JP2002510682A - Indol-3-yl-cyclohexylamine derivative for treating depression (5-HT1 receptor antagonist) - Google Patents

Abstract

  (57) [Summary] Effective in treating disorders of the neurological signs affected by serotonin (5-HT _1A(Receptor active) compounds are provided. Such compounds have the formula (I): Embedded image [Wherein, R₁And R_FiveIs each independently hydrogen, halogen, lower alkoxy, lower alkyl, cyano or trifluoromethyl;_TwoAnd R_FourIs each independently hydrogen, lower alkyl, phenyl or substituted phenyl;_ThreeIs hydrogen or lower alkyl; and X and Y are each independently O, NR₆Or CH_Two(Where R₆Is hydrogen, lower alkyl, phenyl or substituted phenyl)]] or a pharmaceutically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to compounds useful for treating diseases (eg, depression and anxiety) affected by disorders of the nervous system affected by serotonin. More specifically, the present invention relates to various indol-3-yl-cyclohexylamine derivatives useful for treating such diseases.

BACKGROUND OF THE INVENTION Pharmaceutical compounds that enhance serotonin (5-HT) transmission are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective drugs that affect serotonin act through a variety of physiology, which indicates that such drugs may have a number of undesirable side effects (eg, blurred vision, Dry and sedated). A recently introduced compound, a selective serotonin reuptake inhibitor (SSRI), inhibits the active removal of 5-HT released at the synapse from the synaptic cleft via the presynaptic serotonin transporter. By doing so, it works dominantly. This 5-HT blockade mechanism cannot fully explain their therapeutic activity, as SSRIs require several weeks to exert their full therapeutic effect. This 2-week induction, which occurs before a sufficient antidepressant effect is observed, is presumed to be due to the involvement of the 5-HT _1A autoreceptor, which suppresses the excitatory activity of 5-HT neurons, causing a diminished therapeutic effect. Studies suggest that 5-HT autoreceptor desensitization occurs several weeks after SSRI administration, resulting in a sufficient antidepressant effect in most patients. Therefore, Oshikire negative feedback by using 5-HT _{1 A} antagonist, is believed to accelerate increase the antidepressant response clinical. According to a recent study by Artigas et al. [ Trends in Neurosci. , 19: 378-383 (1996)], 5- _HT1A activity and 5- _HT1A activity were observed in a single molecule. By combining with the inhibition of HT uptake, a stronger and faster acting antidepressant effect can be achieved.

[0003] US Patent 3,058,980 discloses the preparation of compounds of the following formula, which are claimed to exhibit analgesic activity.

[0004]

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[0005] PCT Patent Application Publication No. WO 89-07596A discloses the preparation of compounds of the following formula that are active in various central nervous system disorders, including depression and schizophrenia.

[0006]

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[0007] Recently, US Pat. No. 4,612,312 discloses compounds of the following formula which may be useful as anxiolytics and antihypertensives.

[0008]

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SUMMARY OF THE INVENTION [0009] The present invention relates to novel molecules that have the ability to act simultaneously with the 5-HT transporter at the 5-HT _1A autoreceptor. Such compounds may therefore be useful in treating depression and other serotonin disorders.

The compounds of the present invention have the formula I:

[0011]

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Wherein R ₁ and R ₅ are each independently hydrogen, halogen, lower alkoxy, lower alkyl, cyano or trifluoromethyl; R ₂ and R ₄ are each independently hydrogen, lower R ₃ is hydrogen or lower alkyl; and X and Y are each independently O, NR ₆ or CH ₂ , wherein R ₆ is hydrogen,
Lower alkyl, phenyl or substituted phenyl)] or an indole-3-yl-cyclohexylamine derivative or a pharmaceutically acceptable salt thereof.

The compounds of the present invention preferably have the formula I wherein R ₁ and R ₅ are each independently hydrogen or halogen; R ₂ and R ₄ are each hydrogen; R ₃ is hydrogen; X and Y are each independently a compound represented by O or NR ₆ (where R ₆ is hydrogen)] or a pharmaceutically acceptable salt thereof.

The compounds of the present invention are more particularly selected from the following compounds: (3,4-dihydro-benzo [1,4] oxazin-2-ylmethyl)-[cis-4- (5 -Fluoro-1H-indol-3-yl) -cyclohexyl] -amine; (3,4-dihydro-benzo [1,4] oxazin-2-ylmethyl)-[trans-4- (5-fluoro-1H-indole) (3--3-yl) -cyclohexyl] -amine; (3,4-dihydro-benzo [1,4] oxazin-3-ylmethyl)-[cis-4- (5-fluoro-1H-indol-3-yl)- Cyclohexyl] -amine; and (3,4-dihydro-benzo [1,4] oxazin-3-ylmethyl)-[trans-4- (5-fluoro-1H-indol-3-yl) -cyclohexyl] -amine.

As used herein, the terms “lower alkyl” and “lower alkoxy” are meant to include straight and branched carbon chains having 1-6 carbon atoms. The term "halogen" is meant to include fluorine, chlorine, bromine and iodine. "Substituted phenyl" may include substitution by halogen, lower alkyl, lower alkoxy and cyano groups.

The compounds of formula I may be used in the form of pharmaceutically acceptable acid addition salts having the utility of a free base. Such salts are prepared by methods known in the art, but are formed using either inorganic or organic acids. Such inorganic and organic acids include, for example, fumaric acid, maleic acid, benzoic acid, ascorbic acid, pamoic acid, succinic acid, bismethylene salicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, oxalic acid, propionic acid, tartaric acid , Salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid,
Stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, cyclohexylsulfamic acid, phosphoric acid and nitric acid.

The compounds of the present invention may be prepared by any suitable method known to those skilled in the art.
However, the compounds of the present invention may be prepared according to any one of Schemes 1-3 below. In these schemes, the intermediate compounds exemplified below are identified in parentheses. The compounds made in each of these schemes have been identified by reference to the appropriate examples.

The compounds of Formula I are generally prepared by all routes shown in Schemes 1-3 below. In these schemes, the intermediate compounds exemplified below are identified in parentheses. The compounds prepared in each of Schemes 1-3 have been identified by reference to the appropriate examples.

[0019]

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[0020]

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[0021]

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The present invention will now be described in more detail by the following specific but non-limiting examples.

Intermediate 1 4- (5-Fluoro-1H-3-indolyl) -cyclohex-3-enone ethylene.
Ketal 5-fluoroindole (5.4 g, 0.04 mol), 1,4-cyclohexanedione-monoethylene ketal (12.5 g, 0.08 mol) was added to potassium hydroxide
It was put in 60 mL of N methanol solution. The reaction mixture was heated at reflux for 4 hours. The reaction was cooled, the product was isolated by filtration, washed with methanol and 10.1 g of product (
93%) as a white solid. 153-155 ° C.

Intermediate 2 4- (5-Fluoro-1H-3-indolyl) -cyclohexanone ethylene ketal 4- (5-Fluoro-1H-3-indolyl) -cyclohex-3-enone in ethanol (200 mL) -Ethylene ketal (2.7 g, 0.01 mol) and 10
The mixture of% palladium / carbon (1.2 g) was hydrogenated for 4 days. The catalyst was filtered off and the filtrate was concentrated. The product was dried in vacuo to give 2.8 g (100%) of the product as a white solid. 183-185 ° C.

Intermediate 3 4- (5-Fluoro-1H-3-indolyl) -cyclohexanone 4- (5-Fluoro-1H-3-indolyl) -cyclohexanone in 200 mL of (1: 1) tetrahydrofuran-hydrochloric acid (1N)・ Ethylene ketal (2.8 g, 0.1 g)
(01 mol) was stirred at room temperature for 16 hours. The mixture was concentrated to half volume. The aqueous layer was extracted with ethyl acetate. The organic extract was washed with brine, dried (over anhydrous sodium sulfate) and filtered. The crude product was purified by flash chromatography (40% ethyl acetate in hexane) to give 2.1 g (91%) of the product as a yellow solid. 112-114 ° C.

Intermediate 4 2,3-Dihydro-2H-benzo [1,4] oxazine-2-carboxylic acid ester 2-aminophenol (10.0 g, 0.089 in acetone (100 mL)
Mol), anhydrous potassium carbonate (15.2 g, 0.108 mol) was added, followed by 2,2
Ethyl 3-dibromopropionate (23.6 g, 0.092 mol) was added in four portions at reflux temperature. The reaction mixture was stirred at reflux for 21 hours and cooled. Solids were removed by filtration and the filtrate was concentrated. The residue was dissolved in cold 1N sodium hydroxide and extracted with ethyl ether. The combined organic extracts were washed with brine, dried (over anhydrous sodium sulfate), filtered, and concentrated. Chromatography (ethyl acetate / hexane: 1/2) provided 6.25 g (34.4%) of the product as a brown oil.

Intermediate 5 3,4-dihydro-2H-benzo [1,4] oxazin-2-yl) -methanol 2,3-dihydro-2H-benzo [1,4] oxazine in anhydrous tetrahydrofuran (60 mL) 2-Carboxylic acid ethyl ester (11.9 g, 19.0 mmol)
To a solution of was added a 2M solution of lithium borohydride (15 mL) at room temperature. After stirring the reaction for 1 hour, it was quenched by slow addition of methanol. After 2 hours, water (100 mL) was slowly added and the reaction mixture was added to ethyl acetate (4 × 100 mL)
Extracted. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under vacuum. Purification by chromatography (ethyl acetate / hexane / methanol: 3/6/1) gave 1.96 g (62%) of the product as an oil. MS
(EI) m / e 165 (M +).

Intermediate 6 2-Hydroxymethyl-2,3-dihydro-2H-benzo [1,4] oxazine-4-carboxylate tert-butyl ester 3,4-dihydro-2H in anhydrous tetrahydrofuran (200 mL) -Benzo
To a solution of [1,4] oxazin-2-yl) -methanol (10.7 g, 65.0 mmol) was added di-tert-butyl dicarbonate (62 g) in tetrahydrofuran (40 mL) slowly. The reaction was heated at reflux for 4 hours, cooled to room temperature and then water (100 mL)
And extracted with ethyl ether (3 × 100 mL). The organic layer was washed with water (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (ethyl acetate / hexane: 1/2) showed the product 12
.9 g were obtained as a white solid (75%). 93.5-94.5 ° C; MS (EI
) m / e 265 (M +). Elemental analysis (as C ₁₄ H ₁₉ NO _4): Calculated: C, 63.38; H, 7.22 ; N, 5.28 Found: C, 63.53; H, 7.32 ; N , 5.38

Intermediate 7 t-Butyl-2,3-dihydro-2H-benzo [1,4] oxazine-4-carboxylate-2-methyltosylate 2-Hydroxymethyl- in anhydrous pyridine (15 mL) 2,3-dihydro-2H-benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester (80 mg, 0
0.3 mmol) and p-toluenesulfonyl chloride (86 mg) was stirred at room temperature overnight. The reaction mixture was quenched with 1N HCl (20 mL) and extracted with methylene chloride (3 × 20 mL). The organic layer was washed with 1N HCl (2 × 20 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (ethyl acetate / hexane: 1/2) provided 120 mg (94%) of the product as a thick oil. MS (FAB) m / e 419 (M + Na). Elemental analysis (as C ₂₁ H ₂₅ NO ₆ S): Calculated: C, 60.13; H, 6.01; N, 3.34 Found: C, 60.13; H, 6.11; N, 3.56

Intermediate 8 t-Butyl-2,3-dihydro-2H-benzo [1,4] oxazine-4-carboxylate-2-methylazide t-Butyl-2, in anhydrous dimethylformamide (150 mL) 3-dihydro
-2H-benzo [1,4] oxazine-4-carboxylate-2-methyltosylate (1
4.9 g, 33.9 mmol) and sodium azide (4.4 g, 67.7 mmol)
)) Was heated at 60 ° C. for 20 hours. The reaction mixture was poured into water (150 mL) and extracted with methylene chloride (3 × 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Purification by chromatography (hexane) provided 8.7 g (88%) of the product as a white solid. 82-83 ° C. Elemental analysis (as _{C 14 H 18 N 4 O 3} ): Calculated: C, 57.92; H, 6.25 ; N, 19.30 Found: C, 58.07; H, 6.21 N, 19.03

Intermediate 9 t-Butyl-2,3-dihydro-2H-benzo [1,4] oxazine-4-carboxylate-2-methylamine in tetrahydrofuran (150 mL) containing water (4 mL) t-butyl-
2,3-dihydro-2H-benzo [1,4] oxazine-4-carboxylate-2-methylazide (6.25 g, 21.6 mmol) and triphenylphosphine (6.4 g)
) Was stirred at room temperature for 18 hours. The solvent was removed under vacuum. The residue was dissolved in ethyl ether (100 mL). After adding hexane (50 mL), the precipitated triphenylphosphine oxide was separated by filtration. The filtrate was concentrated and the residue was purified by chromatography (5% methanol in methylene chloride) to give 7.2 g of the product, which contained a small amount of triphenylphosphine oxide. MS (FAB) m / e
265 (M + H ^< + ^> ).

Intermediate 10 (t-butyl-3,4-dihydro-benzo [1,4] oxazine-4-carboxylate-
2-methyl)-[cis-4- (5-fluoro-1H-indol-3-yl) -cyclohexyl
] -Amine 4- (5-Fluoro-1H-indol-3-yl) -cyclohexanone (0.74 g, 3.2 mmol) in 1,2-dichloroethane (14 mL), t-butyl-2,3-
Dihydro-2H-benzo [1,4] oxazine-4-carboxylate-2-methylamine (0.80 g, 3.02 mmol), sodium triacetoxyborohydride (1.0
g, 4.5 mmol) and acetic acid (0.18 mL, 3.2 mmol) at room temperature.
Stirred for .5 hours. The reaction was quenched with 1N sodium hydroxide and extracted with methylene chloride. The combined organic extracts were washed with brine, dried (over anhydrous sodium sulfate), filtered, and concentrated. Chromatography (ethyl acetate / hexane: 3/7 to 5/5) provided 1.40 g of the title compound as a cis / trans mixture. It was used without further separation.

Example 1 (3,4-dihydro-benzo [1,4] oxazin-2-ylmethyl)-[cis-4- (5-fluoro-1H-indol-3-yl) -cyclohexyl] -amine and (3,4-dihydro-benzo [1,4] oxazin-2-ylmethyl)-[trans-4- (5-fluoro-1
H-Indol-3-yl) -cyclohexyl] -amine cis / trans- (t-butyl-3,4-dihydro-benzo [1,4] oxazine-4-carboxylate-2 in methylene chloride (15 mL). To a solution of -methyl)-[4- (5-fluoro-1H-indol-3-yl) -cyclohexyl] -amine was added trifluoroacetic acid (5 mL) at room temperature. After stirring the reaction mixture at room temperature for 2 hours, the solvent was removed. A small amount of methanol was added to the residue and the solution was adjusted to pH> 9 with 2N NaOH. The aqueous layer was extracted with methylene chloride. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by chromatography _{(EtOAc / MeOH / NH 4 OH} : 99/1 / 0.5) to afford the cis isomer 0.41g (35%) as a white solid. 65-67 ° C. The HCl salt of the cis isomer was prepared in ethyl acetate. 120 ° C (decomposition). Elemental analysis (as _{C 23 H 26 FN 3 O ·} 2HCl): Calculated: C, 61.06; H, 6.24 ; N, 9.29 Found: C, 61.06; H, 6 . 40; N, 8.71 The trans isomer was isolated as a white solid in 19% yield (0.22 g). 66-68 ° C. The HCl salt of the trans isomer was prepared in ethyl acetate. Melting point 1
55 ° C (decomposition). Elemental analysis (as _{C 23 H 26 FN 3 O ·} HCl · 0.75H 2 O · 0.33EtOH): Calculated: C, 63.71; H, 6.85 ; N, 9.16 Found: C, 63.40; H, 6.70; N, 8.97

Example 2 (3,4-dihydro-benzo [1,4] oxazin-3-ylmethyl)-[cis-4- (5-fluoro-1H-indol-3-yl) -cyclohexyl] -amine and (3,4-dihydro-benzo [1,4] oxazin-3-ylmethyl)-[trans-4- (5-fluoro-1
H-Indol-3-yl) -cyclohexyl] -amine 4- (5-Fluoro-1H-indol-3-yl) -cyclohexanone (0.578 g, 2.5 mmol) in 1,2-dichloroethane (11 mL) ), 3-aminomethyl-1,4-benzoxazine (0.411 g, 2.5 mmol), sodium triacetoxyborohydride (0.78 g, 3.5 mmol) and acetic acid (0.14 mL, 2. (5 mmol) was stirred at room temperature for 5 hours. The reaction was quenched with 1N sodium hydroxide and extracted with methylene chloride. The combined organic extracts were washed with brine,
Dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by chromatography _{(EtOAc / MeOH / NH 4 OH} : 99/1 / 0.5) to afford the cis isomer 0.63g (66%) as an oil. The fumarate salt of the cis isomer was prepared in isopropanol. 208-209 ° C. Elemental analysis _{(C 23 H 26 FN 3 O} · 0.5C 4 H 4 O 4 · 0.3H 2 O · 0.24i-
As PrOH): Calculated: C, 67.55; H, 6.73; N, 9.19 Found: C, 67.75; H, 6.69; N, 8.99. 33% (0.32 g) isolated as an oil. The fumarate salt of the trans isomer was prepared in isopropanol. Melting point 275-277
° C (decomposition). Elemental analysis (as _{C 23 H 26 FN 3 O ·} 0.5C 4 H 4 O 4 · 0.3H 2 O): Calculated: C, 67.79; H, 6.51 ; N, 9.49 Found: C, 67.58; H, 6.47; N, 9.18.

The activity of the compounds of the present invention is demonstrated by the following standard pharmacological tests.

[0036] PCR cloning of the human 5-HT _1A receptor subtype from a human genomic library has been previously reported by Chanda et al. [Molecular.
Pharmacology ( Mol. Pharmacol. ), 43: 516 (1993)]. Through this study, we adopted the human 5-HT _1A receptor stable Chinese hamster ovary fine vesicular systems expressing subtype (5-HT _1A .CHO cells). Cells were maintained in DMEM supplemented with 10% fetal calf serum, non-essential amino acids and penicillin / streptomycin.

After growing the cells as a monolayer to 95-100% confluence, the membrane was harvested for binding studies. Gently scrape cells from culture plate, transfer to centrifuge tube,
Centrifuge in buffer (50 mM Tris; pH 7.5) (2000 rpm for 10 minutes,
(4 ° C.). The resulting pellet was aliquoted and stored at -80 ° C. On the day of the assay, cells were thawed on ice and resuspended in buffer. [ ³ H] 8-OH
Studies were performed using -DPAT as radioligand. Binding assays were performed in a 96-well microtiter plate with a final total volume of buffer of 250 μL. Competition experiments were performed using seven concentrations of unlabeled drug and a final ligand concentration of 1.5 nM. Non-specific binding was determined in the presence of 10 μM 5-HT. Saturation analysis was performed using [ ³ H] 8-OH-DPAT at concentrations ranging from 0.3 to 30 nM. After incubation at room temperature for 30 minutes, ice-cold buffer was added and the M-96 Brandel cell harvester (Gaithersburg) was added.
), Maryland), the reaction was stopped by rapid filtration through a GF / B filter presoaked in 0.5% polyethyleneimine for 30 minutes.

[0038] Chisamu (Cheetham) that used by al [neuro Pharmacology, 32 (Neu rophamacol.): 737 (1993)] using a similar protocol was measured affinity of a compound for serotonin transformer Porter . Briefly, frontal cortical membranes prepared from male Sprague-Dawley rats were incubated with ³ H-paroxetine (0.1 nM) at 25 ° C. for 60 minutes. All tubes also contained either excipients, test compounds (1-8 concentrations), or saturating concentrations of fluoxetine (10 μM) that defined specific binding. After stopping all reactions by adding ice-cold Tris buffer, the conjugate was separated from free ³ H-paroxetine by rapid filtration using a Tom Tech filtration device. The radioactivity of the conjugate was measured using Wallac 120
Quantification was performed using a 5 Beta Plate ^R counter. IC ₅₀ values were determined using non-linear regression analysis. This is the case for Cheng and Prusoff
[Biochemical Pharmacol. , 22: 3099 (19
73)]; Ki = IC50 / ((radioligand concentration) / (1 + KD)).

[ ³⁵ S] -GTPγS binding assays were performed using Lazareno and Birdsall (
Birdsall) [British Journal of Pharmacology ( Br. J. Pharmacol. ), 109: 1120 (1993)]. Briefly, membrane fragments of the 5-HT _1A cloned receptor (used in the 5-HT _1A receptor binding assay) were stored at -70 ° C until needed. When needed, the membrane was quickly thawed, centrifuged at 40,000 × g for 10 minutes, and assay buffer (25 mM HEPES, 3 mM MgCl ₂ , 100 mM NaCl, 1 mM EDTA, 10 μM GDP, 500 mM DTT, pH 8). .0) at 4 ° C for 10 minutes. These membranes were then added to [ ³⁵ S] GTPγS (1 nM) in the presence of excipients, test compounds (1-8 concentrations), or an excess of 8-OH-DPAT that defined maximal agonist response.
For 30 minutes at 30 ° C. By adding ice-cold Tris buffer, after all the reaction was stopped, filtered hastily have use a filtration apparatus Tom Tech (Tom Tech ^R), the bound from free ^[35 S] GTPγS separation did. Agonists to increase the amount of binding of ^{[3 5} S] GTPγS, antagonists not increase the binding.
Bound radioactivity was counted and analyzed as described above.

[0040] The following assay was performed using 25 mM HEPES, 5 mM theophylline (theo
phylline) and DMEM containing 10 μM pargyline.
Performed by incubating at 20 ° C. for 20 minutes. Functional activity was assayed by treating cells with forskolin (final concentration 1 μM) followed immediately by treatment with test compounds (six concentrations) at 37 ° C. for an additional 10 minutes. In separate experiments, six concentrations of antagonist were pre-incubated for 20 minutes before adding 10 nM 8-OH-DPAT and forskolin. The reaction was stopped by removing the medium and adding 0.5 mL of ice-cold assay buffer. Plates were stored at −20 ° C. before assessing cAMP formation by the cAMP SPA assay (Amersham).

The results of the tests using the compounds of Examples 1 and 2 are shown in the table below.

[0042]

[Table 1]

The compounds of the present invention can be administered orally or parenterally, as such, or in combination with conventional pharmaceutical carriers. Applicable solid carriers include one or more of which can also act as a flavoring agent, lubricant, solubilizer, suspending agent, filler, flow agent, compression aid, binder, or tablet disintegrant. The above substances or encapsulating materials can be mentioned. In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Any solid carrier known to those skilled in the art may be used with the compounds of the present invention. Particularly suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose,
Methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.

Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs of the compounds of the invention. The compounds of the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. Liquid carriers include other agents such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavors, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers or osmotic pressure regulators. Can be included. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly as described above with additives such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (monohydric alcohols and polyhydric alcohols). Alcohol, for example
Glycols and derivatives thereof, and oils such as fractionated coconut and peanut oils. For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid compositions for parenteral administration.

Liquid pharmaceutical compositions that are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The composition for oral administration may be in the form of a liquid or solid composition.

Preferably, the pharmaceutical compositions containing the compounds of the present invention are in unit dosage form, for example, as tablets or capsules. In such form, the composition is subdivided into unit doses containing appropriate quantities of a compound of the present invention. The unit dosage form can be a packaged composition, for example, packeted powders, vials, ampoules, filled syringes or liquid sachets. Alternatively, the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

The therapeutically effective amount and dosage regimen of the compound of the invention administered will include patient weight, age, gender and treatment status, disease severity, route and frequency of administration, and the particular compound employed. Depends on various factors and can therefore vary widely.
However, it is envisaged that the above pharmaceutical compositions may contain a compound of the present invention in a range of about 0.1 to about 2000 mg, preferably about 0.5 to about 500 mg, more preferably about 1 to about 100 mg. It is. The planned daily dose of the active compound is about 0.01 to about 100 mg / kg body weight. The daily dose can conveniently be administered 2 to 4 times a day.

The present invention may be embodied in other specific forms without departing from its spirit and essential attributes, and as such are intended to be indicative of the scope of the invention rather than the foregoing specification. Reference should be made to the appended claims.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS , JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Ping Chou United States 08536 Plainsborough, NJ 08536 , Marion Drive No. 28 F term (reference) 4C063 AA01 BB09 CC54 DD06 EE01 4C086 AA01 AA02 AA03 BC74 GA07 GA09 MA01 MA04 NA14 ZA12

Claims (8)

[Claims] 1. The formula: embedded image Wherein R ₁ and R ₅ are each independently hydrogen, halogen, lower alkoxy, lower alkyl, cyano or trifluoromethyl; R ₂ and R ₄ are each independently hydrogen, lower alkyl, phenyl Or substituted phenyl; R ₃ is hydrogen or lower alkyl; and X and Y are each independently O, NR ₆ or CH ₂ (where R ₆ is hydrogen,
Lower alkyl, phenyl or substituted phenyl)] or a pharmaceutically acceptable salt thereof. 2. R ₁ and R ₅ are each independently hydrogen or halogen; R ₂ and R ₄ are each hydrogen; R ₃ is hydrogen; and X and Y are each independently O or NR. _6. The compound according to claim 1, wherein R ₆ is hydrogen, or a pharmaceutically acceptable salt thereof. 3. (3,4-dihydro-benzo [1,4] oxazin-2-ylmethyl)
The compound according to claim 1, which is-[cis-4- (5-fluoro-1H-indol-3-yl) -cyclohexyl] -amine. 4. (3,4-dihydro-benzo [1,4] oxazin-2-ylmethyl)
The compound according to claim 1, which is-[trans-4- (5-fluoro-1H-indol-3-yl) -cyclohexyl] -amine. 5. (3,4-dihydro-benzo [1,4] oxazin-3-ylmethyl)
The compound according to claim 1, which is-[cis-4- (5-fluoro-1H-indol-3-yl) -cyclohexyl] -amine. 6. (3,4-dihydro-benzo [1,4] oxazin-3-ylmethyl)
The compound according to claim 1, which is-[trans-4- (5-fluoro-1H-indol-3-yl) -cyclohexyl] -amine. 7. A compound of the formula: Wherein R ₁ and R ₅ are each independently hydrogen, halogen, lower alkoxy, lower alkyl, cyano or trifluoromethyl; R ₂ and R ₄ are each independently hydrogen, lower alkyl, phenyl Or substituted phenyl; R ₃ is hydrogen or lower alkyl; and X and Y are each independently O, NR ₆ or CH ₂ (where R ₆ is hydrogen,
A lower alkyl, phenyl or substituted phenyl)] or a pharmaceutically acceptable salt thereof. 8. A method of alleviating the symptoms of depression in a patient in need thereof, comprising the step of formulating an antidepressant effective amount in said patient: Wherein R ₁ and R ₅ are each independently hydrogen, halogen, lower alkoxy, lower alkyl, cyano or trifluoromethyl; R ₂ and R ₄ are each independently hydrogen, lower alkyl, phenyl Or substituted phenyl; R ₃ is hydrogen or lower alkyl; and X and Y are each independently O, NR ₆ or CH ₂ (where R ₆ is hydrogen,
Lower alkyl, phenyl or substituted phenyl)] or a pharmaceutically acceptable salt thereof.