KR20000022044A - Indoline derivatives useful as 5-ht-2c receptor antagonists - Google Patents

Abstract

PURPOSE: Indoline derivatives useful as 5-ht-2c receptor antagonists are provided, which is used to treat melancholia, epilepsy, obsession, and consternation. CONSTITUTION: The invention relates to heterocyclic compounds of formula (I) or a salt thereof wherein R¬1 is hydrogen or C1-6 alkyl; R¬2, R¬3 and R¬4 groups are independently hydrogen, halogen or C1-6 alkyl optionally substituted by one or more fluorine atoms, having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders such as anxiety.

Description

Indoline Derivatives Useful as 5-HT-2C Receptor Antagonists

The present invention relates to a compound having pharmacological activity, a method for preparing the compound, a composition containing the compound and its use in treating CNS symptoms.

PCT / EP96 / 00368 (SmithKline Beecham plc) describes indole and indolin derivatives described as having 5HT _{2C / 2B} receptor antagonist activity. Novel compounds have been found that fall within the overall domain of PCT / EP96 / 00368 but are not specifically disclosed in the specification, which surprisingly has an improved 5HT _2C receptor antagonist activity profile (enhancement of activity and duration of action after oral administration). Found. 5HT _2C receptor antagonists include CNS symptoms such as anxiety, depression, epilepsy, obsessive compulsive disorder, migraine, Alzheimer's disease, sleep disorders, eating disorders (e.g. anorexia and bulimia), panic attacks, drugs (e.g., Cocaine, ethanol, nicotine and benzodiazepines) are believed to be useful in the treatment of symptoms related to head injury such as withdrawal, schizophrenia, and spinal cord injury and / or hydrocephalus. In addition, the compounds of the present invention are expected to be useful for the treatment of certain GI (gastrointestinal) disorders, such as IBS (irritable bowel syndrome) as well as microvascular diseases such as macular edema and retinopathy.

Accordingly, the present invention provides, in a first aspect, a compound of formula (I) or a salt thereof.

In the above formula,

R ¹ is hydrogen or C _1-6 alkyl,

R ² , R ³ and R ⁴ groups are independently hydrogen, halogen, or C _1-6 alkyl optionally substituted with one or more fluorine atoms.

The C _1-6 alkyl group, alone or as part of another group, may be straight or branched chain.

Suitably, R ¹ is hydrogen or C _1-6 alkyl, preferably R ¹ is hydrogen.

Suitably, the R ² , R ³ and R ⁴ groups are independently hydrogen, halogen, or C _1-6 alkyl optionally substituted with one or more fluorine atoms. Preferably, R ² is C _1-6 alkyl substituted with at least one fluorine atom, in particular CF ₃ , and R ³ is C _1-6 alkyl, especially methyl; R ² is hydrogen and R ³ is halogen, in particular bromine; Or C _1-6 alkyl substituted with one or more fluorine atoms, in particular CF ₃ . Preferably, R ⁴ is hydrogen or C _1-6 alkyl, in particular methyl.

Specific compounds of the present invention

5-methyl-1- [2- (pyridin-2-ylmethyloxy) pyridin-5-ylcarbamoyl] -6-trifluoromethylindolin,

1- [2- (pyridin-2-ylmethyloxy) pyridin-5-ylcarbamoyl] -5-trifluoromethylindolin,

5-methyl-1- [2- (pyridin-2-ylmethyloxy) -3-methylpyridin-5-ylcarbamoyl] -6-trifluoromethylindolin,

5-bromo-1- [2- (pyridin-2-ylmethyloxy) pyridin-5-ylcarbamoyl] -indolin,

1- [2- (pyridin-2-ylmethyloxy) pyridin-5-ylcarbamoyl] -6-trifluoromethyl-indolin, and

Pharmaceutically acceptable salts thereof.

Compounds of formula (I) are acids, for example conventional pharmaceutically acceptable acids such as maleic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid, lactic acid, mandelic acid, tartaric acid and methane Acid addition salts with sulfonic acids can be formed.

In addition, the compounds of formula (I) may form N-oxides or solvates, for example hydrates, and the present invention includes these forms. When referred to herein, the term "compound of formula (I)" is understood to include these forms as well.

Certain compounds of formula (I) may exist in stereoisomeric forms, including enantiomers, and the invention encompasses each of these stereoisomeric forms, including racemates, and mixtures thereof. Different stereoisomeric forms may separate one from the other by conventional methods, or any particular isomer may be obtained by stereospecific or asymmetric synthesis. In addition, the present invention includes any tautomeric forms and mixtures thereof.

The compounds of the present invention are reacted using, for example, standard methods as described in PCT / EP96 / 00368, for example by reacting a compound of formula (II) with a compound of formula (III) It can be prepared by optionally forming a salt.

In the above formula,

R ¹ , R ² , R ³ and R ⁴ are as defined in formula (I),

A and B contain the appropriate functional group (s) necessary to form -NHCO- moieties in the reaction, and suitable A and B groups

(i) A is -N = C = O and B is hydrogen, or

(ii) A is -NHCOL and B is hydrogen;

(iii) A is -NH ₂ and B is COL, or

(iv) A is halogen, B is -CONH ₂ , where L is a leaving group. Examples of suitable leaving groups L include halogen (eg chloro, bromo), imidazole, or phenoxy or phenylthio optionally substituted with one or more halogens, for example.

Compounds of formulas (II) and (III) can be prepared using known methods or methods analogous to known methods, for example those described in International Patent Nos. 95/01976 and PCT / EP96 / 00368.

In addition, novel intermediates of formulas (II) and (III) also form part of the invention.

Pharmaceutically acceptable salts can be prepared conventionally by reaction with the appropriate acid or acid derivative. N-oxides can be conventionally formed by reaction with hydrogen peroxide or percarboxylic acid.

Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT _2C receptor antagonist activity and have CNS symptoms such as anxiety, depression, epilepsy, obsessive compulsive disorder, migraine, Alzheimer's disease, sleep disorders (24 hour cycle) Disorders), eating disorders (e.g. anorexia and bulimia), panic attacks, withdrawal, schizophrenia, and spinal injuries resulting from abuse of drugs (e.g. cocaine, ethanol, nicotine and benzodiazepines), and / or It is believed to be useful for the treatment of symptoms related to head injury, such as hydrocephalus. In addition, the compounds of the present invention are expected to be useful in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular edema and retinopathy.

Accordingly, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof, which are used in particular as therapeutic substances in the treatment or prevention of such symptoms.

The present invention also provides a method of treating or preventing said condition in a mammal, including a human, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. .

In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of such symptoms.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Pharmaceutical compositions of the invention can be prepared by mixing at ambient temperature and atmospheric pressure, as appropriate, usually prepared for oral, parenteral or rectal administration, for example tablets, capsules, oral preparations, powders, It may be in the form of granules, sugar tablets, powders for solutions, solutions for injection or infusion or as suspensions or suppositories. Compositions for oral administration are often preferred.

Tablets and capsules for oral administration may be in unit dosage form and may contain conventional excipients such as binders, fillers, tablet lubricants, disintegrants and acceptable wetting agents. Tablets may be coated according to methods known in the conventional pharmaceutical art.

Oral preparations may be, for example, in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be in the form of dry products which are dissolved in water or other suitable vehicle before use. Such preparations may contain customary additives such as suspending agents, emulsifiers, non-aqueous vehicles (including cooking oil), preservatives, and conventional flavoring or coloring agents as desired.

For parenteral administration, fluid unit dosage forms are prepared using a compound of the invention or a pharmaceutically acceptable salt and sterile vehicle thereof. Depending on the vehicle used and its concentration, the compound may be suspended or dissolved in the vehicle. In the preparation of solutions, the compounds may be dissolved for injection, filled into appropriate vials or ampoules and filtered sterilized prior to closure. Advantageously, adjuvants such as local anesthetics, preservatives and buffers are dissolved in the vehicle. To improve stability, the composition is filled into vials, then frozen and water is removed under reduced pressure. Parenteral suspensions are prepared in substantially the same manner except that the compounds are suspended instead of dissolved in the vehicle and cannot be sterilized by filtration. Compounds can be sterilized by exposure to ethylene oxide prior to suspension in sterile vehicles.

Advantageously, surfactants or wetting agents are included in the composition to facilitate uniform distribution of the compound.

The composition may contain 0.1 to 99% by weight, preferably 10 to 60% by weight of active substance, depending on the method of administration.

The dosage of the compound used to treat the above-mentioned symptoms will vary in a conventional manner depending on the severity of the symptoms, the weight of the patient, and other similar factors. However, a suitable unit dosage of the general standard may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg, and such unit dosage may be at least once a day, for example 1 It may be administered two or three times daily, such that the total daily dose ranges from about 0.5 to 100 mg, and such treatment can be extended to weeks or months.

When administered according to the invention there will be no unacceptable toxic effects on the compounds of the invention.

The following description and examples illustrate the preparation of the compounds of the invention.

<Description 1>

5-nitro-2- (pyridin-2-ylmethyloxy) pyridine (D1)

2-pyridylcarbinol (7.5 g, 0.069 mol) in dry dimethylformamide (190 mL) was cooled to −20 ° C. and treated under argon partitioned into 80% dispersion of sodium hydride in mineral oil (2.07 g, 0.069 mol). . The mixture was stirred at -20 ° C for 2 h. 2-Chloro-5-nitropyridine (8.83 g, 0.058 mol) was added and the mixture was stirred at −20 ° C. for 0.5 h, then warmed to rt and stirred for 18 h. Water was added dropwise and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane, washed with 10% aqueous sodium hydroxide solution and then water, dried (Na ₂ SO ₄ ) and evaporated under reduced pressure to afford the title compound (12.2 g, 91%) as an orange solid.

¹ H NMR (250 MHz; CDCl ₃ ) δ (ppm): 5.61 (2H, s), 6.98 (1H, d, J = 8), 7.21-7.31 (1H, m), 7.45 (1H, d, J = 8), 7.73 (1H, dt, J = 2,7), 8.40 (1H, dd, J = 3,8), 8.65 (1H, d, J = 3), 9.10 (1H, d, J = 2) .

<Description 2>

5-amino-2- (pyridin-2-ylmethyloxy) pyridine (D2)

5-nitro-2- (pyridin-2-ylmethyloxy) pyridine (D1, 2.0 g, 0.0087 mol) in ethanol (70 mL) tin (II) chloride (8.3 g, 0.044 mol) in concentrated HCl (15 mL) ). The mixture was heated at 50 ° C. for 0.5 h. After cooling to room temperature, the mixture was diluted with water, basified with 10% aqueous sodium hydroxide solution, extracted with ethyl acetate, dried (Na ₂ SO ₄ ) and evaporated under reduced pressure to give the title compound (1.36 g, 78%) was obtained.

¹ H NMR (200 MHz; CDCl ₃ ) δ (ppm): 3.38 (2H, br s), 5.43 (2H, s), 6.73 (1H, d, J = 8), 7.06 (1H, dd, J = 3 9), 7.13-7.26 (1H, m), 7.45 (1H, d, J = 8), 7.58-7.77 (2H, m), 8.60 (1H, d, J = 5).

<Description 3>

Phenyl N- [2- (pyridin-2-ylmethyloxy) pyridin-5-yl] carbamate (D3)

5-amino-2- (pyridin-2-ylmethyloxy) pyridine (D2, 1.36 g, 0.0068 mol) in dichloromethane (50 mL) was cooled to 0 ° C. under argon. Triethylamine (1.04 mL, 0.0075 mol) is added, then phenyl chloroformate (0.94 mL, 0.0075 mol) is added dropwise, the mixture is stirred at rt for 4 h, washed with water, (Na ₂ SO ₄ ) Dry and evaporate under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate to afford the title compound (1.9 g, 87%) as a solid.

¹ H NMR (250 MHz; CDCl ₃ ) δ (ppm): 5.49 (2H, s), 6.85 (1H, d, J = 7), 7.08-7.50 (8H, m), 7.70 (1H, dt, J = 2,8), 7.91 (1H, d, J = 7), 8.14 (1H, d, J = 3), 8.62 (1H, d, J = 3).

<Description 4>

(2-nitro-5-trifluoromethylphenyl) acetonitrile (D4)

4-nitrobenzotrifluoride (5 g, 0.026 mol) and 4-chlorophenoxycetonitrile (4.86 g, 0.029 mol) in dry DMF (50 mL) were added potassium-t-butoxide in dry DMF (30 mL). (6.4 g, 0.057 mol) was added dropwise to the solution at -10 ° C under argon for 1 hour. After further stirring the mixture for 3 h at −10 ° C., the mixture was poured into 5N HCl / ice water (1: 1) (300 mL) and extracted with DCM (3 × 200 mL). The DCM extract was washed with 10% aqueous sodium hydroxide solution, 5N hydrochloric acid and brine, dried (Na ₂ SO ₄ ) and evaporated under reduced pressure. The resulting oil was chromatographed on silica gel eluting with 20% ethyl acetate / 60-80 ° C. petroleum ether to give the title compound (1.9 g, 32%) as an orange oil.

¹ H NMR (200 MHz; CDCl ₃ ) δ (ppm): 4.26 (2H, s), 7.87 (1H, d, J = 8), 8.02 (1H, s), 8.31 (1H, d, J = 8) .

<Description 5>

5-trifluoromethylindole (D5)

(2-nitro-5-trifluoromethylphenyl) acetonitrile (D4, 1.9 g, 0.0088 mol) in 90% EtOH / H ₂ O (25 mL) and acetic anhydride (0.25 mL) was added 10% Pd / C (1 g) hydrogenated at 50 psi in the presence and at room temperature for 2 hours. After the catalyst was filtered through diatomaceous earth, the solvent was removed under reduced pressure. The residue was basified with saturated aqueous potassium carbonate solution, extracted with DCM, dried (Na ₂ SO ₄ ) and evaporated under reduced pressure. The residue was chromatographed on silica gel eluting with 30% ethyl acetate / 60-80 ° C. petroleum ether to afford the title compound (1.0 g, 65%) as a non-white solid.

¹ H NMR (200 MHz; CDCl ₃ ) δ (ppm): 6.65 (1H, t, J = 1), 7.30 (1H, t, J = 1), 7.36-7.58 (2H, m), 7.94 (1H, s), 8.34 (1H, broad singlet).

<Description 6>

5-trifluoromethylindolin (D6)

5-trifluoromethylindole (D5, 1.0 g, 0.0057 mol) in acetic anhydride (25 mL) was treated with sodium cyanoborohydride (1.7 g, 0.027 mol) under argon and stirred at room temperature for 2 hours. . The mixture was poured into water (200 mL), basified with 40% aqueous sodium hydroxide solution, extracted with DCM, dried (Na ₂ SO ₄ ) and evaporated under reduced pressure. The residue was chromatographed on silica gel eluting with 20% ethyl acetate / 60-80 ° C. petroleum ether to afford the title compound (0.45 g, 45%) as light yellow oil.

¹ H NMR (250 MHz; CDCl ₃ ) δ (ppm): 3.07 (2H, t, J = 8), 3.65 (2H, t, J = 8), 4.02 (1H, br s), 6.60 (1H, d , J = 7), 7.28 (1H, t, J = 2), 7.30 (1H, s).

<Description 7>

(5-methoxy-2-nitro-4-trifluoromethylphenyl) acetonitrile (D7)

A mixture of 1-methoxy-4-nitro-2-trifluoromethylbenzene (93 g, 0.421 mol) and 4-chlorophenoxycetonitrile (77.55 g, 0.463 mol) in dry DMF (500 mL) was added to -10. To a stirred solution of KO ^t Bu (103.85 g, 0.927 mol) in dry DMF (400 mL) at 占 폚 was added dropwise over 0.75 hours. After the addition was complete, the resulting purple solution was kept at -10 ° C for 1 hour and poured into a mixture of ice / water (1.5 L) and 5M aqueous HCl solution (1.5 L). The resulting mixture was extracted with dichloromethane (3 × 1 L). The combined extracts were washed with water (3 L), dried (Na ₂ SO ₄ ) and evaporated under reduced pressure. The residue is chromatographed on silica gel using 10-40% ethyl acetate / petroleum ether as eluent to afford the crude product which is recrystallized from ethyl acetate / petroleum ether to give the title compound (85.13 g, 78%) as a white solid. It was. Melting point: 103-104 캜.

¹ H NMR (CDCl ₃ ) δ: 4.10 (3H, s), 4.37 (2H, s), 7.34 (1H, s), 8.53 (1H, s).

<Description 8>

5-methoxy-6-trifluoromethylindole (D8)

Add (5-methoxy-2-nitro-4-trifluoromethylphenyl) acetonitrile (D7) (85 g, 0.327 mol) in ethanol / water (9: 1, 1.6 L) and acetic anhydride (16 mL). Hydrogenated at room temperature with 0.5% (50 g) of 10% palladium on carbon at psi. The reaction mixture was filtered and evaporated under reduced pressure. The residue was partitioned between aqueous K ₂ CO ₃ solution (1 L) and dichloromethane (2 × 1 L), and the combined organic extracts were dried (Na ₂ SO ₄ ) and evaporated to give the title indole (67.63 g, 96%) was obtained.

¹ H NMR (CDCl ₃ ) δ: 3.94 (3H, s), 6.53 (1H, m), 7.21 (1H, s), 7.32 (1H, m) 7.64 (1H, s), 8.25 (1H, br s) .

<Description 9>

5-methoxy-6-trifluoromethylindolin (D9)

Indole (D8) (67.63 g, 0.315 mol) in acetic anhydride (500 mL) was treated by dividing with sodium cyanoborohydride (40 g, 0.637 mol) with stirring at room temperature. After 3 hours at room temperature, the reaction mixture was diluted with water (500 mL) and basified while cooling with 40% aqueous NaOH solution. The mixture was then extracted with dichloromethane (3 × 500 mL) and the combined extracts were dried (Na ₂ SO ₄ ) and evaporated to afford the title compound (67.73 g, 99%) as a non-white solid.

¹ H NMR (CDCl ₃ ) δ: 3.07 (2H, t), 3.58 (2H, t), 3.67 (1H, br s), 3.83 (3H, s), 6.83 (1H, s), 6.88 (1H, s ).

<Description 10>

5-hydroxy-6-trifluoromethylindolin (D10)

A mixture of 5-methoxy-6-trifluoromethylindolin (D9, 7.5 g, 34.3 mmol) and iodotrimethylsilane (12.5 mL, 89.3 mmol) in dry chloroform (70 mL) was heated at reflux for 65 h. It was. Methanol was then added with careful stirring to cool the mixture, and then the solvent was removed under reduced pressure. The residue was treated with saturated sodium bicarbonate solution and water until basic and extracted with dichloromethane / methanol. The organic extract was washed with brine, dried and evaporated. The residue was extracted with ether in a Soxhlet apparatus and the resulting solution was concentrated three times to give the title compound (2.85 g, 41% in total) that was produced. Melting point:> 180 DEG C (decomposition).

¹ H NMR (CDCl ₃ / CD ₃ OD) δ: 3.02 (2H, d, J = 8), 3.52 (2H, d, J = 8), 4.00 (3H, s), 6.77 (1H, s), 6.83 (1H, s).

<Description 11>

1-acetyl-5-hydroxy-6-trifluoromethylindolin (D11)

A mixture of indolin (D10, 2.84 g, 14 mmol) and acetic anhydride (1.32 mL, 14 mmol) in dry dichloromethane (50 mL) was stirred at room temperature for 3 hours and then evaporated. The residue was treated carefully with saturated sodium bicarbonate solution and the solid product was filtered off, washed with water and dried to give the title compound (3.28 g, 96%). Melting point: 244 to 247 ° C.

¹ H NMR (d ₆ -DMSO) δ: 2.10 (3H, s), 3.11 (2H, t, J = 8), 4.06 (2H, t, J = 8), 6.88 (1H, s), 8.18 (1H , s).

<Description 12>

1-acetyl-6-trifluoromethyl-5-trifluoromethylsulfonyloxy-indolin (D12)

At 0 ° C. trifluoromethanesulfonic anhydride (1.52 g, 5.4 mmol) was added to a solution of acetylindolin (D11, 1.19 g, 4.9 mmol) in dry pyridine (10 mL). The mixture was then stirred overnight while slowly warming to room temperature. The mixture was partitioned and evaporated, the residual liquid diluted with water and the precipitate filtered off. The crude product was dissolved in dichloromethane and the solution was washed with 1N hydrochloric acid and brine, dried and evaporated to afford the title compound (1.77 g, 96%).

¹ H NMR (CDCl ₃ ) δ: 2.28 (3H, s), 3.32 (2H, t, J = 8), 4.19 (2H, t, J = 8), 7.29 (1H, s), 8.60 (1H, s ).

MS m / z = 378 (MH ⁺ )

<Description 13>

5-Methyl-6-trifluoromethylindolin (D13)

Trifluoromethylsulfonyloxyindolin (D12, 1.77 g, 4.69 mmol), lithium chloride (0.60 g, 14.1 mmol) and bis (triphenylphosphine) palladium (II) chloride in dry dimethylformamide (15 mL) To a mixture of (0.10 g, 0.14 mmol) was added tetramethyltin (0.72 mL, 5.2 mmol). The mixture was heated at 110 ° C. for 3.5 h, then cooled and evaporated. The residue was partitioned between dichloromethane and water and the organic phase was washed with brine, dried and evaporated. The crude product was dissolved in ethanol (30 mL), 10% aqueous sodium hydroxide solution (7.5 mL) and sodium hydroxide solid (1 g) were added and the mixture was heated at reflux overnight. Ethanol was removed under reduced pressure, and the residue was diluted with water and extracted with dichloromethane. The organic extract was washed with brine, dried and evaporated. The residue was chromatographed on silica gel (50 g) and eluted with suction with 2: 1 ether / petroleum ether to afford the title compound (0.70 g, 74%). Melting point: 43-44 캜.

¹ H NMR (CDCl ₃ ) δ: 2.34 (3H, s), 3.02 (2H, t, J = 8), 3.57 (2H, t, J = 8), 3.78 (1H, broad), 6.85 (1H, s ), 7.00 (1 H, s).

<Description 14>

3-methyl-5-nitro-2- (pyridin-2-ylmethyloxy) pyridine (D14)

2-pyridylcarbinol (1.96 g, 18 mmol) in dry dimethylformamide (20 mL) was cooled to −20 ° C. and treated by dividing with sodium hydride (0.48 g of 80% dispersion in mineral oil, 16 mmol). The mixture was stirred at -20 ° C. under argon for 1 hour, then a solution of 2-chloro-3-methyl-5-nitropyridine (2.07 g, 12 mmol) in dry dimethylformamide (10 mL) was added and the mixture was Allow to warm over 16 hours at room temperature. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (3 × 100 mL) and 10% aqueous sodium hydroxide solution (75 mL). The combined organic phases are dried (Na ₂ SO ₄ ) and evaporated under reduced pressure to give a residue, which is flash column chromatographed using 1: 1 ethyl acetate / petroleum ether as eluent to give the title compound (1.47 g, 51%) was obtained.

¹ H NMR (250 MHz; CDCl ₃ ) δ (ppm): 2.38 (3H, s), 5.63 (2H, s), 7.25 (1H, m), 7.43 (1H, d, J = 8), 7.71 (1H , m, J = 8,1), 8.22 (1H, d, J = 2), 8.62 (1H, d, J = 5), 8.92 (1H, d, J = 2).

<Description 15>

5-amino-3-methyl-2- (pyridin-2-ylmethyloxy) pyridine (D15)

3-Methyl-5-nitro-2- (pyridin-2-ylmethyloxy) pyridine (D14, 1.42 g, 5.8 mmol) in ethanol (100 mL) tin chloride in concentrated HCl (10 mL) at 60 ° C. (II ) (5.68 g) solution dropwise. The mixture was stirred at 60 ° C. for 1 h, then cooled, diluted with water and basified with 40% aqueous sodium hydroxide solution. The aqueous solution was extracted with dichloromethane (3 × 100 mL), dried (Na ₂ SO ₄ ) and evaporated under reduced pressure to afford the title compound (1.24 g, 100%) as a brown liquid.

¹ H NMR (250 MHz; CDCl ₃ ) δ (ppm): 2.23 (3H, s), 5.44 (2H, s), 6.90 (1H, t, J = 13), 7.18 (1H, t, J = 7) , 7.44 (1H, d, J = 8), 7.48 (1H, d, J = 8), 7.68 (1H, m, J = 7), 8.59 (1H, d, J = 4).

<Example 1>

5-methyl-1- [2- (pyridin-2-ylmethyloxy) pyridin-5-ylcarbamoyl] -6-trifluoromethylindolin (E1)

A mixture of indolin (D13, 0.30 g, 1.49 mmol), phenylcarbamate (D3, 0.48 g, 1.5 mmol) and triethylamine (0.20 mL, 1.5 mmol) in dry acetonitrile (10 mL) was quickly warmed up The complete reaction solution was generated and stirred overnight at room temperature. The reaction was poured into water (50 mL) and the precipitate was filtered off, washed with water and dried. The crude product was chromatographed on silica gel eluting with 4% methanol / dichloromethane. The eluted product was recrystallized from dichloromethane / methanol to give the title compound (0.35 g, 55%). Melting Point: 219-220 ° C.

NMR (d ₆ -DMSO) δ: 2.36 (3H, s), 3.22 (2H, t, J = 8), 4.15 (2H, t, J = 8), 5.40 (2H, s), 6.93 (1H, d , J = 8), 7.25 (1H, s), 7.32 (1H, dd, J = 7,5), 7.45 (1H, d, J = 7), 7.80 (1H, t, J = 7), 7.90 ( 1H, dd, J = 8,2), 8.15 (1H, s), 8.23 (1H, d, J = 2), 8.57 (1H, d, J = 5), 8.67 (1H, s).

<Example 2>

1- [2- (pyridin-2-ylmethyloxy) pyridin-5-ylcarbamoyl] -5-trifluoromethylindolin (E2)

Phenyl N- [2- (pyridin-2-ylmethyloxy) pyridin-5-yl] carbamate (D3, 0.20 g, 0.62 mmol) in dry dimethylformamide (10 mL) is 5-trifluoromethyl. Treated with doline (D6, 0.12 g, 0.62 mmol) and heated at 100 ° C. for 1 h. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane, washed with 10% aqueous sodium chloride solution (Na ₂ SO ₄ ), dried and evaporated under reduced pressure. The resulting oil was chromatographed on silica gel eluting with 2% methanol / dichloromethane and digested with diethyl ether to give the title compound (0.08 g, 31%) as a non-white solid.

¹ H NMR (250 MHz; d ₆ -DMSO) δ (ppm): 3.28 (2H, t, J = 10), 4.19 (2H, t, J = 10), 5.40 (2H, s), 6.94 (1H, d, J = 10), 7.28-7.37 (1H, m), 7.40-7.58 (3H, m), 7.82 (1H, dt, J = 2,7), 7.90 (1H, dd, J = 2,7) , 8.00 (1H, d, J = 10), 8.26 (1H, d, J = 3), 8.56 (1H, d, J = 7), 8.75 (1H, s).

<Example 3>

5-methyl-1- [2- (pyridin-2-ylmethyloxy) -3-methylpyridin-5-ylcarbamoyl] -6-trifluoromethylindolin (E3)

5-amino-3-methyl-2- (pyridin-2-ylmethyloxy) pyridine (D15, 0.5 g, 2.3 mmol) in dichloromethane (30 mL) was cooled to -20 ° C under argon. Triethylamine (0.32 mL, 2.3 mmol) was added followed by the dropwise addition of phenyl chloroformate (0.35 mL, 2.8 mmol). The mixture is allowed to warm to room temperature, diluted with dichloromethane (100 mL), washed with aqueous sodium bicarbonate solution (50 mL), dried (Na ₂ SO ₄ ) and evaporated under reduced pressure to phenyl N-2- [3- Methyl- (pyridin-2-ylmethyloxy) pyridin-5-yl] carbamate was obtained. The crude carbamate was subjected to 5-methyl-6-trifluoromethylindolin (D7, 0.47 g, 0.0023 mol, 1 equiv) and triethylamine (1 mL in DMF (30 mL) at 100 ° C. under argon for 2 hours. ) And then cooled. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (3 × 100 mL) and 10% aqueous sodium hydroxide solution (50 mL). The combined organic phases are dried (Na ₂ SO ₄ ) and evaporated under reduced pressure to give crude product which is flash chromatographed with 5% methanol / dichloromethane as eluent and recrystallized from dichloromethane / 60-80 ° C. petroleum ether. The title compound (0.27 g, 28%) was obtained as white crystals. Melting point: 188-189 ° C.

¹ H NMR (250 MHz; CDCl ₃ ) δ (ppm): 2.29 (3H, s), 2.40 (3H, s), 3.25 (2H, t, J = 9), 4.09 (2H, t, J = 9) , 5.51 (2H, s), 6.36 (1H, br s), 7.07 (1H, s), 7.20 (1H, t, J = 7), 7.43 (1H, d, J = 8), 7.68 (1H, m , J = 7,1), 7.77 (1H, d, J = 1), 7.82 (1H, d, J = 1), 8.23 (1H, s), 8.59 (1H, d, J = 4).

MS m / z = 443 (MH ⁺ )

<Example 4>

5-Bromo-1- [2- (pyridin-2-ylmethyloxy) pyridine-5-ylcarbamoyl] -indolin (E4)

Using the same method as in Example 1, phenyl N- [2- (pyridin-2-ylmethyloxy) pyridin-5-yl] carbamate (D3) and 5-bromoindolin were converted to the title compound. Melting point: 138 to 139 ° C.

<Example 5>

1- [2- (pyridin-2-ylmethyloxy) pyridin-5-ylcarbamoyl] -6-trifluoromethyl-indolin (E5)

Using the same method as Example 1, phenyl N- [2- (pyridin-2-ylmethyloxy) pyridin-5-yl] carbamate (D3) and 6-trifluoromethylindolin (International Patent No. 96/23783) was converted to the title compound. Melting point: 178 to 179 deg.

<Pharmacological data>

In vitro binding of [ ³ H] -mesulergine to 5-HT _2C clones in rats or humans expressed in 293 cells

Compounds were tested according to the method outlined in International Patent No. 94/04533. The compounds of the Examples had a pKi of about 8.6-9.5 in human cells.

MCPP-Induced Hypocomotion

Compounds were tested according to the method outlined in International Patent No. 94/04533. The compounds of the Examples showed good activity with prolonged duration of action after 1-5 mg / kg oral administration to rats.

Claims (10)

A compound of formula (I) or a salt thereof. <Formula (I)> In the above formula, R ¹ is hydrogen or C _1-6 alkyl, R ² , R ³ and R ⁴ groups are independently hydrogen, halogen, or C _1-6 alkyl optionally substituted with one or more fluorine atoms. The compound of claim 1, wherein R ¹ is hydrogen. The compound of claim 1 or 2, wherein R ² is hydrogen or CF ₃ . The compound of any one of claims 1-3, wherein R ³ is hydrogen, bromine, CF ₃ or methyl. The compound of any of claims 1-4, wherein R ⁴ is hydrogen or C _1-6 alkyl. The method of claim 1, 5-methyl-1- [2- (pyridin-2-ylmethyloxy) pyridin-5-ylcarbamoyl] -6-trifluoromethylindolin, 1- [2- (pyridin-2-ylmethyloxy) pyridin-5-ylcarbamoyl] -5-trifluoromethylindolin, 5-methyl-1- [2- (pyridin-2-ylmethyloxy) -3-methylpyridin-5-ylcarbamoyl] -6-trifluoromethylindolin, 5-bromo-1- [2- (pyridin-2-ylmethyloxy) pyridin-5-ylcarbamoyl] -indolin, 1- [2- (pyridin-2-ylmethyloxy) pyridin-5-ylcarbamoyl] -6-trifluoromethyl-indolin, and Compounds which are pharmaceutically acceptable salts thereof. A process for preparing a compound of formula (I) comprising reacting a compound of formula (II) with a compound of formula (III), followed by optionally forming a pharmaceutically acceptable salt thereof. <Formula (II)> <Formula (III)> In the above formula, R ¹ , R ² , R ³ and R ⁴ are as defined in formula (I), A and B contain the appropriate functional group (s) necessary to form -NHCO- moieties in the reaction, and suitable A and B groups (i) A is -N = C = O and B is hydrogen, or (ii) A is -NHCOL and B is hydrogen; (iii) A is -NH ₂ and B is COL, or (iv) A is halogen, B is —CONH ₂ , where L is a leaving group, and examples of suitable leaving groups L include halogen (eg chloro, bromo), imidazole, or eg halogen Optionally substituted phenoxy or phenylthio. The compound according to any one of claims 1 to 6, which is used for treatment. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient. Use of a compound according to any one of claims 1 to 6 in the manufacture of a medicament for the treatment of anxiety and / or depression.