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    • 专利摘要:
    Novel cis-isomeric derivatives of 4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine of the formula: wherein R is hydrogen or normal alkyl or from 1 to 3 carbon atoms, R2 is normal alkyl of from 1 to 3 carbon atoms, Z is phenyl substituted by X and Y where X and Y are each hydrogen, fluoro, chloro, bromo, trifluoromethyl, alkoxy of from 1 to 3 carbon atoms or cyano, with at least one of X and Y being other than hydrogen, and W is hydrogen, fluoro, chloro, bromo, trifluoromethyl or alkoxy of from 1 to 3 carbon atoms, and the pharmaceutically acceptable acid addition salts and pharmaceutical compositions thereof are useful as antidepressant agents. These compounds act to block the synaptosomal uptake of serotonin (5-hydroxy-tryptamine), thereby alleviating serotonin abnormalities at central receptor sites.
    公开号:SU1014467A3
    申请号:SU802999197
    申请日:1980-10-28
    公开日:1983-04-23
    发明作者:Маккован Виллард；Армон Харберт Чарльз；Кеннет Кое Билли；Ричард Краска Аллен
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of new derivatives of cis-4nyl-1, 2,3, -tetrahydro-1-naphthyls of the general formula KRiRc TC KS where R is hydrogen or C, -nR is C -C-n-alkyl; R is a hydrogen atom, chlorine or C —C-alkoxy; R, and R.  - atoms of hydrogen, fluorine, chlorine, bromine or trifluoromethyl groups, and at the same time RiHRg-He are atoms of hydrogen or their salts.  The compounds produced by this method have antidepressant properties.  Some 4-phenyl-1, 2,3, -tetrahydro-1-cha tylamine derivatives are known, for example cis-1-phenyl-1, 2,3, -1-tetrahydro-1-on thylamine hydrochloride show a pronounced antidepressant effect 1.  The known reaction of the reductive amination of ketones, which consists in the interaction of ketones with primary or secondary amides, in the presence of an acid catalyst, followed by reduction of the intermediate with sodium borohydride G2.  The aim of the invention is to expand the means of raising a living organism.  This goal is achieved by the described method for the preparation of cis- | -phenyl-1,2,3, -tetra-1-naphthylamine derivatives of general formula I, where R ,.  Rj.     5 have the indicated values, or their salts, which is based on the known reductive amination reaction of ke467 tones and consists in the fact that the compound of the general formula </ BR> where Ry, A. and R has the indicated meanings, is treated with a general amine: formulas.  (Ill) where RX (and R have the indicated meanings in the presence of an acidic catalyst, such as titanium tetrachloride, followed by reduction of the resulting intermediate with sodium borohydride and isolation of the desired product in free form or as a salt.  Example.  cis- / 1S // 1R / - J-Methyl- - (3, -dichlorophenyl) -1, 2,3, -tetrahydro-1-naphthylamine hydrochloride.  L) 3. Lichlorobenzophenone, Anhydrous AlClj (219 g, 1.64 mol added in portions over the course of a minute to a stirred solution of 3, dichloro-benzoyl chloride (313.5 g, 1.50 mol) in a mixture of benzene (1.125 l) and dichloromethane (75 ml while maintaining the temperature of the mixture at the level C during the addition.  The reaction mixture is kept for another 1 hour, then poured into 2.5 liters of ice mixed with water and stirred until the complex is decomposed, then the organic and aqueous layers are separated and the organic layer is combined with organic phase after the first washing of the aqueous layer with ethyl acetate.  The resulting organic layer is washed twice with water and once with saturated brine, dried over anhydrous MgSO4, decolorized with activated charcoal and evaporated in vacuo.  The residue is recrystallized from tOO ml of a hot ethyl acetate-pentane mixture.  Obtain 156.8 g of the desired product, yield, t. square  100-102 seconds  Elemental analysis.  Found,%: C b2,17; H 3.6; C1 28.06.  31 Calculated,%: C, 62.21; H 3.21; C1 28.25.  B) 3 Ethoxycarbonyl- - (3 dichlorophenyl) -4-phenylbut-3 enoic acid.  A solution of 3, -Dichlorobenzophenone (398 g, 1.58 mol) in tert-butyl alcohol is treated successively with potassium tert-butylate (1b9 g, 1.5 mol) and diethyl succinate (02 ml 2, t mol).  A slightly exothermic reaction takes place and the initially clear solution solidifies as solid mass.  The reaction mixture is slowly heated to reflux, and at this temperature the mixture becomes a white suspension, after which it is stirred at reflux in a nitrogen atmosphere for 16 hours.  Then the reaction mixture is cooled and poured into 2 liters of ice-water mixture.  The resulting mixture is acidified with 10% HC1 and Ext. Shave with ethyl acetate (3 times 1 p. The combined ethyl acetate extract is extracted with 1N.  The NECON (3 times 1 L) and the combined aqueous alkaline extract are washed with ethyl acetate (2 N is cooled until, slowly acidified to a pH below 1.0 with concentrated HCl and extracted with ethyl acetate (R 2 L).  The combined ethyl acetate extract was dried with anhydrous MgSO4 and evaporated in vacuo.  The desired product is obtained in the form of a light yellow oil, slightly contaminated with diethyl succinate (77 g, yield 80S;).  An analytical sample is crystallized from petroleum ether (t. square  128-130 C - Elemental analysis.  Found,%: C 60.37; H, 35; C1 18.61.  Calculated,%: C 60.17; H 4.26; C1 18.70.  B) (3 f-Dichlorophenyl) -phenylbut-3 enoic acid.  A suspension of 3-ethoxycarbonyl- - (3, -Dichlorophenyl) - | -phenylbut-3-enoic acid (227 g, 0.60 mol) in a mixture of aqueous HBg: ice on acetic acid (1: 1, 1.80 l) is stirred at reflux temperature for 36 hours and then cooled to room temperature.  A resinous substance was separated from the reaction mixture, which was separated by decanting the aqueous layer, and then dissolved in ethyl acetate (2 L).  The resulting organic solution was extracted with aqueous MnDON (2 X 2 L).  The combined extract is cooled to, slowly acidified to a pH below 1.0 with concentrated HCl and extracted with ethyl acetate (X 1 L).  The ethyl acetate extract is washed with water, dried () and evaporated in vacuo to a light brown oil (120 g), which is crystallized from hexane (91, g, yield 50, t. square  115-120 ° C).  An analytical sample of the title compound is crystallized from hot ethyl acetate-hexane.  Elemental analysis.  Found,%: C 62.56. ; N C, 02; C1, 23.22, Calculated, ° C: C, 62.58; And 3, C1 28.10.   (- (3, -Dichlorophenyl-4-phenylbutanoic acid.  A solution of k- (3, -dichlorophenyl) -phenyl by-3-enonic acid (223 g, 0.73 mol) in ethyl acetate (2 l) is hydrogenated over 8 g of catalyst (Pd / C) at atmospheric pressure and room temperature until the termination of selection hydrogen (about 2C h).  The catalyst is separated by filtration and the filtrate is evaporated in vacuo to light.  brown oil containing traces of solvent (yield about 100).  An analytical sample of the title compound is crystallized from hexane {t. square  118-120С).  Elemental analysis.  Found,%: C 62.08; H P, 5b; C1 23.16.  Calculated,%: 62,17; H 4.57; C1 22.94.  E) 4- (3,4-Dichlorophenyl) -3,4-dihydro-1- (2H) -naphthalenone.  A solution of 4- (3,4-dichlorophenyl) -4-phenylbutanoic acid (228 g, 0.74 mol) in toluene (1.2 l) is treated with thionyl chloride {66 ml, 0.90 mol).  The resulting solution is heated under reflux for 75 minutes, ensuring the capture of gaseous HC1 released from the boiling reaction solution.  The reaction solution is then evaporated in vacuo to give 230 g of a light brown oil.  The oil was dissolved in carbon disulphide (MnO ml) and the resulting solution was added to a well stirred suspension of AlCl (1.5 kg, 12.5 mol) in carbon disulfide (1.20 L) while maintaining the addition temperature.  After the addition is complete, the reaction mixture is stirred for 16 hours at room temperature and then slowly poured onto ice (log reaction).  The resulting suspension is extracted with ethyl acetate (2 X 4 L), the extract is washed with water, saturated aqueous sodium bicarbonate solution, dried and evaporated under vacuum to a residue, which is crystallized from hexane (500 ml) to give the desired product (lOlJ g, yield, t. square  99 101C).  Elemental analysis.  Found, I: C 66.06; H A, 28.  Calculated,%: C, 66.00; H, 1b.  E) Target compound (cis-racemate).  Solution - (3, (-dichlorophenyl) -3, -dihydro-1- (2H) -naphthalenone (50 g, 0.17 mol) in tetrahydrofuran (800 m cooled to 0-5С and treated with 52 ml (1.20 mol ) methylamine (condensed at 0 ° C).  Tetrachloride titans (10 ml, 0.08 / mol) are added dropwise to the resulting solution (log reaction) at. stirring the reaction mixture at a temperature below during the period of addition. After the addition is complete, the reaction mixture is stirred for 17 hours at room temperature under a nitrogen atmosphere and then filtered.  The solid is washed thoroughly with tetrahydrofuran and the combined filtrates are concentrated in vacuo to 600 ml with removal of excess methylamine.  Further evaporation to dryness and trituration of the residue with hexane gives a Schiff base (t. square  145-146 ° C).  Schiff base containing concentrate is hydrogenated for 2 hours over catalyst () at atmospheric pressure and room temperature.  Hydrogen withdrawal is stopped after 2 hours of reaction.  After removing the catalyst by filtration, the reaction mixture is evaporated in vacuo.  The residue is dissolved in anhydrous diethyl ether (1 L).  The resulting solution is treated with gaseous hydrogen chloride to obtain a white precipitate.  This precipitate was combined with the product obtained in the second series of the experiment, starting from 0.15 mol of (3, -Dichlorophenyl) -3, -dihydro-1, holds about 70 cis-racemate and 30% trans-racemate H-methyl- - (3 , -dichlorophenyl) -1, 2,3, -tetrahydro-1-naphthylamine hydrochloride, dissolved in hot methanol (2 L).  After addition of diethyl ether (1200 ml) and cooling overnight, the desired compound precipitated (7 g, t. square  290-291 ° C).  The supernatant is evaporated in vacuo to a dry residue and the residue is triturated with acetone.  A triturated precipitate (about 9P | cis-racemate, 10 trans-racemate) is crystallized from methanol: ether (1: 1), another 20 g of the title compound are obtained (t. square  289-290s).  The total yield (b7 D-) of naphthalenone is 68.  Elemental analysis.  Found, I: C 59.79; H 5, iO; N it, 16; C1 30. 83  Calculated Z: C 59.53; H 5.29; N, 09; C1 31,  Example 2  cis- (15) -M-Methyl- - (3, -dichlorophenyl) -1,2,3, -tetrahydro-1-naphthylamine hydrochloride.  &amp; 7.1 g of cis- / 15 // 1K / -M-methyl- - (3, -dichlorophenyl) -1,2,3, tetrahydro-1-naphtylamine hydrochloride is distributed between 20% aqueous NaOH and ethyl acetate to obtain a solution of the free base cis racemate (60.2 g, 0.197 mol) in ethyl acetate.  This solution is dissolved in absolute ethanol (600 ml) and treated). - (-) - mandelic acid (29.9 h g, 0.197 mol).  The resulting mixture is heated on a steam bath to ensure dissolution, and then kept at room temperature overnight to obtain a white crystalline substance.  This substance is separated by filtration, washed with diethyl ether and air dried (38.7 g, t. square  188-189C) and then recrystallized from hot absolute ethanol (32.6 g, t. square 190ISI c).  Additional portion (, A g, t. square  190-191 ° C) is obtained by evaporation of the mother liquors in vacuo to a residue, followed by crystallization of the residue from boiling ethanol (150 ml).  The combined portion of the salt of almond acid is suspended in ethyl acetate (about 2 liters).  The ethyl acetate suspension is treated with a 10% aqueous solution of NaOH, thereby converting 71 amine to the free base.  The resulting ethyl acetate solution is dried, diluted with diethyl ether (2L), and then treated with excess gaseous hydrogen chloride to form a gel-like suspension, which crystallizes overnight.  The crystalline product (salt with HC1) is separated by filtration, washed with diethyl ether and dried in air (-5i96 g, yield,%, t. square  ), + 37.9 ° (. , C 2).  Elemental analysis Found,%: C 59.2; H 5, N 5, P5; C1 ZP, 8.  i Calculated,%: C 59.58; H 5.29; . N “, 09; C1 31,  .  Example 3  cis- (1H) -M-Methyl- - (3,1-dichlorophenyl) -1, 2, 3,4-tet hydro-1-naphtylamine hydrochloride.  According to the procedure of Example 2, the target compound is obtained using L - {+) - mandelic acid instead of B - (-) - mandelic acid as a selective precipitant (t. square   ), Co ". % -37.25 (methanol).  Elemental analysis.  Found,%: C 58.43; H 5.57; N 3.91.  Calculated,%: C 59.58; H 5.29; N it, 09.  Examples k-6.  cis-N-methyl- - (-chlorophenyl) -, 2,3, -tetrahydro-1-naphthylamine hydrochloride.  According to the procedure of Examples 1-3, the target compound is obtained from 4-chlorobenzophenone and its enantiomeric forms are separated.  The results are shown in Table.  one.  Example 7  cis / 15 // lRf-M-Me tyl- | - (-fluorophenyl) -1, 2,3,4-tetrahydro-1-naphthylamine hydrochloride.  l) 3 Ztoxycarbonyl- - (4-fluorophenyl) -4-phenylbut-3-enoic acid.  A solution of t-fluorobenzophenone (g, 0.21 mol) diethyl succinate, 6 g, 0.25 mol) and potassium tert-butylate 23.7 g, 0.21 mol) and tert-butanol (250 ml) is stirred at the boil with reverse refrigerator for 6 and then stirred at room temperature for 16 hours  The reaction mixture is then acidified with 6N.  hydrochloric acid (200 ml is evaporated in vacuo to remove tert-butanol and extracted with diethyl ether and X 250 ml).  The combined ether extract is extracted with 10% -n 78.  aqueous ammonium hydroxide (2 x X 350 ml).  The aqueous phase is washed with diethyl ether (2 X 200 ml}, re-acidified with 6N.  hydrochloric acid and re-extracted with ether (2 X 00 ml).  The ether extract is dried (. ), filtered and evaporated in vacuo to an oil, which is crystallized from hexone (100 ml).  Get kQ g of the target product, yield 70, so square  98-99s.  Elemental analysis.  Found, Z: C 69, H 5.36; F 6.09.  Calculated,%: C 69.50; H 5.22; F 5.78.  B) - (- Fluorophenyl) -phenylbut-3-enoic acid.  3-Ethoxycarbonyl-A- (t-fluorophenyl) - + - phenylbut-3-enoic acid (kj g, 0, mol) is added to a mixture of glacial acetic acid (1000 ml) and aqueous hydrobromic acid (500 ml) obtained the mixture is stirred at reflux for 1b h.  The reaction mixture is then concentrated in vacuo and the concentrate is extracted with diethyl ether (3 X 500 ml).  The ether extract is extracted with aqueous ammonium hydroxide (5 x 200 ml).  The aqueous layer is acidified with 6N.  hydrochloric acid to pH 6.5 and again extracted with diethyl ether (3.times x 250 ml).  The ethereal extract is dried (MHZOD), filtered, and evaporated in vacuo to an oil, which solidifies on standing.  Trituration with hexane gives 15 g of the desired product (yield, k7l, t. square  98-1OO C).  Elemental analysis.  Found, I: C 7.69; H 5, F 7,17.  Calculated,%: C 7.99; H 5.11; F 7, and.  c) (4-Fluorophenyl) -4-phenylbutanoic acid.  A solution of - (- fluorophenyl) - t-phenylbut-3-enoic acid (15 g, 0.068 mol) in ethanol (200 ml) is hydrogenated over 1.0 g of catalyst (10% Pd / C) for 2 hours at room temperature. Hydrogen temperature and pressure 3.52 kgf / cm.  The reaction mixture is then filtered and evaporated in vacuo to obtain a solid, which is recrystallized from a mixture of diethyl and petroleum ether (10.6 g, yield 70, t. square  75-75,).  Elemental analysis.  Found,%: C H 5.87; F 7J5.   Calculated,%: C H 5.85; F 7.36.  d) | - {1-Fluorophenyl) -alpha-tetralo / 4- ((-AtorLenyl) -4-phenylbutanoic acid (5 g, 0.019 mol, is treated with anhydrous hydrofluoric acid (20 ml) and the resulting mixture is stirred for 16 min at room temperature.  The reaction mixture is then diluted with water (100 ml) and extracted with diethyl ether (200 ml), the ether extract is washed with a saturated aqueous solution of sodium bicarbonate (50 ml), washed with water (50 ml), dried (MgSO4), filtered and evaporated in vacuum to obtain a solid which is recrystallized from boiling hexane (3.2 g, yield b9.  t. square  7 75С), Elemental analysis.  Found,%: C 80.00; „H 5.66.  Calculated,%: C 79.98; H 5.5.  D) Target compound (cis-racemate).  A solution of 4- (4-fluorophenyl) alfatetralone (3.0 g, 0.012 mol) in toluene (50 ml) is cooled to 10 ° C and treated at this temperature with methylamine (2.0 g, 0 mol) and then dropwise titanium tetrachloride reed (1.73 g, 0.009 mol) is added.  The reaction mixture is stirred for 16 hours at room temperature, filtered and evaporated in vacuo.  The crude 1-imine is dissolved in methanol (50 ml), the methanol solution is treated with sodium borohydride (1.0 g, 0.026 mol) and the mixture is stirred for 16 h.  at room temperature.  The reaction mixture is then evaporated in vacuo to an oily solid, which is dissolved in diethyl ether (200 ml).  The ether solution is washed with water (3 X 50 ml), dried (MriSO), filtered and evaporated in vacuo to an oil.  The oil is chromatographed on silica gel using ethyl acetate / hexane / diethylamine (16/16 / 0.3) for the elution to separate the cis and trans isomers.  The cis isomer is eluted first and treated with gaseous hydrogen chloride.  The hydrochloride is recrystallized from cm. Use methanol and ether to obtain 38P mg of the chain 710 compound (cis-racemlt, Aihop 1U, t. square  281-282С).  Elemental analysis.  Found,%: C b9.79; H 6.48; Nb78.  Calculated,%: S b9,98; H 6, N 4.80.  Examples 8-14.  In accordance with the procedures of Examples 2, 3 and 7, cis-isomeric compounds are obtained from the corresponding substituted benzophenones, in some cases divided into their enantiomeric forms given in Table.  2  The starting substituted benzophenones for Examples 3-14 were prepared as described for 4-trifluoromethylbenzophenone.  A) 4-Trifluoromethylbenzophenone.  A 2.91 M solution of phenyl magnesium bromide in diethyl ether (90 ml, 0.26 mol) is added dropwise over 45 minutes to a solution of 4-trifluoromethylbenzonitrile (40 g, 0.23 mol) in diethyl ether (400 ml), the resulting mixture is stirred for 3 days at room temperature, then cooled with ice, slowly treated with a saturated aqueous solution of ammonium chloride (150 ml) and then 1N.  HC1 (100 ml).  The ether layer is removed and the aqueous layer is extracted with diethyl ether (2 X 200 ml).  Three ether layers are combined, washed with 1N.  HCl (2 x 100 ml), washed with water (2 x 200 ml), dried (MgSO4), treated with activated carbon, filtered and evaporated in vacuo to obtain a solid, which is then crystallized from 200 ml of hot hexane (36 g , output 621, t. square  107-108c).  An analytical sample of the title compound was recrystallized from hexane (t. square  PB-PV C).  Example 15  cis- /. 15 // 1Я / -Y-methyl-4- (4-chlorophenyl) -7-chloro-1,2,3,4-tetrahydro-1-naphthylamine hydrochloride.  Analogously to Example 7 (A-B and D), the indicated compound (cis-racemate) is obtained from 4,4-dichlorobenz:) phenone (m. square  300-301 ° C).  Elemental analysis.  Found,%: C 59.64; H 5, P6; N 4.13.  Calculated,%: C 59.55; H 5.29; N 4.09.  Instead of stage G, G: p / g / 1 method is used.  nin g) (-chlorophenyl) -7-chloro-alfatetralon.  , -DI-C-chlorophenyl) -butanoic acid (3.5 g, 0.01113 mol) is treated with polyphosphoric acid (80 g) and the resulting mixture is treated for A h at 120 ° C.  The reaction mixture is then poured onto crushed ice and the product is extracted with diethyl ether (3 X 150 ml).  The combined ether extract was washed with a saturated aqueous solution of sodium bicarbonate (3 x 100 ml), washed with water (1 PO ml), dried (MgSO4), filtered and evaporated in vacuo.  Receive the specified tetraloi; (2.2 g), yield 1%, t. square  10b-1P7 ° C.  PRI and MER 16.  CIS- / 15 // thyl- (t-bromophenyl) -1, 2,3, i-tetrahydro-1-naphthylamine hydrochloride.  Analogously to examples 7 (A, B, and D) and 15 G, this compound is obtained from β-bromobenzophenone (m square 27).  Elemental analysis.  Found %: C 57, H 5.29; M.  Calculated,%: C 57. 89; H 5.3; N 3.97.  Instead of stage 7B using the following method.  c) 4- (4-Bromophenyl) -phenylbutanoic acid.  A solution of k- (4-bromophenyl) -i-Oenilbut-3 enoic acid (5.0 g, 0.0157 mol) in glacial acetic acid (50 ml) is treated with 5b, aqueous hydroiodic acid (22.5 ml) and red phosphorus, the receiving mixture is stirred at the boil under reflux for 16 hours  The reaction mixture is then cooled to room temperature, diluted with a saturated aqueous solution of sodium chloride (250 ml) and extracted with methylene chloride (250 ml. The extract is washed with a saturated aqueous solution of sodium chloride (2 x 100 ml), dried (MgSO4) and evaporated in vacuo.  The desired product is used in the next step without purification (5 g oil, about 99% yield).  Example 17  cis- / 15 // lR / -N-M thyl- - (4-methoxyphenyl) -1, 2,3, A-tetra hydro-1-naphtylamine hydrochloride.  A) 1 -Hydroxy-1- (4-methoxyphenyl) tetralin.  712 Glt t solution of f-bromoanisole (25 g, 0.13 mol) on tetrahydrofuran (100 ml).  Magnesium (3, g, 0.123 mol) is treated with a small portion of this solution and heated until the reaction (55c) begins.  The remaining solution is added dropwise and after the addition is complete, the mixture is stirred for 2 hours at.  After that, the reaction mixture is cooled to room temperature and a solution of 1-tetralone (17.92 g, 0.123 mol) in tetrahydrofuran (100 ml) is slowly added to it.  Stirring is continued at room temperature for 16 hours after the addition is complete.  Then, diethyl ether (200 ml) and water (200 ml) were added to the reaction mixture, followed by the addition of a 101% aqueous solution of ammonium chloride (100 ml).  The ether layer was separated, dried (MgSO4), filtered and evaporated in vacuo to give an oil, which was used without further purification in the next step (ll8 g, yield 581).  B) 1 - (-Methoxyphenyl) -3, 4-dihydronaphthalene.  A solution of 1-hydroxy-1 - (- methoxyphenyl) -tetralin (18 g, 0.071 mol) in toluene (250 ml) is treated with I-toluene sulfonic acid (5 mg) and the resulting solution is stirred. with reflux for 16 hours, until complete removal of water using a Dean-Stark trap.  The reaction mixture is then cooled to room temperature, washed successively with 1 /, - aqueous sodium bicarbonate solution (100 ml), water (100 ml), dried (MD &amp; P) and evaporated in vacuo to give an oil, which is purified by chromatography on silica gel ( elution with a gradient mixture of hexane-toluene).  12 g of the title compound are obtained (yield 67, oil).  c) 1 - (- Methoxyphenyl) -tetralin.  1 (14-Methoxyphenyl) -3, -dihydronaphthalene (12 g, 0.051 mol) was added to a mixture of catalyst (10 × FU on carbon, 1.0 g) and ethanol (250 ml) and hydrogenated for k hours at room temperature. temperature and pressure of hydrogen.  Then the reaction mixture is filtered and evaporated in vacuo to an oil, which is used in the next stage without further purification (11.2 g, yield 92.5-).  D) 4-Hydroxy-A- {4-methoxyphenyl) -1-tetralone.  1- (4-Methoxyphenyl) -tetrapin {11.2 g, O, O mol) pacTBOpfflOT in a solution of potassium permanganate (36.7 g in acetone (1.6 l) and water (33 ml) and the resulting mixture is stirred at boiling reflux for 16 h.  The reaction mixture is then filtered, again treated with potassium permanganate (36.7 g) and stirred at reflux for a further 16 hours.  This process is repeated until three cycles of reaction are performed. After the third 16-hour reaction period, the reaction mixture is filtered, treated with activated carbon, filtered and evaporated in vacuo to dryness.  The residue was dissolved in ethyl acetate (200 ml) and the ethyl acetate solution was washed with a saturated aqueous solution of sodium chloride (200 ml), filtered, washed again with a saturated aqueous solution of sodium chloride (200 ml), dried (MgSO4), filtered and evaporated in vacuo to give solid which is recrystallized from a mixture of ethyl acetate and hexane (3.8 g, yield 23%).  L) M-Methyl-β-hydroxy-4- (methoxy phenyl) -1,2,3, itotetrahydro-1-naphthylamine.  A solution of 4-hydroxy - - (- methoxyphenyl) -1-tetralone (3.9 g, 0.0138 mol in tetrahydrofuran (40 ml) is cooled before and the cooled solution is treated with methylamine (5 ml), followed by the dropwise addition of titanium tetrachloride (1 ml).  The resulting mixture was stirred for 16 hours at room temperature, filtered and evaporated in vacuo to give an oil, which was dissolved in absolute ethanol (20 ml).  The ethanol solution is treated with sodium borohydride (1.0 g, 0.026. mol) and stirred for 1 h at room temperature.  Then the reaction mixture was evaporated in vacuo, the residue was dissolved in ethyl acetate (125 ml).  The ethyl acetate solution is washed with water (125 ml), a saturated aqueous solution of sodium chloride (125 ml), dried (KgSO), filtered and evaporated in vacuo to give an oil, which is used in the next stage without further purification (G, 67 yield 83, mixture cis and trans isomers).  E) -Methyl - - (4-methoxyphenyl) -1, 2-dihydro-1-naphthylamine hydrochloride.  A solution of N-methyl-β-hydroxy-4- (i-methoxyphenyl) -1, 2,3, -tetrahydro-1-naphthylamine (1.9 g, P, 00b9 mol, a mixture of cis and trans isomers) in diethyl ether (50 ml is treated with gaseous hydrogen chloride.  The solution is evaporated in vacuo to give a white solid, which is recrystallized from ethyl acetate 1.5 g, yield 72%, T. Submarine 221222 0.  G) Target compound (cis-racemate).  W-Methyl-il-methoxyphenyl) -1, 2-dihydro-1-naphthylamine hydrochloride (l, 5 g, 0, mol} is mixed with ethanol (30 ml) and 10% palladium on carbon as a catalyst 250 mg) , hydrogenation is carried out for 4 hours at room temperature and a hydrogen pressure of 3.16 kgf / cm.  The reaction mixture is filtered and evaporated to dryness in vacuo.  The residue is chromatographed on silica gel (eluted with ethyl acetate containing 1% ammonium hydroxide) to separate the cis and trans isomers.  The cis isomer is converted to the hydrochloride, which is recrystallized from a mixture of chloroform and diethyl ether (221 mg, yield 16, t. square  22it-226 ° C,).  Elemental analysis.  Found,% -.  C, 70.61; H 7.52; M i, 64.  Calculated,%: C 71.15; H 7.29; N 1.61.  Examples 18-19.  According to the procedure of Example 17, the compounds (cis-racemates) shown in Table 2 are obtained from 2-bromoanisole and 3-bromo-isol. 3  Example 20  cis- / 15 // 1R / - / -Methyl- - (2, t-dichlorophenyl) -1,2,3, -tetrahydro-1-naphthylamine hydrochloride.  According to the method of example 15, the specified connection (CIS-racemate, t. square  288289 C) is obtained from 2, -dichlorobenzophenone.  Example 21  cis- / 1 / 1D / -N-fletil- (- (-chlorophenyl) -7-methoxy-1,2,3, {-tetrahydro-1-naphthylamine hydrochloride.  According to the procedure of Example 17 (A, G – E), the indicated compound (cis-racemate) is obtained from 4-bromochlorobenzene and 6-methoxy-1-tetralone.  Steps B and C of example 17 are omitted.  Instead of stage G.  use the following technique.  g) Target compound (cis-racemate).  A solution of N-methyl-C-chlorophenyl) -7-methoxy-1, 2-dihydro-1-naphthylamine hydrochloride (1.6 g, (, 8 mmol) in tetrahydrofuran is treated with a talizer — PtOj (1.0 g ), saturated with gaseous HC1 and hydrogenated for 2 hours at room temperature and hydrogen pressure (3.52 kgf / cm).  The isolated reaction product is converted to the free base and chromatographed on silica gel (elution with ethyl acetate containing 1% ammonium hydroxide to separate the cis and trans isomers of the cis isomer is converted to hydrochloride, which is crystallized from ethyl acetate (300 mg,% yield% , t square  27b-277s) Elemental analysis.  Found,%: C 63.60; H 6.0; N 3.99.  Calculated,%: C 63.91; H 6.26; N C, C.  Example 22  cis- / IS / / 1R | -N, N-Dimethyl- - (3-trifluoromethylphenyl) -1 2,3, -tetrahydro-1-naphthylamine maleate.  According to the method of example 7 (LH), the target compound (cis-racemate) is obtained from 3-trifluoromethylbenzophenone (t. square  120-121 ° C, 1 / i mol per mole of the title compound).   Elemental analysis.  Found,%: C 62.97; H 5, + 9; N3.11.  Calculated,%: C 62.79; H 5.61; N3.18.  D) Target compound (cis-rasmat).  A solution of 4- (3-trifluoromethylphenyl) -alpha-tetralone (3.0 g, 0.010 mol in toluene (50 ml) is treated with dimethylamine (3 ml, 0 mol) under ice-cooling, and then titanium tetrachloride (add 1 dropwise , 2 ml, 0,011 mol).  Then the reaction mixture is stirred for 16 hours at room temperature, filtered, and evaporated in vacuo to dryness.  The crude enamine is added to a mixture of glacial acetic acid (5 ml), sodium borohydride (1.3 g, 0.03 mol, and tetrahydrofuran (50 ml), and the mixture is stirred for 3 hours at room temperature.  The reaction mixture is then evaporated in vacuo to an oily solid, which is treated with water (100 ml) and extracted with diethyl ether (200 ml).  The ether extract is dried (MDBHC), filtered and evaporated in vacuo.  The remaining oil to separate the cis- and trans-isomers is chromatographed on silica gel using a mixture of 0.5 diethylamine and hexane for elution, cis-Isomer is eluted first.  The eluted fractions were evaporated in vacuo, dissolved several times in methanol, and again evaporated in vacuo to dryness (0.99 g).  The residual oil was dissolved in methanol (15 ml) and the methanol solution was treated with maleic acid (0.36 g, 0.0031 mol), heated to dissolve the acid, and then evaporated in vacuo to a semi-solid, which was crystallized by dissolving E with ethyl acetate, followed by adding diethyl ether.  Obtain 0.80 g of the target product, yield 18%.  Example A.  Using the procedure of Example 22, the compounds (cis-racemates) shown in Table 2 are prepared from suitable substituted benzophenones.  four.  Example 2 bv  Using the procedure of Example 17, the following compounds are obtained (cis-racemates 7 and their salts, starting from 2-fluoro - "- bromoanisole and 2-fluoro-5-bromoanisole, respectively: Example Compound 2k B cis / 15 / / 1" / - M-Methyl-1 - (3-fluoro- (-methoxyphenyl) -1, 2, 3, 4-tetrahydro-1-naphthylamine cis- | 15 / / lR / - l-Methyl-4- {3-methoxy- 4 -fluorophenyl) -1, 2, 3, 4-tetrahydro-1 -naphthylamine. PRI me R 7. five.  Clocade of the synaptosomatic reverse serum backbone serotonin 15HT, dopamine (DA) and noradrbnalino (NE) in vitro under the action of cis- (15) -M-methyl-4- (3, dichlorophenyl) -1, 2,3, A-tetrahydro-1 -naphthylamine hydrochloride.  Male rats Sprague-Dawley CD weighing 180-220 g were used to study the blockade.  The crude synaptosomatic fraction of Corpus Strlatum rats (for determining capture 5HT and DA) or hypothalamus tissue (for capture NE) is prepared by homogenizing tissue (25 Mj, / r wet product) cooled on ice 0.32 M sucrose containing 1 mg / ml glucose , 0.0001 M EDTA and Tris- (hydroxymethyl) -aminomega (pH.  The centrifugal homogenate at 1000 g for 10 minutes at O-sediment is discarded, and the supernatant is centrifuged at T / OOP 8 for 20 minutes at 0- C.  The resulting precipitate is re-suspended in ice-cold 0.32 M spharose solution (pH 7) at 10 ml / g of the initial tissue (wet) for Corpus Striatum and 5 ml / g of the initial tissue (mora) for the hypothalamus. : 26 mM Tris- {hydroxymethyl) -aminomethane, adjusted to pH 7, (by adding HCI containing 12 mM NaCl, 4.5 mM KCl, 0.0125 mmol nialamide hydrochloride and 2.9 mm CaCl1) Duplicate portions of 0.1 ml of tissue suspension is incubated for 10 minutes at 37 ° C with 0.02 ml of a solution containing a known amount of the named test compound, and 1, About ml of incubation buffer containing additionally 1 mg / ml of glucose and O, OOP mM of labeled monoamine (C-5HT, 4C-TA or H-HE). After incubation, the mixture is filtered through myeloric filters (0.5 µm) and the filters are washed with incubation buffer.  The filtered materials are dissolved in 1.0 ml of 2-methoxyzanol and analyzed for radioactivity using a liquid scintillation estimator (capture at 0 ° C is taken as a clean background radiation), Capture RSPSmit | | wiked in picomol x 5 HT, DA, or NE per 1 mg of protein (protein is determined by measuring with folin's phenolic reagent).  The value of 1Ct | -Q is the concentration of the named test compound (expressed in micro moles per liter in approximately 1 ml of the incubation mixture) inhibiting seizure by 50 cfp. In other words, with a value calculated for non-test compound, the control portions are estimated from the graphs of the percentage of inhibition of uptake versus the concentration in the semi-graphic coordinates.  This value is O, Obmol for 5HT 1.3 µmol for 0.5 µmol for NE.  The ratio (5HT) / 1G (NE) is Examples According to the method of Example 25, the blockade of sympapsomatic reverse flow in V / i t r o is determined for compounds with (3 fold tables).   718 Example 50.  Potentiation of induced 5 hydroxytryptosymptomes in vivo behavioral under the action of cis- (1S) -N-methyl- - (3, 4-dichlorophenyl) -1, 2,3, -tetrahydro-1-naphthylamine hydrochloride.  Groups of 10 male Swiss V / ebster CD mice weighing 17–21 g, subjected to starvation, were given various oral doses of the named test compound and after 1 hour intraperitoneally 5 hydroxytryptophan (5HTP) at a dose of 100 mg / kg body weight.  This dose of 5HTP itself does not cause any obvious behavioral effects, but causes a syndrome that occurs in tremor in mice that have been injected with substances that block serotonin uptake.  Assessment of the condition of the mice by the presence of this symptom is made by an inexperienced observer 10-20 minutes after the administration of 5HTP.  A value of 05-0 (the oral dosage level at which a symptom appears) is estimated at 1.0 mg / kg body weight by tremor.  Examples  Using the procedure of Example 50 for the following compounds, the potentiation of a 5-hydroxytryptophan-induced tremor is determined.  The results are shown in Table.  6  Example 68  The ability of cis- | 15 / -H-methyl- - (3, -dichlorophenyl 152, 3, -tetrahydro-1-naphthylamine hydrochloride to counteract reserpine-induced hypothermia in mice. A certain number of Swiss V / ebster CD male mice (17-21 g) placed in a room with an ambient temperature of 20 C.  Mice are individually kept in plastic chambers with a cardboard bottom.  All mice were given subcutaneously with an injection of reserpine 2 mg / kg body weight, and they were left at 20 ° C for 18 hours.  The rectal temperature of the mice is then measured and immediately we are then divided into five groups of mice for testing.  Either salt (control) or the named test compound (10 mg / kg body weight) was orally administered to each group and the resulting temperature was rectally measured 2 hours later.  The mean rectal temperature (t standard deviation) for five mice injected. said test compound is 20,, 3c for the two-hour mark, in comparison (; -
    1910
    average value for business in the control group of 20.41}, 2 ° C for the two-hour mark. This fact is consistent with other indications that resistance to reserpine hypothermia does not correlate with inhibition of norepinephrine uptake, but not with inhibition of serotonin uptake.
    Example b9. Ability of cis- (1 S) -M-methyl-A- (3, 1-dichlorophenyl) -1, 2,3 I (-tetraphydro-1-naphthylamine hydrochloride to counteract induced X-chloramphetamine (PCA) depletion of serotonin in the brain of rats (n V i VO.
    Substances that block serotonin uptake exhibit a dose-dependent counteraction to the serotonin-depressant effect of PCA, a drug that involves the interaction of 5 NT with 5HT neurons to ensure its action. Sprague-Dawley CD male rats (130-220 g) in groups of five individuals receive two simultaneous subcutaneous injections or a named test compound (at different dosages b, 5 mg / kg of body weight XRD and water + 6.6 mg / kg of body mass XRD, or water + water (control). Rats are decapitated after hours and their brains are completely analyzed for serotonin content using the Bogdansky method. Brain homogenates in 0.2 N. HCl are alkalinized with borate buffer and extracted with butanol. The soluble phase is then extracted with 0, 1N HC1. The aqueous extracts are acidified with concentrated C1 and the characteristic fluorescence of serotonin is measured on a spectrophotometer. ED, i.e., i.e., the dose giving treatment of the induced mean to control MPF. (% J average for different dosages of the named test compound (mg / kg) get the following values MPE,: DosMPE 0.107.9 0.322k 1.0017 3, 10.057 17.857 32.066 From the given data, the value of,), i.e. the dosage giving 50 tf) 720
    A PCA of serotonin istocene, graphically evaluated on a semilogarithmic scale of 0.2 mg / kg body weight.
    Example 70. Reduction of behavioral paternity in vivo (modified Porsolt method) under the action of cis- (1S) -N-methyl- - (3, h-dichlorophenip) -1 12, 3, 4-tetrahydro-1-naphtylamine
    0 hydrochloride.
    Use the modified technique described by Porsolt. A number of male Swiss Webs5 ter CD mice weighing 25-30 g are kept in standard laboratory conditions for at least one week prior to the experiment. Then, groups of 10 animals are injected subcutaneously with either the named test compound at the indicated dose or the receiving medium of the preparation (5% Emulphor, 5% ethanol, 90% normal saline). After 1 h, the mice are individually placed in 1 L beakers containing water at P. up to a height of 7 cm from the bottom. Starting from the second minute after immersion, each mouse is observed for signs of immobility, expressed in swimming without movement in water. Ten observations are made, each of which is evaluated as O - an animal d It floats, tries to choose, or M is not moving. For each individual, the number of positive observations is counted and an average immobility score is calculated for a group of ten individuals. For analysis, depending on the dosage, this data is converted into MPE (.) (maximum possible effect) defined as: days for test X 100% l NOSE reduction in immobility compared to control, as determined by linear regression analysis, is 7.6 mg / kg body weight for the named test compound. Example 71-77. According to the method of Example 10, a decrease in the degree of behavioral ramp was determined for the above compounds. The results are shown in Table. 7rtj
    PG X
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    Table 5
    2k
    P, 07
    Contrast 3.5
    ,
    example
    H - high activity, M - medium activity. 1, low activity.
    For the blockade of the zaphoat 5 NT iBA H, 1G. mennye 1 µmol; M 1Sgd1 5 µmolbJ;
    B, 1Cr. More than 5 µmol. The blockade of capture, ME, H, K, is less than 0.1 μmol;
    M, 1 with a CQ of 0.1-0.5 μmol; Ij, ICg-Q down 0, S μmol.
     The isoacetic compound is iis-p5 I 1R / -N-methyl-4- (1) enyl-1, 2,3, -tetoagylo-V-naphthylamine hydrochloride.
    Q.kn
    0.175 1.8
    1 .I
    Table 6
    66
    67
    | rinechenie.
    a - Explicit tremor is absent at 10 mg / kg, the highest dose tested
    b - there is no obvious tremor at 32 mg / kg, the highest dose tested;
    n is the known compound cis- {15 (1 R) -M-methyl-A-phenyl-1, 2,3.-tetra hydro-1-naphtylamine hydrochloride.
    32-56
    Sopostab
    vital
    example
    Table
    权利要求:
    Claims (1)
    [1]
    The method of obtaining. Derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthylamine of the general formula I where R is a hydrogen atom or C, -C a- n 1 4 3 alkyl;
    R z is C ^ -C 3 -n-alkyl;
    R ^ is an atom of hydrogen, chlorine or
    C ^ -Se alkoxy group;
    R4 and R are hydrogen, fluorine, chlorine bromine or trifluoromethyl groups, and at the same time, Rd and R ^ are not hydrogen atoms or their salts, characterized in that the compound of the general formula C where:. Rj, R 4 and Rig have the indicated meanings, are treated with an amine of general formula III
    HNP 4 R 2 , where R ^ and R ^ have the indicated meanings, in the presence of an acidic catalyst such as titanium tetrachloride, followed by reduction of the obtained intermediate compound with sodium borohydride and isolation of the desired product in free form or in the form of a salt.
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    同族专利:
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    法律状态:
    优先权:
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