 1-methyl-2-piperazinil-6-bromo-1,2,3,4-tet - raidernation.

4 g of 1-methyl-6-bromo-1,2,3,4-tetrahydronaphthalen-2-it 2,89 g of piperazine were heated at the boil under reflux over night in 100 ml of toluene containing 5 g of 4A molecular sieves and 50 mg p-toluenesulfonic acid. The reaction mixture was filtered and the filtrate evaporated. To the residue was added cyanoborohydride sodium (1,05 g), 100 ml of THF and 10 ml of methanol. Periodically to the solution under stirring was added gaseous HCl at a temperature of the ice bath until then, until the solution became acidic.

This reaction mixture was stirred at room temperature overnight and evaporated. The residue was extracted with ether and water. Acid-water part was podslushivaet on cold sodium hydroxide and was extracted with ether. The ether extract was dried over magnesium sulfate, filtered and evaporated, giving an oil. Diclorhidrato Sol was obtained by adding gaseous HCl to the free base in ethanol in the cold. Recrystallization diclorhidrato salt from methanol gave 0.45 g of target compound, so pl. 243-245aboutC.

C15H23it was mentioned above, the compounds of this invention are useful for selectively inhibiting the uptake of serotonin. Therefore, another embodiment of the present invention is a method of inhibiting the uptake of serotonin in mammals which comprises the administration to a mammal requiring increased neurotransmission of serotonin, a pharmaceutically effective amount of the compounds of this invention.

The term "pharmaceutically effective amount", as used here, represents the number of compounds of the invention, which is able to inhibit consumption (absorption) of serotonin. Specific dose assigned to receive connections, according to this invention, will depend of course the specific circumstances of the specific case, including, for example, entered the compound, route of administration and the condition being treated. A typical daily dose usually contains about 0.01 to 20 mg/kg of active compound of the present invention. Preferred daily doses generally be approximately 0.05-10 mg/kg, and ideally about 0.1-5 mg/kg

The compounds can be administered using a variety of methods, including oral, rectal, transdermal (through to the gain is they have a long term and therefore is able to inhibit the consumption of serotonin within an extended period of time. Also characteristic of the compounds of the present invention is the fact (as was found), they display a low degree of toxicity towards mammals. Finally, the compounds of the invention are extremely selective as inhibitors of the uptake of serotonin in relation to the absorption of other monoamines.

It was shown that a large variety of physiological functions affected serotonergically neural systems of the brain. Believe that as such, the compounds of this invention have the ability to treat a variety of disorders in mammals associated with these neural systems, such as disorder, depression, alcoholism, pain, memory loss, anxiety and Smoking. Therefore, the present invention also provides methods of treating the above disorders at doses above for inhibiting the uptake of serotonin in mammals.

The following experiment was conducted to demonstrate the ability of compounds of the present invention to inhibit the will"ptx2">

Male rats Sprague-Dawley (110-150 g) from Harlan industries Cumberland, 1N) was fed to satiety "Purina Chow" for at least 3 days before they were used in the studies. Rats were killed by decapitation. The brain of all animals were removed and was cut off (opened). The cerebral cortex homogenized in 9 volumes of medium containing of 0.32 M sucrose and 10 mm glucose. After differential centrifugation at 1000 g for 10 min and 17000 g for 28 min separated the crude synaptosomal preparations. The final tablets suspended in the same medium and kept in ice until such time as they will be used on the same day.

Synaptosomal uptake of 3N-serotone (3N-5-hydroxytryptamine,3N-NT) was determined as follows. Cortical synaptosome (equivalent to 1 mg of protein) were incubated at 37aboutC for 5 min in 1 ml Krebs-bicarbonate medium containing also 10 mm glucose, 0.1 iproniazida, 1 mm ascorbic acid, 0.17 mm, EDTA and 50 nm3N-NT. The reaction mixture was immediately diluted with 2 ml ice Krebsbachgnath buffer and filtered under vacuum using a collection of cells (Brandel, Gaithersburg, MD). Filters were rinsed tag, containing 10 ml scintillation fluid (PCS, Aruersham. Qrbington Heights, IL). Radioactivity was measured using liquid scintillation spectrophotometer. The accumulation of3N-NT at 4aboutWith presents the background and was subtracted from all samples.

Repeating the experiment described above for compounds of similar structure, the received data activity for comparison with the activity of the compounds of the present invention (see tab. 1 and 2).

A distinctive feature of the products of the claimed method is the presence of 2-provisions of tetralin. Unlike conventional structural analogues containing 2-position mono - or dialkylamino group or dipiperidino cyclic amino group, the products of the method according to the invention are much more superior activity by inhibition of the absorption of serotonin, as evidenced by the data presented in the table. 1 evaluation results of the various compounds of the present invention. In table. 1 in the first column indicate the number of the example of the evaluated compounds; the following 7 columns indicate the structure of the evaluated compounds in combination with the formula presented in the header; in the penultimate column shows the salt form is evaluated with the tion, required for inhibiting the uptake of3N-NT 50%, and are shown in table. 1 in the form of values IC50. The number in parentheses, if specified, are the inhibition percentage at 1000 nm.

The compounds of this invention are converted into finished preparative form including a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient it.

The compositions are preferably formulated in dosage unit form, each dosage typically contains about 0.1-500 mg, and preferably about 1-250 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as single doses to humans and other mammals, each unit contains a defined quantity of active material calculated to provide the desired therapeutic effect, in combination with a suitable pharmaceutical carrier.

The following examples of finished products are only illustrative and in no way are intended to limit the scope of the invention.

The finished product 1.

Hard gelatin capsules are prepared with setil-2-Pipera-

sinil-6-chloro-1,2,3,4-tet - raidernation 250 Starch, dried 200 magnesium Stearate 10 Total: 460

The above ingredients are mixed and filled into hard gelatin capsules in the amount of 460 mg.

The finished product 2.

The tablet is prepared using the following ingredients:

Quantity (mg/tablet

Dichlorhydrate

CIS-1-methyl-2-Pipa-

retinyl-1,2,3,4-tet - raidernation 250

Cellulose, micro - crystalline 400

Silicon dioxide, smoke 10 Stearic acid 5 Total 665

The components are mixed and pressed to form tablets each weighing 665 mg

The finished products 3.

Aerosol solution is prepared with the following content, wt.%:

Dichlorhydrate

2-piperazinil-6-

chloro-1,2,3,4-Tetra - gerenation 0.25 Ethanol 29,75

Propellant 22 (Chlorodifluoromethane) 70,00

The active compound is mixed with ethanol and the mixture added to a portion of propellant 22, cooled to -30aboutWith, and transferred to a filling device. Then in a stainless steel container serves the required number and diluted with the remainder of propellant. Then the container is supplied with the valve element.

the ith follows:

Demolet 2-(N-methyl-

piperazinil)-8-chloro-

1,2,3,4-tetrahydro - naphthalene 60 mg Starch 45 mg

Microcrystalline cellulose 35 mg

Polyvinylpyrrolidone

(as 10% solution in water) 4 mg

Sodium carboxy - methyl starch 4.5 mg magnesium Stearate 0.5 mg Talc 1 mg Total 150 mg

The active ingredient, starch and cellulose are passed through sieve No. 45 mesh U.S. and thoroughly mix. An aqueous solution containing polyvinylpyrrolidone, mixed with the resultant powder and the mixture is then passed through a sieve U.S. No. 14 mesh. The granules thus obtained, dried at 50aboutWith and pass through a sieve U.S. No. 18 mesh. Sodium carboxymethyl-starch, magnesium stearate and talc, previously passed through sieve # 60 mesh U.S., then added to the granules which, after mixing pressed on teletrauma car, giving tablets each weighing 150 mg

The finished preparation 5.

Capsules, each containing 80 mg of the active ingredient, are made as follows:

Dichlorhydrate 2-Pipa-

retinyl-5-bromo-8-methoxy-

1,2,3,4-tetrahydro - naphthalene 80 mg Starch 59 mg

Microcrystal - symbolic cellulose 59 mg magnesium Stearate 2 mg Total 200 mg

The active ingredient, the new capsule in the amount of 200 mg.

The finished preparation 6.

Medical candles or suppositories, each containing 225 mg of active ingredient are made as follows:

hydrate dichlorhydrate 2-

(N-methylpiperazine)-5-

formyl-8-methoxy-

1,2,3,4-tetrahydro - naphthalene 225 mg

Glycerides of saturated fatty acid 2000 mg Total 2225 mg

The active ingredient is passed through sieve # 60 mesh U.S. and suspended in the glycerides of saturated fatty acids, previously melted using the minimum heat needed. The mixture is then poured into the form to spark a nominal capacity of 2 g and allowed to cool.

The finished drug 7.

Suspensions, each containing 50 mg of active ingredient per dose in 5 ml, prepared as follows:

Dichlorhydrate 2-

(N-methylpiperazine)-5-

cyano-8-methoxy-

1,2,3,4-tetrahydro - naphthalene 50 mg

Sodium carboxy - methyl cellulose 50 mg Syrup 1.25 ml

A solution of benzoic acid 0.10 ml of Corrigent optional Dye On request

Purified water to total amount 5 ml

The active ingredient is passed through a sieve No. 45 mesh U.S. and is mixed with the sodium carboxymethyl cellulose and syrup to form a homogeneous pavani. Then add sufficient water to obtain the desired volume.

The finished preparation 8.

Ready intravenous drug can be obtained in the following way:

Dichlorhydrate 2-(N-methyl-

piperazinil)-8-methoxy-

1,2,3,4-tetrahydro - naphthalene 100 mg

Isotonic, physiological - ecological solution 1000 ml

The solution of the above ingredients is usually administered intravenously at a rate of 1 ml/min to a subject suffering from depression.

The method of obtaining derivatives of 1,2,3,4-tetrahydronaphthalene General formula

< / BR>
where R is hydrogen or methyl;

R1is hydrogen or methyl;

X is a group-CH2CH2or-CH2CH2CH2-;

R2is hydrogen, halogen, C1- C3-alkoxy and C1- C3-alkyl;

R3is hydrogen or halogen;

R4is hydrogen, halogen, C1- C3-alkyl and C1- C3-alkoxy;

R5is hydrogen, C1- C3-alkyl and C1- C3-alkoxy, provided that when R1is methyl, R2and R4at the same time can be hydrogen if R1is hydrogen, one of R2and R4is hydrogen and the other is other than hydrogen;

R5may not be in the od;

or their pharmaceutically acceptable acid salt additive, characterized in that the compound of General formula

< / BR>
where R1- R5have the specified values,

subjected to interaction with the compound of General formula

< / BR>
where R has the above meaning,

and restore the resulting product.

 

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1 tbl, 1 ex

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