KR840002020B1 - Process for the preparation of trans-4-phenyl-1,2,-3,4-tetrahydro-1-naphthalen amine derivatives - Google Patents

Abstract

The title compds. [I; R1 = H or C1-3 alkyl; R2 = C1-3 alkyl; Z = optionally substituted Ph; W = H, F, Cl, Br, trifluoromethyl, C1-3 and their salts, useful as antidepressant pharmaceuticals, were prepd. by the condensation of II with HNR1R2 in the presence of an acid catalyst. The effectiveness of I in blocking synaptosomal uptake of serotonin was demonstrated.

Description

Method for preparing trans-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine derivative

The present invention relates to a novel trans-4-phenyl-1,2,3,4-tetrahydro-1-naphthaleneamine derivative of the general formula (I) useful as an antidepressant and a method for preparing a pharmaceutically toxic acid addition salt thereof will be.

In the above formula

R ₁ is selected from the group consisting of hydrogen and C ₁ to n-alkyl;

R ₂ is C ₁ to C ₃ alkyl;

Z is

Wherein X and Y are each selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, C ₁ to C ₃ alkoxy and cyano, provided that at least one of X and Y is not hydrogen )ego ;

W is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl and C ₁ to C ₃ alcohols.

Serotonin and norepinephrine are known as important chemical messengers involved in the transmission of neurostimulation in the brain. These messengers are released at specific sites on pre-synaptic cells and reach specific sites on post-synaptic cells to carry out the transmission of stimuli. The effect of these messengers is lost as they are taken up by metabolic or presynaptic cells. Antidepressants make up the majority of antidepressant drugs that can block the presynaptic uptake of norepinephrine in the brain and thus mitigate norepinephrine abnormalities at adjacent postsynaptic receptor sites. It is also widely accepted in the chemical chemistry field that drugs that can block the presynaptic absorption of serotonin in the brain are another category of antidepressants.

US Pat. Nos. 4,029,731 and 4,045,488 describe a series of 4-phenyl-1,2,3,4-tetrahydronaphthalen-1-amines and substituted amines useful as antidepressants. Preferred compounds described in these patents are trans- (1R) -N-methyl-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamineenantiomer and pharmaceutically toxic acid addition salts thereof. to be.

It has surprisingly been found that derivatives of trans-isomers of certain novel 4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamines are useful as antidepressants.

The term "trans-isomer" refers to the relative arrangement of the NR ₁ R ₂ and Z groups on the cyclohexene ring (ie they are arranged on opposite sides of the ring). Since carbons 1- and 4 of the general formula (I) have been asymmetrically substituted, each trans-compound has an optically active (for 1-carbon) trans- (1R) and trans- (1S) enantiomer. There are two enantiomers shown. Preferred compounds are trans- (1R) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamineenantiomer and its pharmaceutically harmless Acid addition salts.

The present invention provides a novel antidepressant of formula (I), a novel pharmaceutical composition containing a compound of formula (I) in an amount that can effectively combat mental depression with an active ingredient in a pharmaceutically innocent carrier, an effective amount of the above-mentioned A new method of combating depression is characterized by the administration of a compound of Formula (I).

The compounds of the present invention exhibit antidepressive and appetite-reducing effects in vivo in mammals, including humans. This effect is achieved by essentially blocking uptake of norepinephrine or serotonin (5-hydroxy-tryptamine) or both in neuromuscular junction cells. The monoamine oxidase and cholinergic effects of the compounds of the present invention are almost negligible.

"Pharmaceutically nontoxic" acid addition salts mean nontoxic salts at a dosage. Pharmaceutically nontoxic acid addition salts of the free bases of the present invention are organic acids (eg hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, phosphoric acid, acid phosphoric acid, acetic acid, Lactic acid, maleic acid, fumaric acid, citric acid, acid citric acid, tartaric acid, azuric acid, succinic acid, gluconic acid and zaccharic acid).

The excellent pharmaceutical activity of the trans-isomer compounds of formula (I) is due to (1R) -enantiomers. Thus, a preferred group of compounds of general formula (I) consists of racemic mixtures of (1R) -enantiomers with (1R)-and (1S) -enantiomers of said compounds. Such preferred groups are referred to below as group A.

Preferred groups of group A are R ₁ is hydrogen or methyl, R ₂ is methyl, Z is 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3-bromophenyl and 4-bromophenyl Compound selected from the group consisting of. These compounds have excellent serotonin uptake blocking effect as well as excellent norepinephrine uptake blocking effect.

Another preferred group of compounds of Group A are those in which R ₁ is methyl, R ₂ is methyl, W is hydrogen, and Z is 3-trifluoromethyl-phenyl and 4-trifluoromethyl-phenyl Selected compound. These compounds exhibit activity that blocks uptake at the synaptic site very selectively for serotonin than norepinephrine. It has important pharmacological activity, which is thought to be advantageous for treating some form of depression, as it selectively blocks serotonin from being absorbed at the synaptic site. In recent years, the antidepressant activity of two new drugs, gemeridine and fluvoxamine, is due to the ability to selectively block the uptake of serotonin (relative to norepinephrine uptake).

Particularly useful compounds are the (1R) -enantiomers or (1S) (1R) racemic forms of the following compounds and their acid addition salts which are pharmaceutically toxic.

Trans-N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine,

Trans-N-methyl-4- (4-bromophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine,

Trans-N-methyl-4- (4-chlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine,

Trans-N, N-dimethyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine,

Trans-N, N-dimethyl-4- (4-chlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine,

Trans-N, N-dimethyl-4- (3-trifluoromethyl) -1,2,3,4-tetrahydro-1-naphthalenamine,

Trans-N-methyl-4- (4-chlorophenyl) -7-methoxy-1,2,3,4-tetrahydro-1-naphthalenamine and

Trans-N-methyl-4- (4-chlorophenyl) -7-chloro-1,2,3,4-tetrahydro-1-naphthalenamine.

In addition, the (1S) -enantiomers of trans-N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthaleneamine also provide surprisingly good norepinephrine and serotonin uptake. It is a compound of interest that has shown its action to block.

The present invention provides that the cis- and trans-isomer base compounds of formula (I) are hydrogenated to hydrogenate the compounds of formula (V), and then the trans-isomer bases of formula (I) are separated from the mixture obtained. Characterized in that the present invention relates to a method for preparing a trans-isomer base of formula (I) and a pharmaceutically toxic acid addition salt thereof.

In the above formula

R ₁ is selected from the group consisting of hydrogen and C ₁ to C ₃ n-alkyl;

R ₂ is C ₁ to C ₃ n-alkyl;

Z is

Wherein X and Y are each selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl and cyano, provided that at least one of X and Y is not hydrogen;

W is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl and C ₁ to C ₃ alkoxy.

The compounds of the present invention can be prepared by methods well known to those skilled in the art.

Compounds wherein R ₁ is hydrogen and X or Y (or both) are alkoxy can be prepared from 1-tetrarone or substituted derivatives thereof according to the following scheme.

The first step in the synthesis process is to react tetraron with a suitable Grignard reagent and then hydrolyze it. The resulting compound is dehydrated with acid and then hydrogenated to yield the 1- (substituted phenyl) -tetrarin compound (optionally substituted with W). This compound is oxidized with potassium permanganate in the presence of water to afford a 4-hydroxy-1-tetraron derivative. The substituted tetrarons are condensed with H ₂ NR ₂ , a suitable primary amine in the presence of an acid catalyst (eg TiCl ₄ ), and then reduced with a complex metal hydride to give 1-alkylamine. Dehydration of the resulting 4-hydroxy-1-alkylamine with acid and hydrogenation of the dehydrated product yielded 1,2,3,4-tetrahydro-1-alkylamine compounds (cis- and trans-racemates) do. In some cases steps 2 (dehydration) and step 3 (hydrogenation) of the reaction can be omitted.

Compounds of the invention wherein R ₁ is alkyl can also be prepared according to the above scheme. The 4-hydroxy-1-tetraron derivative is condensed with a suitable secondary amine HNR ₁ R _{2 in} the presence of an acid catalyst (eg TiCl ₄ ) to give 3,4-dihydro-4-aryl-4-hydroxy-1 -Dialkylnaphthalenamine compound is obtained, followed by reduction with sodium borohydride in the presence of acetic acid to give 1,2,3,4-tetrahydro-4-aryl-4-hydroxy-1-dialkyl naphthalene amine. . Synthetic routes not described above are the same as in the above scheme.

Optionally substituted tetraron starting materials, such as 1-tetraron, are commercially available. Not commercially available can be prepared by synthetic methods well known in the art.

The product of the above-described synthesis is a cis- and trans-isomer mixture. These isomers can be separated by methods well known in the art, such as fractional crystallization or chromatography. Cis-isomer compounds are described in Patent Application No. 090,240, filed November 1, 1979, entitled "Antidepressant cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalene amine derivative". It is described in more detail.

The process for isolating the racemates of the trans-isomer compounds of the present invention with (1R)-and (1S) -enantiomers involves the preparation of trans-racemic freebase solutions with D-(-)-mandelic acid, L-(+ It can be carried out by treatment with an optically active, optionally precipitated acid, such as) -mandelic acid, (+)-10-camphorsulfonic acid or (-)-10-camphorsulfonic acid, the somewhat insoluble produced here Diastereomeric salts are separated by crystalline precipitation.

Acid addition salts of the free base of formula (I), whether racemic or optically active, are conventionally used to mix the amine base with a suitable acid in a suitable solvent and to recover the salt by evaporation or add a nonsolvent to precipitate the salt. It can manufacture by a method. Hydrochloride can be easily prepared by giving hydrogen chloride to a solution of an amine base in an organic solvent.

Antidepressant activity and related pharmacological activity of the compounds of the present invention

(1) The ability to influence the mouse's efforts to escape from the water tank (porsolt mouse "abandonment behavior" test)

(2) the ability to enhance behavioral symptoms induced by 5-hydroxytryptophan in vivo in mice

(3) the ability to block uptake of serotonin, norepinephrine and dopamine by synaptic proximal brain cells in rats in the nose and in vitro by the method [Koe, B., Journal of Pharmacology and Experimental Therapeutics; 199 (3), pp. 649-661 (1976).

As described above, the trans isomer compound of the present invention is easily used as an antidepressant. The trans isomers of the present invention described herein can be orally or parenterally administered as antidepressants because they do not cause pharmacological side effects in the animals administered upon their administration. Generally, such antidepressant compounds are administered within the range of about 0.3 to 10 mg per kg of body weight per day, and the dosage can be adjusted according to the route of administration and the condition of the animal to be treated.

When the compound of the present invention is used to treat depression, the compound may be administered alone or in combination with a pharmaceutically innocuous carrier in the two routes described above. Can be. More specifically, the novel compounds of the present invention can be administered in a variety of different formulations, which can be mixed with various pharmaceutically inert carriers to form tablets, capsules, lozenges, troches, hard candies, powders, sprays, It may be prepared in the form of an aqueous suspension, injectable solution, elixir, syrup and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. Moreover, such oral pharmaceutical preparations may be appropriately sweetened and / or flavored using various types of reagents commonly used. Generally, the compounds of the present invention may be contained in the range of about 0.5 to 90% by weight of the total amount of the composition, which is an amount sufficient to supply the desired unit dose. The compounds of the present invention may exist in various polymorphs, ie they are in various crystalline forms.

For oral administration, tablets may contain a variety of excipients (e.g. sodium citrate; calcium carbonate and calcium phosphate) and disintegrants (e.g. starches, preferably potato or pork potato starch, alginic acid and certain silicate complexes) and binders (e.g. polyvinyl). Pyrrolidone, sucrose, gelatin and acacia) and the like. In addition, lubricants (eg magnesium stearate, sodium lauryl sulfate and talc) are often used for tableting. Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules, with preferred fillers being lactose or milk sugar and high molecular polyethylene glycols. In the case of oral administration of aqueous suspensions and / or elixirs, the essential active ingredients can be mixed with various sweetening or flavoring agents, pigments or dyes, emulsifiers and / or suspending agents, or diluents (e.g., water, ethanol, Propylene glycol, glycerin and mixtures thereof).

To prepare for parenteral administration, a solution of the compound of the present invention dissolved in sesame oil or peanut oil or aqueous propylene glycol or N, N-dimethyl formamide and a sterile aqueous solution of a water-soluble, non-toxic inorganic and organic acid addition salt described above can be used. Can be. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent firstly isotonicized with sufficient saline and glucose. Such specific aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injections. In this regard, the sterile aqueous medium used herein is readily obtained by standard techniques well known to those skilled in the art.

Representative dried solid pharmaceutical compositions are prepared by mixing the following materials in the following weight ratios.

After thoroughly mixing the dried composition, tablets are compressed with the resulting mixture, each tablet containing 100 mg of the active ingredient. Other tablets are prepared in a similar manner to contain 5, 10, 25 and 50 mg of the active ingredient, in which case the amount of naphthaleneamine salt used is appropriately adjusted.

Other representative dried solid pharmaceutical compositions are prepared by mixing the following materials in the following weight ratios:

Trans- (1R) -N-methyl-4- (3,4-dichloro phenyl) -1,2,3,4-tetrahydro-1-naphthalene

Amine Hydrochloride 50

Calcium Carbonate 20

Polyethylene Glycol (Average Molecular Weight 4000) 30

The dried solid mixture is stirred thoroughly to give a powdery product that is uniform in all respects. Soft and hard gelatin capsules containing the pharmaceutical composition are prepared, wherein each capsule contains 50 mg of the active ingredient.

The following examples illustrate the invention and the invention is not limited thereto.

Example 1

Trans- (1S) (1R) -N-methyl-4- (4-methoxyphenyl) -1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride

A) 1-hydroxy-1- (4-methoxyphenyl) tetrarin

A solution of 4-bromo-anisole (25 g, 0.134 mol) in tetrahydrofuran (100 ml) is prepared. Magnesium (3.24 g, 0.123 mol) is treated with a small amount of this solution and heated (55 ° C.) until the reaction starts. The remainder of the solution is added dropwise and after the addition is complete the mixture is stirred at 55 ° C. for 2 hours. The reaction mixture is cooled to room temperature and a solution of 1-tetrarone (17.92 g, 0.123 mol) in tetrahydrofuran (100 ml) is added slowly. Stirring is continued at room temperature for 16 hours after the addition is complete. Ether (200 ml) and water (200 ml) are added to the reaction mixture followed by 10% aqueous ammonium chloride solution (100 ml). The ether layer was separated and dried (MsSO ₄ ), filtered and evaporated in vacuo to yield an oil which was used for the next step without further purification (18 g, 58% yield).

B) 1- (4-methoxyphenyl) -3,4-dihydro-naphthalene

A solution of 1-hydroxy-1- (4-methoxyphenyl) -tetrarin (18 g, 0.071 mol) in toluene (250 ml) was treated with p-toluene sulfonic acid (5 mg) and the resulting solution was then Dean-Stark trap The mixture is stirred under reflux for 16 hours while the water is completely removed by means of a Dean-stark trap. The reaction mixture was then cooled to room temperature and subsequently washed with 10% aqueous sodium bicarbonate solution (100 ml), water (100 ml) and saturated aqueous sodium chloride solution (100 ml), dried (MgSO ₄ ) and evaporated in vacuo to afford an oil. Purification by silica gel chromatography (eluted with hexane-toluene) afforded 12 g of the title compound (67% yield, oil).

C) 1- (4-methoxyphenyl) tetrarin

1- (4-methoxyphenyl) -3,4-dihydro-naphthalene (12 g, 0.051 mol) was added to a mixture of 10% Pd / C (1.0 g) and ethanol (250 ml) and 50 psi at room temperature for 4 hours. Hydrogenated with H ₂ . The reaction mixture is then filtered and evaporated in vacuo to give an oil which is used for the next step without further purification (11.2 g, 92.5% yield).

D) 4-hydroxy-4- (4-methoxyphenyl) -1-tetraron

Dissolve 1- (4-methoxyphenyl) tetrarin (11.2 g, 0.047 mole) in a solution of acetone (1.6 L) and potassium permanganate (36.7 g) in water (33 ml), and then the resulting solution was refluxed for 16 hours. Stir. The reaction mixture is filtered, treated once again with potassium permanganate (36.7 g) and stirred under reflux for 16 hours. This process is continued until all three reaction cycles have progressed. After completion of the third cycle of the reaction for 16 hours, the reaction mixture is filtered, treated with activated carbon, filtered and evaporated under vacuum to obtain a residue. The residue was taken up in ethyl acetate (200 ml), the ethyl acetate solution was washed with saturated aqueous sodium chloride solution (200 ml), filtered and again washed with saturated aqueous sodium chloride solution (200 ml), dried (MgSO ₄ ), filtered and vacuum Evaporation under gives a solid which is then recrystallized from a mixture of ethyl acetate and hexanes (3.9 g, 23% yield).

E) N-methyl-4-hydroxy-4- (4-methoxyphenyl) -1,2,3,4-tetrahydro-1-naphthalenamine

A solution of 4-hydroxy-4- (4-methoxyphenyl) -1-tetrarone (3.9 g, 0.0138 mol) in tetrahydrofuran (40 ml) was cooled to 0 ° C. and the cooled solution was methylamine (5 ml). And continue adding dropwise titanium tetrachloride (1 ml). The resulting mixture was stirred at rt for 16 h, filtered and then evaporated in vacuo to afford an oil which was dissolved in anhydrous ethanol (20 ml). The ethanol solution is treated with sodium borohydride (1.0 g, 0.0264 mol) and stirred at room temperature for 1 hour. The reaction mixture is evaporated under vacuum to afford a residue, which is taken up in ethyl acetate (125 ml). The ethyl acetate solution was washed with water (125 ml), washed with saturated aqueous sodium chloride solution (125 ml), dried (MgSO ₄ ), filtered and evaporated in vacuo to yield an oil which was then used in the next step without further purification ( 3.4 g, 83% yield, mixture of cis- and trans-isomers).

F) N-methyl-4- (4-methoxyphenyl) -1,2-dihydro-1-naphthalenamine hydrochloride

N-methyl-4-hydroxy-4- (4-methoxyphenyl) -1,2,3,4-tetrahydro-1-naphthalenamine (1.9 g, 0.0069 mol, cis- and trans in ether (50 ml) A mixture of isomers) with gaseous hydrogen chloride. The solution is evaporated in vacuo to afford a white solid which is then recrystallized from ethyl acetate (1.5 g, 72% yield, melting point 221-222 ° C.).

G) Title compound (cis-racemate)

N-methyl-4- (4-methoxyphenyl) -1,2-dihydro-1-naphthaleneamine hydrochloride (1.5 g, 0.0049 mol) was mixed with ethanol (30 ml) and 10% Pd / C catalyst (250 mg). Mix and hydrogenate with 45 psi H ₂ at room temperature for 4 hours. The reaction mixture is filtered and evaporated in vacuo to give a residue. The residue is chromatographed on silica gel (eluted with ethyl acetate containing 1% ammonium hydroxide) to separate the cis- and trans-isomers. The trans-isomer is converted to a hydrochloride salt and recrystallized from a mixture of chloroform and ether (461 mg, 31% yield, melting point 230-233 ° C.),

Elemental Analysis: Calculation: 71.15% C, 7.29% H, 4.61% N,

Found: 70.60% C, 7.45% H, 4.51% N,

[Examples 2 to 3]

The following compound (trans-racemate) is prepared from 2-bromoanisole and 3-bromoanisole in a similar manner as described in Example 1.

Example 4

Trans- (1S) (1R) -N-methyl-4- (4-chlorophenyl) -7-methoxy-1,2,3,4-tetrahydro-1-naphthalene amine hydrochloride

The title compound (trans-racemate) is prepared from commercially available 4-bromochlorobenzene and 6-methoxy-1-tetraron in a similar manner as described in Examples 1A, D-F. Steps B and C of Example 1 are omitted.

The following process is used instead of step 1G.

G) Title compound (trans-racemate)

Trilute a solution of N-methyl-4- (4-chlorophenyl) -7-methoxy-1,2-dihydro-1-naphthalenamine hydrochloride (5.1 g, 0.015 mole) in trifluoroacetic acid (24 g) To the solution of triethylsilane (1.76 g) in fluoroacetic acid (10 g) was added and the resulting mixture was stirred at 60 ° C. for 2 hours. The reaction mixture is cooled to room temperature and treated with water (200 ml) and ether (200 ml). Discard the ether layer and extract the aqueous layer with ethyl acetate (2 x 100 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (3 × 100 ml), washed with water (200 ml), dried (MgSO ₄ ), filtered and evaporated under vacuum to obtain an oil which was then crystallized with 50 ml of ether (cis- Racemate, melting point 275-276 ° C., 2.0 g).

The mother liquor obtained from the crystallization of cis-racemate is evaporated under vacuum to give an oil which is chromatographed on silica gel. The fraction containing the trans-isomer with ethyl acetate containing 1% ammonium hydroxide was evaporated under vacuum to give an oil which was then dissolved in chloroform (50 ml) and converted to a hydrochloride salt. Crystallize HCl with ethyl acetate (20 mg, 0.4% yield, melting point 217-219 ° C., 1/4 mole of water per mole of title compound, elemental analysis)

Calculated Value: 63.07% C, 6.32% H, 4.09% N,

Found: 63.08% C, 6.22% H, 4.18% N).

[Examples 5 to 5a]

The following compounds (trans-racemate) and acid addition salts thereof from 2-fluoro-4-bromo-anisole and 2-fluoro-5-bromo-anisole in the same manner as described in Example 1, respectively. Manufactures:

Example 6

In vitro serotonin (5HT), dopamine (DA), and trans- (1R) -N-methyl- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride Blocking uptake of norepinephrine (NE) neuromuscular junction cells

Sprague-Dawley CD male rats (Charles River Laboratories, Inc. Wilmington, Mass) weighing 180-220 g are used in this process. The crude neuromuscular synaptic cell fraction of rat striatum (for uptake of 5HT and DA) or hypothalamus (for uptake of NE) tissue contains 1 mg / ml of glucose, 0.0001M EDTA and tris (hydroxymethyl) aminomethane The tissue is prepared by homogenizing (25 ml / g, wet) the tissue in ice-cold 0.32 M sucrose at pH 7.4. The homogenizations are centrifuged at 1,000 × g at 0-4 ° C. for 10 minutes, then the pellet is discarded and the supernatant is centrifuged at 17,000 × g at 0-4 ° C. for 20 minutes. The resulting pellet is resuspended in ice cold 0.32M sucrose (pH7.4) solution with 10 ml / g original tissue (wet) as striatum and 5 ml / g original tissue (wet) as hypothalamus. 26 mM Tris (hydroxymethyl) amino methane, 124mM NaCl, 4.5mM KCl, 1.2mM KH ₂ PO ₄ , 1.3mM MgCl ₂ .6H ₂ O, 0.001mM Ascorbic Acid, 0.012mM adjusted to pH7.4 with HCl A culture buffer containing alamide hydrochloride and 2.8 mM CaCl ₂ was prepared as follows: A 0.12 aliquot of a tissue suspension containing 0.02 ml of a solution containing a predetermined amount of test compound for 10 minutes at 37 ° C. and Additionally incubate with 1.0 ml of the culture buffer solution containing 1 mg / ml of glucose and 0.0001 mM labeled monoamine ( ¹⁴ C-5HT, ¹⁴ C-DA or ³ H-NE). After incubation the mixture is filtered through a 0.45 micron Millipore filter and the filter is washed with culture buffer. The filtered material is dissolved in 1.0 ml of 2-methoxyethanol and analyzed for radioactivity by liquid scintillation counting (absorption at 0 ° C. as a spinning blank). Absorption is calculated as 5HT, DA or NE pico water per mg of protein (protein is measured with polyphenol reagent). The concentration of the test compound, IC ₅₀ (expressed as micromoles per liter in about 1 ml culture mixture), which blocks the absorption by 50% from that calculated by the control aliquot without test compound, is 0.039 micromole for 5HT and DA for 0.044 micromolar and 0.017 micromolar for NE is estimated from a plot of% inhibition of absorption versus concentration on the semilog paper.

[Examples 7 to 11c]

As described in Example 6, neuromuscular synaptic cell uptake was as follows for the following compounds in vitro:

aH = high activity, M = normal activity, L = low activity. Absorption block for 5HT and DA: H = IC ₅₀ is less than 1 micromolar; M = IC ₅₀ is 1 to 5 micromol; L = IC ₅₀ is at least 5 micromolar; Absorption block for NE; H = IC ₅₀ is 0.1 micromolar or less; M = IC ₅₀ is 0.1 to 0.5 micromolar; L = IC ₅₀ is at least 0.5 micromolar, b-trans- (1S) (1R) -N-methyl-4-phenyl-1,2,3,4-tetrahydro-1-naphthaleneamine hydrochloride (US Patent No. 4,029,731).

c-trans- (1S) (1R) -N, N-dimethyl-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride (US Pat. No. 4,029,731).

Example 12

Reduction of Aerated Behavior In Vivo by Trans- (1R) -N-Methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine Hydrochloride (Modified Pole Salt method)

Variations of the procedure described in the following literature are used (see Porsolt et al., Arch. Int. Pharmacodyn 229, pp. 327-336 (1977)).

Multiple Swiss-Webster CD male mice weighing 25-30 g are bred under standard laboratory conditions at least one week prior to testing. Subcutaneously inject the indicated test compound or carrier (5% Emulsion: 5% Ethanol: 90% Saline) at a given dose to the group of 10 mice. After an hour, the mice are individually transferred to a 1-liter beaker containing 25 cm water at 7 cm depth.

Two minutes after immersion, immobility is characterized every 30 seconds, characterized by floating without movement in water for individual mice. All ten observations, each labeled 0 and 1, indicate "0 being the animal moving and swimming to run away" and "1 being the animal not moving." The average observed number is calculated for the group of ten by adding up the results observed in the individual mice. To analyze the dose-response, this data is converted to the MPE% (maximum possible effect) value as follows.

MPE 50%, a dose that reduces 50% immobilization to the control from the data, is 1.2 mg / kg (body weight) as determined by linear regression analysis for the named test compound.

Example 13

Reducing abandonment of behavior in vivo is measured for the following compounds in the same manner as described in Example 12.

Example 14

5-hydroxytryptophan in vivo with trans- (1S) (1R) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride The behavioral symptoms caused by

A group of five fasted Swiss-Webster male mice weighing 17-21 g (Charles River Laboratories Inc; Wilmington, Mass) was orally administered at various doses of the named test compound at 100 mg / kg 5-hydroxy. Loxitriptophan (5HTP) is administered intraperitoneally. The administered dose of 5HTP shows no pronounced behavioral effect, but treatment with serotonin uptake inhibitors exhibits symptoms including tremor. Mice assesses the onset of this symptom by "unexplained observer" between 10 and 20 minutes after 5HTP treatment. The ED ₅₀ value (oral dose at which symptoms develop) for tremor is estimated to be 3.2 to 10 mg / kg body weight.

Example 15

The degree of enhancement of the 5-hydroxy troptophan-induced tremor in the same manner as described in Example 14 is determined by an in vivo test on the following compounds.

No tremors were observed at the 32 mg / kg highest dose tested.

Claims (1)

Characterized by hydrogenating the compound of formula (V) to obtain a cis- and trans-isomer base mixture, and then separating the trans-isomer base from the mixture obtained to obtain the trans-isomer base of formula (I) and Method for preparing pharmaceutically harmless acid addition salts.

In the above formula R ₁ is selected from the group consisting of hydrogen and C ₁ to C ₃ n-alkyl; R ₂ is C ₁ to C ₃ n-alkyl; Z is

Wherein X and Y are each selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, C ₁ to C ₃ alkoxy and cyano, provided that at least one of X and Y is not hydrogen ); W is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl and C ₁ to C ₃ alkoxy.