JPS59497B2 - Antidepressant derivative of trans-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine - Google Patents

Description

Detailed Description of the Invention This invention relates to trans-4-phenyl-1,2,3,4-
The present invention relates to antidepressant derivatives of tetrahydro-1-naphthalenamine.

Serotonin and norepinephrine are known to be important transmitters for the transmission of nerve impulses in the brain.

These transmitters are released at specific sites in the pre-synaptic cell and received by specific sites in the post-synaptic cell to complete the transmission of the impulse. The action of these compounds is terminated by metabolism or uptake into cells before the synapse. Drugs that can block norepinephrine uptake before synapses in the brain constitute a large category of antidepressants because they can reduce norepinephrine abnormalities at adjacent postsynaptic receptor sites. . It has also become widely accepted in the field of medicinal chemistry that drugs that can block the presynaptic uptake of serotonin in the brain constitute another large category of antidepressants. US Patent Nos. 4,029,731 and 4,045,488 disclose a series of 4-phenyl-1,2,3,4-tetrahydro-naphthalen-1-amines and substituted amines useful as antidepressants.

Preferred examples in these patents include the enantiomer trans (IR)-N-methyl-
4-phenyl-1,23,4-tetrahydro-1-naphthalenamine and its pharmaceutically suitable acid addition salts. The present inventors surprisingly found that 4-phenyl-1,2
- It has been found that certain novel trans monoisomeric derivatives of 3,4-tetrahydro-1-naphthalenamine are useful as antidepressants. The novel compounds of this invention consist of trans isomer bases of the following formula and their pharmaceutically suitable acid addition salts. In the formula, R1 is hydrogen and has 1 or more carbon atoms.
3, R is normal alkyl having 1 to 3 carbon atoms, and z is
X and Y are each selected from the group consisting of hydrogen, fluoroethylene, chloro, bromo, trifluoromethyl, and alkoxy having 1 to 3 carbon atoms; however, at least one of X and Y is a group other than hydrogen, and W is selected from the group consisting of hydrogen, 7-chlor and 7-methoxy.

Trans isomer refers to the relative orientation of the NRlR2 and z groups on the cyclohexane ring.

(That is, these groups face oppositely to each other with respect to the cyclohexane ring.) Since the carbon atoms at positions 11 and 4 in Formula 1 are asymmetric centers, each trans compound has two optically active enantiomers. The carbon atom at position 1 is referred to as trans-1 (IR) enantiomer and trans-1 (IS) enantiomer. A preferred compound is the enantiomeric trans-1(IR)-N-methyl-4(3,4-dichlorophenyl)-1,2,3°4-tetrahydro-1-naphthalenamine and its pharmaceutically suitable acid addition salts. The compounds of the invention exhibit antidepressant and anorexic activity in vivo in mammals, including humans.

At least a large portion of this activity arises from the ability to block synaptic uptake of either or both norepinephrine or serotonin (5-hydroxytryptamine). has oxidase inhibitory activity.Pharmaceutically suitable acid addition salts are salts that are non-toxic when administered.Pharmaceutically suitable acid addition salts of the free bases of this invention include the non-toxic acid addition salts of the free bases. ,
For example, hydrochloride, bromate, iorate, sulfate, disulfate, phosphate, acid phosphate, acetate, lactate, malate, fumarate, citrate, acid citrate. , tartrates, bitartrates, succinates, gluconates and saccharates can be formed simply by treatment with various mineral or organic acids. Most of the pharmacological activity of the trans isomer compound of Formula 1 resides in its (IR) one enantiomer.

One preferred group of compounds of formula 1 consists of racemic mixtures of the (IR) monoenantiomer and the (IR)- and (IR) monoenantiomers of the above compounds. This preferred group is group A
It is called. One preferred group of compounds of group A is where R1 is hydrogen or methyl, R2 is methyl, z is 3-chlorophenyl,
4-chlorophenyl, 3,4-dichlorophenyl, 3-
A compound selected from the group consisting of promphenyl and 4-promphenyl.

These compounds have a highly desirable combination of excellent norepinephrine uptake blocking activity and excellent serotonin uptake blocking activity. Another preferred group of compounds of group A is where R1 is methyl, R2 is methyl,
It consists of a compound in which W is hydrogen and Z is 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl.

These compounds exhibit synaptic uptake blocking activity that is highly selective for serotonin over norepinephrine. This is an important pharmacological action in view of the belief that a selective block in synaptic uptake of serotonin may be advantageous in the treatment of certain types of mental depression. Recently, two new X. The antidepressant activity of serotonin, zimelidine, and flupoxane was found to be attributable to their ability to selectively block serotonin compared to that of norepinephrine. Particularly valuable are the (IR)-enantiomers and (1-enantiomers) of the following compounds:
S) (IR) Racemate and their pharmaceutically suitable acid addition salts: trans-N-methyl-4-(3.4
-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; trans-N-methyl-4-
(4-promphenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; trans-N-methyl-4
-(4-Chlorphenyl)-1,2,3,4-tetrahydro-1-naphthalenamine retrans-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 retrans-N-N-dimethyl-4-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; trans-N -methyl-4-(
4-Chlorphenyl)-Jmethoxy-1, 2, 3, 4
and trans-N-methyl-4-(4-chlorophenyl)-J-[chlor-1,2,3,4-tetrahydro-1-naphthalenamine.

(IS) one enantiomeric trans-N methyl-
4-(3,4-dichlorophenyl)1,2,3,4-tetrahydro-1-naphthalenamine is also important and exhibits surprisingly good norepinephrine and serotonin blocking activity.

The compounds of this invention can be prepared by methods well known to those skilled in the art.
Compounds in which R1 is hydrogen and neither x nor Y is alkoxy are prepared from substituted benzophenone starting compounds by the following reaction scheme: The first step in the above synthesis is the base-catalyzed StObbe reaction of the substituted benzophenone and diethyl succinate. ) is a condensation. The next step is hydrolysis and decarboxylation, for example with HBr. The resulting 4,4-diarylbutanoic acid was reduced with hydrogen or with HI and red phosphorus on a powder medium to obtain 4,4-diarylbutanoic acid. The next step is, for example, in the presence of HFl polyphosphate or thionyl salt followed by cyclization in the presence of AlCl3 to give the substituted tetralone.
The substituted tetralone is condensed with a suitable primary amine H,NR2 in the presence of a suitable acid catalyst, e.g. TiCl4, to form 1-
The imine is obtained by catalytic hydrogenation or reduction with a metal hydride complex for 1-alkylamines (cis- and trans-
racemic mixture). This translysis ratio is increased by performing the final reduction step with zinc in the presence of acetic acid. Compounds in which R1 is alkyl and neither X nor Y is alkoxy can also be produced by the reaction scheme described above.

Condensation of a substituted tetralone with a suitable secondary amine NHRlR2 in the presence of an acid catalyst, e.g. TiCl4, yields 3.
A 4-dihydro-1-dialkylamine compound is obtained, which is reduced with sodium borohydride in the presence of acetic acid, for example, to give 1,2,3,4-tetrahydro-1-dialkylamine (a mixture of cis- and trans-racemic forms). ). Certain substituted benzophenone starting compounds are commercially available and are 4-chlorobenzophenone, 4-dichlorobenzophenone, 4-fluorobenzophenone, and 4-promobenzophenone.

Those not commercially available can be prepared by a variety of well-known methods, such as reaction of benzene with substituted benzoyl chloride in the presence of AlCl3 or reaction of optionally substituted phenylmagnesium*F bromide with substituted benzonitrile. A compound in which R1 is hydrogen can be produced from a compound in which X or Y or both are alkoxy, 1tetralone or a substituted derivative thereof according to the reaction formula below.

The first step is the reaction of the tetralone with a suitable Grignard reagent, followed by hydrolysis.

The obtained compound is dehydrated with acid and hydrogenated to obtain a 1-(substituted phenyl)-tetralin compound (optionally substituted with W). This compound is oxidized with potassium permanganate in the presence of water to give the 4-hydroxy-1 tetralone derivative. This substituted tetralone is reacted with an acid catalyst such as TiC.
Condensation with a suitable primary amine in the presence of 14 gives the 1-imine, which is then reduced with e.g. a metal hydride complex to give the 1-alkylamine compound (a mixture of cis- and trans-racemates). . In certain cases, the second (dehydration reaction) and third (hydrogenation) steps of the above synthesis can be omitted. Compounds in which R1 is alkyl can also be produced by the above reaction system.

4-Hydroxy- in the presence of an acid catalyst, e.g. TiCl4
1-tetralone derivative and appropriate secondary amine HNR,R
3,4-dihydro-4-aryl-4 by condensation with 2
-Hydroxy-1-dialkylnaphthalenamine compound, which is then reduced with sodium borohydride in the presence of acetic acid to produce 1,2,3,4-tetrahydro-4-aryl-4-hydroxy-1-dialkylnaphthalene. Amine. The remainder of this synthetic route remains unchanged. Some of the optionally substituted tetralone starting compounds,
For example, 1-tetralone is commercially available. Those not commercially available are manufactured by methods well known to those skilled in the art. The products of the above synthetic methods are cis- and trans monoisomers.

These isomers can be separated by methods well known to those skilled in the art, such as fractional crystallization and chromatography. The cis isomer compound is detailed in Patent Application No. 090240 dated November 1, 1979 as an antidepressant derivative of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine.
Are listed. To resolve the racemic trans-isomeric compounds of this invention into their (IR) and (IS) enantiomers, a solution of the trans-racemic free base is prepared by adding D-(h)-mandelic acid, L-. )-mandelic acid, (1)-10-camphorsulfonic acid and &
? -Achieved by treatment with an optically selective precipitating acid such as -10-camphorsulfonic acid.

By this method the salt of the less soluble diastereomer is isolated as a crystalline precipitate. Acid addition salts (either racemic or optically active) of the formula 1Q free base can be precipitated by mixing the ami4 group with a suitable acid in a suitable solvent and evaporating or by adding a non-solvent to the salt. It can be manufactured by

The hydrochloride salt can be easily produced by passing hydrogen chloride through a solution of the above-mentioned amine base in an organic solvent. The antidepressant activity and related pharmacological properties of the compounds of the invention are (
1) Ability to influence mouse efforts to escape from the mouse swim tank (porsol)
(2) the ability to activate 5-hydroxytryprophane-induced behavior in mice in vivo and (3) the ability to activate serotonin; norepinephrine and dopamine by synaptic cells in the rat brain. Koe's ability to block uptake in vitro. B. , Jourma10fPharmaco
1gyandExperimenta1Therape
utics, 199(3), PP 649-661(1
976).

As mentioned above, the trans-isomer compounds of this invention can be used therapeutically as antidepressants.

Although the trans-isomer of the present invention can be administered as an antidepressant by oral or parenteral administration, there are no undesirable X-isomers. Does not produce a chanting effect. In general, these antidepressant compounds usually have a concentration of about 0.3 to about 101 f9/kg (body weight).
/day, but the dosage will necessarily vary depending on the patient's condition and the particular route of administration. When the compounds of this invention are used in the treatment of depressed patients, they can be administered alone or in combination with a pharmaceutical carrier by any of the routes described above, and this administration can be done in one or more doses. can.

More specifically, the novel compounds of this invention can be administered in a variety of different dosage forms. That is, in combination with various pharmaceutical inert carriers, tablets, capsules, lozenges, troches, hard candies, powder sprays, aqueous suspensions, injectable solutions,
It can be made into an elixir, syrup, etc. Such carriers are solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. Additionally, such oral pharmaceutical compositions are suitably sweetened and/or flavored with agents of the type commonly used for such purposes. Generally, the compounds of this invention are present at a level of about 0.5-90% by weight of the total weight of the composition. Thus, this amount will produce the desired unit dosage form. The compounds of this invention can exist in polymorphic forms, ie different crystalline forms. For oral administration, sodium citrate;
Starch, preferably potato or tapioca starch, disintegrating agents such as alginic acid and certain acid complex salts and polyvinylpyrrolidone, sucrose, gelatin and gum arabic, with various adjuvants such as calcium carbonate and calcium bicarbonate. It can be combined with a suitable binder to form a tablet.

Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very convenient for tabletting. Although solid compositions of a similar type can be used as fillers in soft and hard-filled gelatin capsules, the preferred materials are lactose or high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral use, the essential active ingredients are combined with various sweetening and/or flavoring agents. If desired, colorants, emulsifying and/or suspending agents and diluents such as water, ethanol, propylene glycol glycerin and combinations thereof are combined. For parenteral administration, solutions of the compounds of this invention in sesame oil, peanut oil, aqueous polyethylene glycol or N-N-dimethylformamide and sterile aqueous solutions of water-soluble, non-toxic mineral and organic acid addition salts as described above are employed. can.

Such aqueous solutions are suitably buffered, if necessary, and the liquid diluent first made isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection. In this regard, sterile aqueous media are readily available by standard methods well known to those skilled in the art. A typical dry solid pharmaceutical composition is prepared by blending the following materials according to the proportions of the composition below.

After thoroughly blending this dry composition, each tablet contains 1
The tablets were compressed into tablets of such size that they contained 0.00 W of the above active ingredient.

Similarly, tablets containing 5, 10, 25 and 50 η of the above naphthalene amine salt per tablet were compressed using an appropriate amount of the naphthalene amine salt. Another exemplary dry solid pharmaceutical composition was prepared by mixing the following compositions.

The dry solid mixture so produced was then thoroughly mixed into a completely homogeneous powder. Using the above composition, each capsule is 50TIII! Soft elastic and hard-filled gelatin capsules containing the active ingredient were prepared. Example 1 Trans-1(IS)(IR)-N-methyl-4(3.4
-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamide Z hydrochloride (A) 3,4-dichlorobenzoyl chloride 313 in 3,4-dichlorobenzophenone benzene 1.1251 and dichloromethane 757711. Anhydrous AlCl32l97 (1.64 moles) was added portionwise over 35-40 minutes to a stirred solution of 5y (1.50 moles).

The mixture was maintained at 3-5°C during this addition. The reaction mixture was kept at 0-5°C for an additional hour, then 2.
51 into ice water, and stirring was continued until the complex salt was decomposed. The organic and aqueous layers were then separated and the organic layer was combined with an ethyl acetate wash of the aqueous layer. The resulting organic solution was washed twice with water, once with saturated brine solution, and dried (anhydrous MgSO4). This was treated with activated carbon and evaporated in vacuo to give an off-white solid. This was recrystallized from 400 m2 of a mixture of hot ethyl acetate and pentane to obtain a product. (D3-Ethoxycarbonyl-4-(3,4-dichlorophenylbut-3-eno/3,4-dichlorobenzophenone (3) in t-butyl alcohol (1500d))
A solution of potassium t-butoxide (169y, 1.58 mol) and diethyl succinate (40
2 ml (112.4 mol) was continuously treated.

A mildly exothermic reaction occurred and the initial clear solution turned into a solid mass. The reaction mixture was gently heated to reflux to form a stirrable white suspension and refluxed with stirring under nitrogen for about 16 hours. The reaction mixture was then cooled and
Pour into 2 liters of ice water. 10% of the resulting mixture
Acidified with HCl and extracted three times with 1 liter portions of ethyl acetate.

Add ethyl acetate extract to 1 liter each.
Extracted three times with NNH40H, washed the aqueous basic extract with 2 liters of ethyl acetate, cooled to 0-5°C and extracted with concentrated HCl.
In PHL. Acidified to below 0.0 O and extracted four times with 2 liter portions of ethyl acetate. The ethyl acetate extract was consistently dried over MgSO4 and evaporated in vacuo to give a light yellow oil slightly contaminated with diethyl succinate (4777, yield 8).
0%). It was crystallized from petroleum ether and used as an analytical sample. Melting point 128-130℃, elemental analysis value: 4-(3,4-dichlorophenylene-4-J
3 in 1.801 of a 48% aqueous solution of Br and glacial acetic acid (1:1)
-Ethoxycarbonyl-4-(3●4-dichlorophenyl)-4-phenylbut-3-enoic acid (2277,0
．． The suspension of 60 mono(c) was stirred at reflux temperature for 36 hours and cooled to room temperature.

The gaseous material separated from the reaction mixture was isolated by decanting the aqueous layer and dissolved in ethyl acetate (2 liters). The resulting organic layer was extracted twice with 2 liter portions of 10% aqueous NH4OH. Cool the extract to 0~5℃ and concentrate... acidified below O,
It was extracted four times with 1 liter each of ethyl acetate.

Carefully wash the ethyl acetate extract with water and dry (M
gSO4) and evaporated in vacuo to give a light brown oil 1207 which was crystallized from hexane. (91.47, yield 50%, melting point 115-120°C) This was recrystallized from a mixture of hot ethyl acetate and hexane to prepare a sample for analysis. Elemental analysis value: ] 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid (22
A solution of 3y, 0.73 mol) was hydrogenated over a 5% Pd/C catalyst of 8y under pressure at room temperature until hydrogen consumption ceased (approximately 24 hours).

The catalyst was separated, and the slurry was evaporated in vacuo to obtain a light brown oil containing traces of solvent (yield: about 100%). This was crystallized from hexane to provide an analytical sample of the title compound. Melting point 118-12 "C elemental analysis value: U 4-(3.4
-dichlorophenyl)-3,4-dihythro-1-(2H
)-4-(3,4-dichlorophenyl) in 1.2 liters of naphthalenone-
A solution of 4-phenylbutanoic acid (2287, 0.74 mol) was treated with thionyl chloride (66 ml, 0.90 mol) and the resulting solution was heated to reflux for 75 minutes, during which time HCl gas evolved from the refluxing reaction solution. It was released.

The reaction solution was then evaporated under vacuum to give 2307 as a light brown oil. This oil was dissolved in 360 ml of carbon disulfide and the resulting solution was mixed with well-stirred AlCl3 (1.
5 kg, 12.5 mol) in carbon disulfide (1.20 liters). During this addition the temperature of the mixture was
A brown mass was obtained by keeping the temperature below °C. After the addition is complete,
The reaction mixture was stirred for about 16 hours at room temperature and slowly poured onto ice (a violent reaction occurs). The resulting suspension was extracted four times with 2 liters each of ethyl acetate. The extracts were successively washed with water, saturated aqueous sodium bicarbonate, dried, evaporated in vacuo to a residue and crystallized from hexane (500ml) to give the title compound. 10
4.17, yield 48%, melting point 99-101°C Elemental analysis: Calculated value: Cl66. OO%: Hl4. l6% actual value: C
l66. O 6%; Hl 4.23% (F) Title compound (trans-racemate) 4-(3.4
-dichlorophenyl)-3,4-dihythro-1-(2H
) A solution of naphthalenone (13.57, 46.3 mmol) was cooled to 0~5°C and 14 ml of methylamine (316
mmol).

Titanium tetrachloride (4.467, 23.5 mmol) was added dropwise to the solution obtained above resulting in a violent reaction. The reaction mixture was stirred at below 10° C. during the dropwise addition. After the addition was complete, the reaction mixture was stirred at room temperature under nitrogen for 17 hours and strained. The resulting solid was thoroughly washed with toluene and
The P solution was then concentrated in vacuo to remove excess methylamine. Further evaporation to dryness and rinsing with hexane gave the above-mentioned thick base (melting point 145-146°C). A suspension of the above thick base in 75 ml of methanol was cooled to 14°C and then added with sodium borohydride (1.707,4
5 mmol) was added little by little. During this time the temperature rose to about 28°C. The resulting mixture was stirred at room temperature for about 90 minutes, evaporated under vacuum to a gum, diluted with water and ether and filtered. The aqueous layer of this slurry was extracted twice with ether. Keep the organic layer intact and add brine and Mg.
Dry over SO4, evaporate in vacuo to an oil, and chromatograph on silica gel earth, eluting with a solvent mixture of ethyl acetate, hexane, and triethylamine (30:20:1) to separate the cis- and trans-isomers. separated.
This trans isomer was discharged into the second F tank. The eluted fractions containing the trans monoisomer were then evaporated in vacuo to yield 4.27 g of the crude free base of the title compound. Triethylamine was distilled off by adding 100 ml and 50 ml of toluene twice. The free base is then dissolved in ether,
It was converted to the hydrochloride salt by treating the ether solution with hydrogen chloride gas. Trans-racemic 4.677, 33% yield (from naphthalenone), mp 214-216
°C elemental analysis value: Calculated value: C, 59.58%; Hl 5.29%: Nl 4.
O9%: Cll3l. O4%: Actual value: Cl59.59
%: Hl5, 35%: N, 4.04%; C1, 31.0
1% o Example 2 trans-1(IS)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro1-
Naphthalenamine hydrochloride 171η (0.50 mmol)
trans(IS)(IR)-N-methyl-4-(3
4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride was partitioned between aqueous sodium carbonate and ethyl acetate to obtain a solution of the trans-racemic free base in ethyl acetate, which was diluted with water. Wash, Mg
Dry with SO4, evaporate under vacuum and treat with a solution of L-(+)-mandelic acid (76Tf19, 0.50 mmol) in ethanol.

The resulting mixture was evaporated under vacuum to obtain the crude product, which was redissolved in 5 ml of ethanol. This ethanol solution was treated with about 15 d of ether to obtain a crystalline product (92
~, mp 128-130°C), which was recrystallized from a mixture of ethanol, ether and hexane (51η,
melting point 133-135°C). The recrystallized product was partitioned between aqueous sodium carbonate and ethyl acetate to obtain a solution of the free base in ethyl acetate. Wash this with water and use MgSO4
and evaporated under vacuum to a residue. This was dissolved in ether and treated with hydrogen chloride gas to give the HCl salt, which was recrystallized from a mixture of methanol and ether to give a product with the following characteristics. Yield 25.7 TV, yield 15%, melting point 257-258°C, [α] = -39.21
(CH3OH), elemental analysis value: Calculated value: Cl59.58%: Hl5.29%; N, 4.
09%: Actual value: Cl59.3l%: Hl5.44%;
Nl4.46%.

Example 3 Trans-1(IR)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro1-
The mother liquor of one crystal of the (IS) monoenantiomer of 92119 of naphthalenamine hydrochloride example 2 was partitioned between an aqueous sodium carbonate solution and ethyl acetate to obtain an ethyl acetate free base solution, which was washed with water and dried ( MgSO4), evaporated in vacuo and treated with a solution of D-(he)-mandelic acid (41η, 0.27 mmol) in ethanol (5 mO) to give a crystalline product (86W1f1 mp 132-134.5 °C),
This was recrystallized from a mixture of ethanol and ether to give the product 52η, melting point 133.5-135°C.

The recrystallized product was partitioned between aqueous sodium carbonate and ethyl acetate to give a solution of the free base in ethyl acetate, which was washed with water, dried over MgSO4 and evaporated under vacuum to a residue, which was dissolved in ether. and treatment with hydrogen chloride gas to give the HCl salt, which was recrystallized from a mixture of methanol and ether. Yield 32111I! , yield 19% (
(calculated from trans-racemate), melting point 255-25
7°C, [α] = +41.0 (CH, OH). Example 4-6 trans-N-methyl-4-(4-chlorophenyl)-
1,2,3,4-tetrahydro-1-naphthaleneamino hydrochloride It was prepared from commercially available 4-chlorobenzophenone in the same manner as described in Example 1-3, and each enantiomer was separated.

The HCl salts of Examples 5 and 6 were obtained using ether as the recrystallization solvent rather than a mixture of methanol and ether. Example 7 Trans-(IS)(IR)-N-methyl-4-(4-
fluorophenyl)-1, 2, 3, 4 tetrahydro 1
-Naphthalenamide Z-acid acid salt (A) 3-ethoxycarbonyl-4-(4-fluorophenyl)-4-phenylbut-3-enoic acid t-butanol (250TfL0) Commercially available 4-fluorobenzophenone (42y10 .21 mol), diethyl succinate (43.6f7, 0.25 mol) and potassium t-ptoxide (23.77, 0.2
1 mol) solution was refluxed with stirring for 6 hours and stirred for a further 16 hours at room temperature.

The reaction mixture was acidified with 200 ml of 6N hydrochloric acid, evaporated under vacuum to remove the t-butanol and 25 ml of ether.
Extracted twice with 07n1 each. The ether extract was extracted twice with 350 m2 of 10% aqueous ammonium hydroxide solution each time. These aqueous extracts were washed twice with 200 ml portions of ether, reacidified with 6N HCl and extracted again with 2×400 ml portions of ether. The ether extract was washed with MgSO4, filtered and evaporated in vacuo to an oil which was dissolved in hexane and crystallized by straining the flask. 487
, yield 70%, melting point 98-99°C, elemental analysis value: calculated value: Cl 69.5O%; Hl 5.22%: Fl 5.78%
; Actual value: C, 69.34%: H, 5.36%: Fl6
．． O9%o(B) 4-(4-fluorophenyl)-4
-Phenylbut-3-enoic acid 3-ethoxycarbonyl-4-(4-fluorophenyl)-4-phenylbut-3-enoic acid (477, 0.143 mol) in 10 ml of glacial acetic acid
The resulting mixture was stirred and refluxed for 16 hours.

The reaction mixture was then concentrated in vacuo and the concentrate was dissolved in ether 50
Extraction was carried out three times at 0 d each. 4% with extract
Extraction was performed five times with each 200 ml portion of ammonium hydroxide aqueous solution. The aqueous extract was then acidified with 6N HCl to pH 6.5 and extracted again with three 250 ml portions of ether. The ether extracts were constantly dried over MgSO4, filtered, and evaporated in vacuo to an oil that solidified on standing.

Trituration with hexane gave the title compound 157. Yield 47%, melting point 98-100°C, elemental analysis: Calculated value: Cl 74.99%: Hl 5. ll%: Fl7.
4l%: Actual value: C, 74.69%; H, 5.40%:
F, 7.17%.

(Q4-(4-fluorophenyl)-4-phenylbutanoic acid 4-(4-fluorophenyl)-4-phenylbut-3-enoic acid (15V10.0
68 mol) solution of 1.07% Pd for 2 hours at room temperature.
Hydrogenated with 50 psi H2 over /C catalyst.

The reaction mixture was filtered and evaporated in vacuo to a solid which was recrystallized from a mixture of ether and petroleum ether. 1
0.67, yield 70%, melting point 75-75.5°C Elemental analysis: Calculated value: Cl 74.4O%; Hl 5.85%: Fl 7.
36%; Actual value: Cl 74.62%: Hl 5.87%:
Fl7. l5%.

)) 4-(4-Fluorphenyl)-α-tetralone 4-(4-fluorophenyl)-4-phenylbutanoic acid (5V 10.019 mol) was treated with 20 d of hydrofluoric anhydride and the resulting mixture was Stirred at room temperature for 16 hours.

The reaction mixture was then diluted with water (100ml) and extracted with 200ml of ether.

The ether extract was dissolved in 50 ml of saturated aqueous sodium bicarbonate solution.
, washed with 50 ml of water, dried over MgSO4, filtered and evaporated in vacuo to a solid which was recrystallized from boiling hexane to give 3.2f7 product. Yield 69
%, melting point 74-75°C, elemental analysis value: Calculated value: Cl 79.98%: Hl 5.45%; Actual value:
C, 80.00%; H, 5.66%.

;) Title compound (trans-racemate) toluene 50
A solution of 3.0y (0.012 mol) of 4-(4-fluorophenyl)-α-tetralone in WLt was cooled to 10°C and treated with 2.07 (0.064 mol) of dimethylamine at this temperature. , 1.737 (0.009 mol) of titanium tetrachloride was added dropwise for treatment.

The reaction mixture was then stirred for 16 hours at room temperature, filtered and evaporated in vacuo to give the crude 1-imine solid. The crude imine was dissolved in 50 d of methanol, the methanol solution was treated with 1.0 t (0.026 mol) of sodium borohydride, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in vacuo to an oily solid, which was dissolved in 200 m2 of ether. The ether solution was washed with three 50ml portions of water, dried over MgSO4, filtered and evaporated in vacuo to an oil. This oil was chromatographed on silica gel using a solvent mixture of ethyl acetate, hexane and diethylamine 16:16:0.3 as eluent to obtain the cis- and trans-isomers. The trans monoisomer was then eluted to give its hydrochloride salt using hydrogen chloride gas. This hydrochloride was recrystallized from a mixture of methanol and ether to give the title compound 240η.
Yield of trans racemate 7%, melting point 210-211°C,
Five element analysis value: Calculated value: Cl69.98%: Hl6.5
6%; Nl4.8O%; Actual value: Cl69.84%; H
16.49%; N1 4.81%.

10 Examples 8-10 Similarly to Example 7, the following compounds (trans-racemates) were prepared from appropriate substituted benzophenones.

For Example 9, the 1-imine solid was prepared as in Example 7E, but without using the other steps in 7E, and using the following step: ? ) Transformer 1 (IS) (IS)-N-
Methyl-4-(3-trifluoromethylphenyl)-1
・2,3,4-tetrahydro-1-naphthalenamine maleate (from 1-imine) elemental zinc 17 1N
Activated with HC110ml and washed with ethanol and acetone.

The activated zinc was added to a solution of 3,4-dihydro-1-(2H)naphthalenimine (0.907, 296 mmol) in 10 ml of glacial acetic acid. The resulting mixture
Stirred in a 0°C bath for 5 hours. Cool the reaction mixture, ▲
The zinc was removed by filtration and evaporated in vacuo to an oil. This oil was chromatographed on silica gel with the second product oil obtained in Example 7E starting with 16.0 mmol of 1-imine, ethyl acetate, hexane and Diethylamine 30:20:
The cis- and trans-isomers were separated using a mixture of 1 as an eluent.

The title compound was isolated by treating the trans isomer free base with maleic acid in solution. 49
3119, 7% yield oZO The appropriate substituted benzophenone starting compounds for Examples 8-10 were prepared in a similar manner to the preparation of 4-trifluoromethyl-benzophenone shown below.

^) 4-Trifluoromethylbenzophenone 2.91
M phenylmagnesium bromide (90ml, 0.26
mol) was added over 45 minutes to a solution of 4-trifluoromethylbenzonitrile (40t10.23 mol) in 400 ml of ether.

The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then cooled in an ice-water bath and slowly treated with 150 ml of saturated aqueous ammonium chloride solution, followed by 1N HCl
001111. Take out this ether layer,
The aqueous layer was extracted twice with 200ml portions of ether. 1NHC1100d when these three ether layers
Wash twice with 200ml of water, twice with 200ml of water, MgSO
4, treated with activated charcoal, filtered and evaporated in vacuo to give a solid which was crystallized from 200 ml of hot hexane. (36y1 yield 62%, melting point 107-108°C). The title compound was recrystallized from hexane and used as an analytical sample. (
(melting point 116-118°C) Example 11 trans-(IS)(IR)-N-methyl-4(4-chlorophenyl)-J Me[chlor-1,2,3,4-tetrahyto-1-naphthalenamine hydrochloride Example 7A The title compound (trans-racemate) was prepared from commercially available 4,4'-dichlorobenzophenone in a manner similar to that described in -C and E.

Melting point 295-296°C, elemental analysis value: calculated value: C, 59
．． 58%: Hl 5.29%: Nl 4. O9%; Actual value:
Cl59.35%: H15. l2%: Nl4. l3%
The following method was used in place of Example 7D. (V) 4-(4
-Chlorphenyl) -J me[chlorα-tetralone 4,4
-di(4-chlorophenyl)butanoic acid (3.5y.0.
0113 mol) with polyphosphoric acid (807) and the resulting mixture was treated at 120° C. for 4 hours.

The reaction mixture was then poured onto crushed ice and the product was extracted three times with 1 portion of 150Tn of ether. Add the ether extract to saturated aqueous sodium bicarbonate solution
Wash 3 times with 0 ml each (・, wash with 100 ml of water, MgS
Drying with O4, filtering and evaporation in vacuo gave the desired tetralone. 2.2y, yield 67%, melting point 106-107
℃.

Example 12 Trans-(IS)(IR)-N-methyl-4-(4-
promphenyl)-1●2◆3◆4-tetrahytero1
-Naphthalenamine hydrochloride Example 7A. ．． The title compound (trans-racemate) was prepared from commercially available 4-prombenzophenone in a similar manner to methods B and E and Example 11D.

Melting point 288-289°C, elemental analysis value: calculated value: C, 57
．． 89%: Hl 5.43%: Nl 3.97%; Actual value:
Cl57.69%:H, 5.11%:N, 4.00%
The following method was used in place of Example 7C. (C) 4-(4
-promphenyl)-4-phenylbutano glacial acetic acid 50
A solution of 4-(4-promphenyl)4-phenylbut-3-enoic acid (5.07, 0.0157 mol) in
It was treated with 22.5 ml of 6.9% aqueous hydrochloric acid solution and 4.5 y of red phosphorus, and the resulting mixture was stirred at reflux for 16 hours.

The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium chloride solution (250 mO) and diluted with methylene chloride (250 WLI).
Extracted with. This extract was dissolved in a saturated aqueous sodium chloride solution.
Washed twice with 00ml each, dried over MgSO4 and evaporated in vacuo to give the desired butanoic acid derivative, which was used in the next step without further purification. 57 oil was obtained.

Yield 99%. Example 13 Trans-(IS)(IR)-N-methyl-4(4-methoxyphenyl)-1,2,3,4tetrahydro1-
Naphthalenamine hydrochloride (A) 1-hydroxy-1-
(4-methoxyphenyl)tetralin 4-promuanisole (25t10 in tetrahydrofuran 100Tf11)
．． A solution of 134 mol) was prepared.

Add a small amount of this solution to magnesium (3.24t10.
123 mono(he) until the reaction starts (55℃
) heated. The remainder of the solution was added dropwise and after the addition was complete the mixture was stirred at 55° C. for 2 hours. The reaction mixture was cooled to room temperature and a solution of 1 tetralone (17.927, 0.123 mol) in 100 ml of tetrahydrofuran was slowly added. Stirring was continued for 16 hours at room temperature after the addition was complete. Add 200 ml of ether and 200 d of water to the reaction mixture and add 100 ml of 10% aqueous ammonium chloride solution.
added. Separate the ether layer, dry with MgSO4,
Filter and evaporate in vacuo to an oil, which was used in the next step without further purification. Yield 187, Yield 58
%0e) 1-hydroxy-1-(4-methoxyphenyl)-tetralin (1) in 1-(4-methoxyphenyl)-3,4-dihydro-naphthalene toluene 250111
A solution of 8V (10.071 mol) was treated with para-toluenesulfonic acid 5η and the resulting solution was stirred at reflux for 16 hours.

During this time, water was completely removed using a Dean-Stark trap. The reaction mixture was cooled to room temperature, washed successively with 100 ml of 10% sodium bicarbonate solution and 100 ml of saturated aqueous sodium chloride solution, dried over MgSO4 and evaporated in vacuo to an oil, which was chromatographed on silica gel. Purification with a hexane-toluene gradient afforded the title compound 127 as an oil.

Yield 67% o(01-(4-methoxyphenyl)tetralin 1-(4-methoxyphenyl)-3,4-dihydronaphthalene 127 (0.051 mol) with 10% palladium on charcoal catalyst 1 .0y was added to a mixture of 250 ml of ethanol and hydrogenated at room temperature for 4 hours at a hydrogen pressure of 50 p81. The reaction mixture was then filtered and evaporated in vacuo to an oil, which was used as follows without further purification. (11.27, yield 92.5%) (D)
4-hydroxy-4-(4-methoxyphenyl)-1-
A solution of 1-(4
methoxyphenyl)tetralin 11.27 (0.047
mol) and the resulting solution was stirred at reflux for 16 hours.

The reaction mixture was filtered ▲ and again with 3 potassium permanganate.
6.747 and stirred at reflux for an additional 16 hours. This process was continued until all three reaction cycles were completed. After the final 16 hours of reaction time was completed, the reaction mixture was filtered, treated with activated carbon, filtered, and evaporated in vacuo to a residue. Take this in 200ml of ethyl acetate,
Add ethyl acetate solution to 200ml of saturated sodium chloride aqueous solution
Wash with water, filter, and re-wash with saturated sodium chloride aqueous solution 200
Washing with W12, drying with MgSO4, filtering and evaporation in vacuo gave a solid which was recrystallized from a mixture of ethyl acetate and hexane. 3.97, yield 23% 0ZN-methyl-4
-Hydroxy-4-(4-methoxyphenyl)-1・2
・3,4-tetrahydro-1-naphthalenamide 4-hydroxy-4-(4-methoxyphenyl)-1-tetralone 3.9f7 (0.01
38 mol) was cooled to 0° C., the cooled solution was treated with 5 ml of methylamine and 1 ml of titanium tetrachloride was added dropwise.

The resulting mixture was stirred for 16 hours at room temperature, filtered and evaporated in vacuo to an oil which was dissolved in 20 ml of absolute ethanol. Add ethanol solution to sodium borohydride
．． 07 (0.0264 mol) and stirred for 1 hour at room temperature. The reaction mixture was evaporated in vacuo, the residue was taken up in 125 WL of ethyl acetate, and the ethyl acetate solution was dissolved in 125 WL of water.
Washed with 1257 n1 of saturated aqueous sodium chloride solution, dried over MgSO4, filtered and evaporated in vacuo to an oil. This was used in the next step without further purification. Yield 3.4t, yield 83%, mixture of cis and trans monoisomers. 1) N-methyl-4-(4
-methoxyphenyl)-1,2-dihythro-1-naphthalenamine hydrochloride N-methyl-4- in 50 ml of ether
Hydroxy-4-(4-methoxyphenyl)-1・2・
3,4-tetrahydro-1-naphthalenamine 1.97
(0.0069 mol, mixture of cis and trans monoisomers) was treated with hydrogen chloride gas.

The solution was then evaporated in vacuo to give a white solid, which was recrystallized from ethyl acetate. 1.57, yield 72%, melting point 221-222°C o → Title compound (cis-racemate) N
-Methyl-4-(4-methoxyphenyl)-1,2-dihythro-1-naphthalenamine hydrochloride 1.57 (0.0
049 mol) was mixed with 30 d of ethanol and 250 ~ 10% palladium on charcoal catalyst and heated at room temperature with hydrogen pressure of 45 ps.
Hydrogenation was carried out at i for 4 hours.

The reaction mixture was filtered, evaporated in vacuo and the residue was chromatographed on silica gel to separate the cis- and trans monoisomers, eluting with ethyl acetate containing 1% ammonium hydroxide. The trans monoisomer was converted to the hydrochloride salt, which was recrystallized from a mixture of chloroform and ether. Yield 461 ~, yield 31%, melting point 230-233
°C, elemental analysis value: O calculated value: C) 71.15%: H) 7.2 9%; N)
4.6 1%; Actual value: C) 70.60%: H) 7
．． 4 5%; N) 4.5 1%.

Examples 14-15 The following compound (trans-racemate) was prepared in the same manner as in Example 13.
was prepared from 2-bromoanisole and 3-bromoanisole.

Example 16 Trans-(IS)(IR)-N-methyl-4-(2
・4-dichlorophenyl) -1 ・2 ・
3.4-tetrahydro-1-naphthalenamine hydrochloride The title compound (trans-racemate, melting point 195-
195°C).

Example 17 Trans-(IS)(IR)-N-methyl-4-(4
-chlorophenyl)-7-methoxy-1, 2, 3,
4-tetrahydro-1-naphthalenamine hydrochloride example 13
The title compound (trans-racemate) was prepared from commercially available 4-bromochlorobenzene and 6-methoxy-1-tetralone in the same manner as in methods A, D to F.

Steps B and C of Example 13 were omitted. The following method was used in place of Example 13G. 0 Title compound (trans-racemate) N-methyl-4-(4-chlorophenyl)-7-methoxy-1,2-dihydro-1 in trifluoroacetic acid 24y
-Naphthalene amino hydrochloride 5. A solution of ly (0.015 mol) was added to a solution of 1.76 t (0.015 mol) of triethylsilane in trifluoroacetic acid IOV and the resulting mixture was stirred at 60°C for 2 hours.

The reaction mixture was cooled to room temperature and treated with 20 oml of water and 200 oml of ether. Throw away the etheric layer,
The aqueous layer was extracted with three room ml portions of ethyl acetate. This organic layer was washed three times with 100 g each of saturated sodium bicarbonate aqueous solution, washed with 200 ml of water, and washed with MgS
04, filtered and evaporated under vacuum to an oil which was crystallized from 50 m2 of ether. Cissuracemic body. Melting point: 275,276°C, yield: 2.07. The mother liquor obtained from the crystallization of the cis-racemate was evaporated in vacuo to give an oil which was chromatographed on silica gel and eluted with ethyl acetate containing 1% ammonium hydroxide.

The fraction containing the trans isomer was evaporated in vacuo to an oil, which was dissolved in 50 ml of chloroform and converted to the hydrochloride salt. The HCl salt was crystallized from ethyl acetate. 20η, yield 0.4%, melting point 217-219°C, % molecules of water/1 molecule of title compound, elemental analysis: calculated value: Cl
63. O7%: Hl6.32%: N, 4.09%: Actual value: Cl63. O8%: Hl6.22%: Nl4. l8
% Example 18 Trans-(IS)(IR)-N-N-dimethyl-4-
(3-trifluoromethylphenyl)1,2,3,4-
Tetrahydro-1-naphthalenamine maleate example 7
Similarly to AD, the title compound was obtained as a trans-racemate from 3-trifluoromethyl-benzophenone.

Melting point 99.5-101°C, % molecules of water/1 molecule of title compound, elemental analysis: Calculated: Cl62. 16%: H15, 67%: N, 3.
15%: Actual value: Cl62.34%; H15.42%;
N, 3.12% The following method was used in place of Example 7E: (P Title compound (trans-racemate) 4-(3-trifluoromeJZtylphenyl)-α-tetralone (3.07,0. 010 mol) was added with 3 ml of dimethylamine while cooling in an ice bath.
(0.045 mol) and then titanium tetrachloride 1.
2 ml (0.011 mol) were added dropwise.

The reaction mixture was stirred at room temperature for 16 hours, filtered and evaporated in vacuo to give the crude 3,4-dihydro-1-dimethylamino-
A 4-arylnaphthalene solid was obtained. This crude enamine was mixed with 5 d of glacial acetic acid and 1.37 d of sodium borohydride (0.
034 mol) and tetrahydrofuran 50a. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated in vacuo to an oily solid which was treated with 100ml of water and extracted with 200ml of ether.
The ether extract was dried over MgSO4, filtered and evaporated in vacuo to an oil. This oil was chromatographed on silica gel and eluted using a solvent mixture of 0.5% diethylamine and hexane to separate the cis and trans monoisomers. This trans monomer is 2
It eluted first. The eluted fraction was evaporated in vacuo, dissolved several times in methanol and evaporated again in vacuo to give an oil (204
η). This oil was dissolved in methanol, the methanol solution was treated with maleic acid (74~, 0.00064 mol), heated to dissolve the acid, and evaporated in vacuo to give the title compound, which was converted into an ether. Crystallized from a mixture of petroleum ethers. 190 mg, yield 4%, melting point 99.5
-101℃.

Examples 19-20a The following compounds (trans-racemates) were prepared from the appropriate substituted benzophenones in analogy to Example 18: Example 20b-
20c In a manner similar to that described in Example 13, the following compounds (trans-racemate) and their acid addition salts were prepared as 2-fluoro-4-promoanisole and 2-fluoro-5-promoanisole, respectively.

Example 21 Serotonin (5HT) at synapses in vitro
, dopamine (DA) and norepinephrine (NE) uptake in trans-(R)-N-methyl-4-(3.
4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine salt.
D Rat (Jars River Laboratories, Inc. (Ch.
arlesRiverLabOratOries,. I
nc. , Wilmington, Mass.) was used.

For 5HT and DA uptake, rat corpus striatum crude synaptic fractions and for NE uptake, hypothalamic tissue crude synaptic fractions were collected using ice-cold 1η/ ml glucose, 0.0001
in a 0.32 M sucrose solution at pH 7.4 containing MEDTA and tris(hydroxymethyl)aminomethane (2
It was prepared by homogenizing at 5 ml/wet tissue 17).

The homogenate was centrifuged for 10 minutes at 1000G and O-4°C, the pellet was discarded and the supernatant was centrifuged for 20 minutes at 17000G and O-4°C.

The obtained pellets were ice-cooled at 0.32M with a pH of 7.4.
10 m1/y (tissue) for striae in sucrose solution (
The hypothalamus was resuspended at a rate of 5 m1/y (tissue) (wet). 26mM tris(hydroxymethyl)aminomethane with HCl (adjusted to pH 7.4, 124mM NaCl, 4.5mM KC1, 1.
2mMKH2P04, 1.3mM MgC12・6H,0
, 0.001mM ascorbic acid, 0.0125mM Nialamide hydrochloride and 2.8mM CaC12 was prepared as an incubation buffer.

Tissue Suspension 1 in 0.1 d portions for 10 min at 37°C with 0.02 ml of a solution containing a known amount of the title test compound and an additional 0.0001 ml of glucose at 1 rf1f/ml.
It was incubated with 11.0 ml of incubation buffer containing mM labeled monoamine (14C-5HT114C-DA or 3H-NE). After incubation, the mixture was mixed into 0.45 micron millibore (Mil)
The mixture was filtered through an llpOre filter and the filter was washed with incubation buffer. 1.
Dissolved in 0 ml of 2-methoxyethanol, liquid syn*
Radioactivity was measured using a 2-chillation counter.
(The uptake at 0°C was used as the radiation blank.) The uptake was picomole 5HT, . Calculated as DA or NE/~(protein). The protein is folin (FOlln)
Measured by phenol reagent. the concentration of the title test compound (expressed as micromoles per liter in about 1 d of incubation mixture) that inhibits uptake by 50%, calculated based on the uptake calculated for the control sample in which no test compound is present; That is, IC5O was determined from a plot of % inhibition of uptake versus concentration on semi-log paper. As a result, a concentration of 0.039 micromolar for 5HT, a concentration of 0.044 micromolar for DA,
For NE, the concentration was 0.017 micromolar.
Examples 22-40c As in Example 21, the synaptic uptake protocols were determined in vitro for the compounds of the following examples.

Example 41 Reduction of despair behavior in vitro by trans-1 (IR)-N-methyl-4-(3,4-dichlorophenyl)-1, 2, 3, 4-tetrahydro-1-naphthalenamine hydrochloride.
t) etc. in ArcKInt. PharmacOdyh. 2
29, Pp 327-336 (1977) was used.

25-30y Sniss
-Wabster) CD male mice (Charles River Laboratories, Inc., Wilmington, Massachusetts)
Keep the housing cages under standard laboratory conditions for at least one week prior to the experiment and inject 10 mice in each group with a defined dose of the title test compound or vehicle (5% EmulphOr): 5% ethanol; 90% normal saline) was injected subcutaneously.

One hour later, each mouse was placed in a 1-liter picker containing 25°C water to a depth of 7c6t.

For the first 2 minutes after being placed in the water, each mouse was observed every 30 seconds for the presence or absence of immobility, which is characterized by floating motionless in water. A total of 10 observations were made, and each was scored as follows.゛゛o'' = When the animal moves, swims, and tries to escape; ゛゜1'' = When the animal is immobile. The number of positive observations for each mouse was summed to calculate the mean value of immobility for each group of 10 animals. For dose-response analysis, this data was converted to a %MPE (maximum possible effect) value expressed by the following formula: %MPE from the above day.

. That is, the dose that reduced immobility by 50% compared to the control was determined by linear regression analysis. As a result of this analysis,
%MPE5o of the title compound is 1.2? nf7/kg (
weight). Examples 42-50 In vivo despair behavior was determined for the following compounds by the method of Example 41.

Example 51 In vivo 5-hydroxytryptophan-induced behavior of trans-(IS)(IR)-N-methyl-4
-(3・4-dichlorophenyl)-1.2.3
．． 4-tetrahydro-1-naphthalenamine hydrochloride-enhanced fasted Swiss-Webster-CD male mice (weight 17-21 y) (Charles River Laboratories, Inc., Wilmington, MA) were administered to groups of 5 in various groups. administering an oral dose of the above test compound;
One hour later, 100 ~/kg (body weight) of 5-hydroxytryptophan (5HTP) was intraperitoneally administered.

This dose of 5HTP did not cause symptoms such as tremors in the serotonin uptake blocking agent-treated animals. These mice were examined for the presence of this symptom by a blinded observer 10-20 minutes after 5HTP treatment. Oral dose at which this symptom appeared, i.e. ED5
As a result of calculating the o value, for earthquakes it is 3.2 ~ z4q
(body weight) and 10 mf7/kq (body weight). Examples 52-62 Similar to the method of Example 51, 5-hydroxytryptophano-induced tremor enhancement was measured in vivo for the following compounds.

The acute toxicity of the compounds of the present invention in mice is as follows.

Claims (1)

[Scope of Claims] 1. A trans-isomer base of the following formula and a pharmaceutically suitable acid addition salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_1 is selected from the group consisting of hydrogen and normal alkyl having 1 to 3 carbon atoms, R_2 is normal alkyl having 1 to 3 carbon atoms, and Z is ▲ Formula, There are chemical formulas, tables, etc. ▼, where X and Y are selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl, and alkoxy having 1 to 3 carbon atoms, but at least one of X and Y is A group other than hydrogen, W is selected from the group consisting of hydrogen, 7-chloro and 7-methoxy. 2. The compound according to claim 1, which is a (IR)-enantiomer or a mixture of an (IR)-enantiomer and its corresponding (IS)-enantiomer. 3. A patent in which R_1 is hydrogen or methyl, R_2 is methyl, and Z is selected from the group consisting of 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3-bromphenyl, and 4-bromphenyl. A compound according to claim 2. 4. The compound according to claim 3, wherein W is hydrogen. 5. The compound according to claim 3, wherein R_1 is hydrogen. 6. The compound according to claim 2, wherein R_1 is methyl, R_2 is methyl, W is hydrogen, and Z is 3-trifluoromethylphenyl or 4-trifluoromethylphenyl. 7. The compound according to claim 5, wherein W is hydrogen and Z is 3,4-dichlorophenyl. 8. The compound according to claim 4, wherein R_1 is methyl and Z is 3,4-dichlorophenyl. 9. A compound according to claim 7 which is the (IR)-enantiomer. 10 (IR)-enantiomer and its corresponding (IS
)-enantiomer. 11 R_1 is hydrogen, R_2 is methyl, W
(IS)-enantiomer of the compound according to claim 1, wherein is hydrogen and Z is 3,4-dichlorophenyl.