JP2003513969A - N-allyl- (homopiperazinyl) -cyclohexylamine as 5-HT transporter - Google Patents

Abstract

(57) SUMMARY The present invention provides novel compounds and methods and compositions using them in the treatment of central nervous system disorders, including depression and anxiety. These compounds have the formula (I): Wherein Ar is an aryl, arylalkyl or heteroaryl group; R ₁ and R ₂ are independently halogen, optionally substituted alkyl having 1 to 12 carbons or optionally substituted 3 carbons R ₃ is H, optionally substituted alkyl, optionally substituted cyclic alkyl, halogen, alkoxy, haloalkyl, OH, nitro, amino, CN, carboxy, alkoxycarbonyl, alkylcarbonyl, Selected from aminocarbonyl and alkylaminocarbonyl], or a pharmaceutically acceptable salt thereof.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention is influenced by N-aryl-homopiperazinyl-cyclohexylamine derivatives having pharmacological activity, processes for producing them, pharmaceutical compositions containing them, and serotonin. It relates to their use in the treatment of diseases affected by disorders of the nervous system, such as depression and anxiety.

BACKGROUND OF THE INVENTION Drugs that enhance serotonergic neurotransmission are associated with many psychiatric disorders,
For example, it is useful in treating depression and anxiety. First generation non-selective serotonergic drugs act through a variety of physiological functions, which tend to have some side effects. The most recently prescribed drug, the selective serotonin reuptake inhibitor (SSRI), is mainly responsible for actively removing synaptic 5-HT from the synaptic cleft via presynaptic serotonin transport carriers. It works by inhibiting.

Wustrow et al. (Journal of Medicinal Chemistry)
J. Med. Chem.), 1997, 40, 250, as a series of 3- [] dopamine D ₂ partial agonists.
Disclosed is [4-aryl-1-piperazinyl) alkyl] cyclohexyl] -1H-indole.

Cipollina et al. In European Patent Application EP 666258 discloses a series of indolylcycloalkylamines as serotonergic vasoconstrictor agents for the treatment of vascular headache or migraine. There is.

Shiota et al., In PCT International Patent Application No. WO 9744329, disclose a series of cyclic diarylalkyl derivatives (including arylhomopiperazines) as chemokine receptor antagonists. Hidaka et al. In U.S. Pat. No. 5,244,895 and European Patent Application 513,691 disclose a series of aryl cyclic diamines (including arylhomopiperazines) as antiulcer agents. Hidaka et al. Also disclose a series of aryl cyclic diamines (including aryl homopiperazines) as vasorelaxants in US Pat. Nos. 5,081,246; 5,216,150 and 5,245,034.

DISCLOSURE OF THE INVENTION The present invention is affected by N-aryl-homopiperazinyl-cyclohexylamine derivatives having pharmacological activity as 5-HT transporters, and disorders of the nervous system affected by serotonin. Provide their use in the treatment of diseases such as depression and anxiety.

[0007]   According to the invention, formula (I):

[0008]

[Chemical 4]

[Wherein Ar represents an aryl or arylalkyl group (wherein the aryl moiety has 5 to 14 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms) or a heteroaryl group having 5 to 10 ring atoms (herein, , The heteroatoms are the same or different and are selected from oxygen, nitrogen or sulfur); aryl, heteroaryl, or the aryl portion of the arylalkyl is alkyl having 1 to 12 carbons (halogen, hydroxy, nitro,
Optionally substituted with amino or cyano); alkoxy having 1 to 12 carbons,
Thioalkyl having 1 to 6 carbon atoms; perfluoroalkyl having 1 to 6 carbon atoms; hydroxy; nitro; halogen; optionally substituted by 1 to 3 same or different substituents selected from amino or cyano; R ₁ and R ₂ are independently hydrogen; alkyl having 1 to 12 carbons (which may be substituted with halogen, hydroxy, nitro, amino or cyano); or cycloalkyl having 3 to 10 carbons (halogen, carbon Alkyl having 1 to 6 carbon atoms, 1 to
6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, nitro, cyano, amino, carboxy, C 2-7 alkoxycarbonyl, C 2-7 alkylcarbonyl, carbon R ₃ is H; alkyl having 1 to 12 carbons (halogen, hydroxy, nitro, cyano or amino, and optionally substituted with alkoxycarbonylalkyl having 3 to 13 carbons or alkylcarbonyloxy having 2 to 7 carbons); Optionally substituted); cycloalkyl having 3 to 10 carbon atoms (halogen, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, haloalkyl having 1 to 6 carbon atoms, halo having 1 to 6 carbon atoms) Alkoxy, hydroxy, nitro, cyano, amino, carboxy, C2-C7 alkoxycarbonyl, C2-C7 al. Ylcarbonyl, optionally substituted by alkoxycarbonylalkyl or alkylcarbonyloxy of 2 to 7 carbon atoms 3 to 13 carbon atoms); or _{R 3} is halogen, having 1 to 12 carbon atoms alkoxy, carbons 1 to 12 Of haloalkyl, hydroxy, nitro, nitrile, amino, cyano, carboxy, alkoxycarbonyl having 2 to 12 carbon atoms, alkylcarbonyl having 2 to 12 carbon atoms, aminocarbonyl or alkylaminocarbonyl having 2 to 12 carbon atoms] And a pharmaceutically acceptable salt thereof in all crystalline forms.

Examples of Ar include monocyclic, bicyclic or tricyclic aryl groups having 6 to 14 carbon atoms, for example, monocyclic or bicyclic aryl groups having 6 to 10 carbon atoms such as phenyl and naphthyl. , Indenyl, indacenyl, anthracenyl and phenanthrenyl; an arylalkyl group (wherein the aryl moiety is the same as above with the alkyl moiety having 1 to 4 carbon atoms, for example, methyl); Cyclic heteroaryl group (wherein 1-3
Atoms are selected from oxygen, nitrogen and sulphur), eg as above.

Examples of the substituents on Ar are alkyl such as alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl (wherein the alkyl group is halogen, amino, hydroxy). , Cyano and nitro may be substituted); alkoxy such as alkoxy having 1 to 6 carbon atoms, for example, methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, pentoxy and hexyloxy; thioalkyl, for ^{example, SMe, SEt, SPr, S} i Pr, SBu; perfluoroalkyl _{such, CF 3, C 2 F 5} , C 3 F 7, i-C 3 F ₇
Halogen; for example fluorine, chlorine or bromine; nitro; amino and cyano.

Examples of R ₁ (and independently R ₂ ) are hydrogen; an alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl (wherein the alkyl group is
(It may be substituted with halogen, nitro, amino, hydroxy or cyano)
A cycloalkyl group, for example, having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl (wherein, the cycloalkyl group is alkyl having 1 to 4 carbon atoms, for example, methyl or ethyl, halogen , Nitro, amino, hydroxy or cyano).

Examples of R ₃ are hydrogen, an alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl (wherein the alkyl group is substituted with halogen, nitro, amino, hydroxy or cyano). A cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl (wherein the cycloalkyl group is an alkyl group having 1 to 4 carbon atoms, for example, methyl or ethyl, halogen, nitro). ,amino,
Optionally substituted with hydroxy or cyano); chlorine, fluorine; bromine; alkoxy group having 1 to 4 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy; haloalkyl having 1 to 4 carbon atoms, for example, trifluoro Methyl, chloromethyl; haloalkoxy having 1 to 4 carbon atoms, for example, trifluoromethoxy; hydroxy; nitro; amino, cyano; carboxy; alkoxycarbonyl, for example methoxycarbonyl; ethoxycarbonyl; alkylcarbonyl, for example acetyl; propionyl; -CONH ₂ and alkylaminocarbonyl, for example, MeNHCO.

Among the preferred compounds of the invention are compounds of formula (I) wherein Ar is an aryl group having 5 or 6 carbon atoms or a heteroaryl group having 5 to 10 ring atoms; and / or R ₁ and R ₂ is independently H, linear alkyl having 1 to 8 carbons or 3 carbons
And / or R ₃ is H, linear alkyl having 1 to 8 carbons, branched alkyl having 3 to 6 carbons,
Cycloalkyl having 3 to 8 carbon atoms, halogen, alkoxy having 1 to 6 carbon atoms, haloalkyl having 1 to 6 carbon atoms, haloalkoxy having 1 to 6 carbon atoms, hydroxy, nitro,
Nitrile, amino, cyano, carboxy, alkoxycarbonyl having 2 to 6 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, aminocarbonyl and alkylaminocarbonyl having 2 to 6 carbon atoms, and all crystal forms thereof or There are pharmaceutically acceptable salts.

In an even more preferred embodiment of the present invention, Formula (I) [wherein Ar is an aryl group having 6 carbon atoms or a heteroaryl group having 5 to 10 ring atoms; and / or R ₁ and R ₂ are independent. And H, straight-chain alkyl having 1 to 3 carbon atoms or 3 carbon atoms
And / or R ₃ is H, halogen, cyano, CONH ₂ or CO ₂ H] and all crystalline forms or pharmaceutically acceptable salts thereof.

Unless otherwise defined, alkyl, whether used alone or as part of another group, contains 1-12 carbon atoms (eg, having 1-6 carbon atoms).
, For example, straight-chain and branched-chain alkyl groups having 1 to 4 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, i-butyl and t-butyl are included in the term alkyl. In some embodiments of the present invention, alkyl may mean substituted or unsubstituted alkyl. Carbon numbers apply to the carbon skeleton and do not include carbon atoms of substituents such as alkoxy substituents. Halogen, as used herein, means chlorine, bromine, iodine and fluorine.

Aryl, as used herein and in relation to arylalkyl, is 5
14-membered monocyclic or polycyclic groups such as, but not limited to, aromatic rings having 6 to 10 carbon atoms such as phenyl, naphthalene, anthracene, phenanthrene, indene and indacene. Arylalkyl groups have 1 to 4 carbon atoms in the alkyl portion. For example, benzyl. Preferred aryl or arylalkyl are phenyl, benzyl and naphthalene. Depending on the embodiment of the invention, the aryl group or moiety may be substituted with alkyl groups, perfluoroalkyl groups, preferably trifluoromethyl groups, alkoxy groups and halogens.

Heteroaryl, as used herein, refers to a 5-10 membered monocyclic or polycyclic aromatic ring having 1-3 heteroatoms selected from the same or different from S, O or N. Include, for example, furan, thiophene, pyrrole, imidazole, oxazole, thiazole, isoxazole, pyrazole, isothiazole, oxadiazole, triazole, thiadiazole, quinolidine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, naphthyridine,
Examples include, but are not limited to, pteridine, pyridine, pyrazine, pyrimidine, pyridazine, pyran, triazine, indole, isoindole, indazole, indolizine and isobenzofuran. Preferred heteroaryls include, but are not limited to, furan, thiophene, pyrrole, imidazole, oxazole, thiazole, isoxazole, pyrazole, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, quinolidine, quinoline and isoquinoline. Not done. More preferred heteroaryls include furan, thiophene, imidazole, isoxazole, quinoline and pyrazole. In some embodiments of the invention, heteroaryl groups are substituted.

Preferably, the substituted aryl group is substituted with 1 to 3 groups. Substituted heteroaryl groups are preferably substituted with 1 to 3 groups, more preferably 1 to 2 groups. Alkyl and cycloalkyl groups may also be substituted. Suitable substituents include halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, nitrile, amino, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, alkoxycarbonylalkyl and alkylcarbonyloxy. Not limited.

Among the most preferred compounds of the invention are: 3- {4- [4- (2-methoxy-phenyl)-[1,4] diazepan-1-yl] -cyclohexyl} -1H-indole; 8 -{4- [4- (1H-Indol-3-yl) -cyclohexyl]-[1,4] diazepan
3- {4-yl} -quinoline; 3- {4- [4- (2-methoxy-phenyl)-[1,4] diazepan-1-yl] -cyclohexyl} -5-fluoro-1H-indole; 3- { 4- [4- (2-Methoxy-phenyl)-[1,4] diazepan-1-yl] -cyclohexyl} -5-cyano-1H-indole; 3- {4- [4- (2-methoxy-phenyl] )-[1,4] Diazepan-1-yl] -cyclohexyl} -6-fluoro-1H-indole; 8- {4- [4- (5-fluoro-1H-indol-3-yl) -cyclohexyl]- [1,
4] diazepan-1-yl} -quinoline; 8- {4- [4- (5-cyano-1H-indol-3-yl) -cyclohexyl]-[1,4]
Diazepan-1-yl} -quinoline; 8- {4- [4- (6-fluoro-1H-indol-3-yl) -cyclohexyl]-[1,
4] diazepan-1-yl} -quinoline; 3- {4- [4- (3-trifluoromethyl-phenyl)-[1,4] diazepan-1-yl]
-Cyclohexyl} -5-fluoro-1H-indole; 3- {4- [4- (3-trifluoromethyl-phenyl)-[1,4] diazepan-1-yl]
-Cyclohexyl} -5-cyano-1H-indole; 3- {4- [4- (3-trifluoromethyl-phenyl)-[1,4] diazepan-1-yl]
-Cyclohexyl} -6-fluoro-1H-indole; or one pharmaceutically acceptable salt of these compounds.

The cyclohexane compounds of the present invention can exist as 1,4-cis or trans isomers. Such isomers and mixtures thereof are within the scope of the invention. formula
The definition of compounds represented by (I) is understood to include all possible stereoisomers and mixtures thereof having the activity discussed below, where R ₁ , R ₂ or R ₃ contains an asymmetric carbon. It In particular, it includes the racemates and any optical isomers having the required activity. Optical isomers and stereoisomers may be obtained in pure form by standard separation techniques.

Pharmaceutically acceptable salts include lactic acid, citric acid, acetic acid, tartaric acid, succinic acid, maleic acid, malonic acid, oxalic acid, fumaric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid,
Those derived from organic and inorganic acids such as methanesulphonic acid and also known permissible acids. When R ₁ , R ₂ or R ₄ contains a carboxyl group, a base such as an alkali metal (Na, K, Li) or an alkaline earth metal (Ca or Mg) is used to form a salt of the compound of the present invention. You may.

As already mentioned, the compounds of formula (I) have an affinity for the 5-HT reuptake transporter and are affected by disorders of the nervous system affected by serotonin, for example: Useful for the treatment of depression and anxiety, sleep disorders, sexual dysfunction, alcohol and cocaine addiction, cognitive enhancement and related problems. The present invention therefore also provides a pharmaceutical composition comprising a compound of the invention in combination or association with a pharmaceutically acceptable carrier or excipient.

The composition is preferably adapted for oral or subcutaneous administration. However, they may be adapted for other modes of administration.

The compositions of the present invention may be formulated with conventional excipients such as fillers, disintegrants, binders, lubricants, flavoring agents and the like. They are formulated in conventional manner, eg in a manner similar to that used for known antihypertensives, diuretics and β-blockers. Applicable solid carriers or excipients include flavoring agents, lubricants, solubilizing agents, suspending agents,
It may include one or more substances or encapsulating materials which may also act as fillers, flow agents, compression aids, binders or tablet disintegrants. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain up to 99% of active ingredient. Suitable solid carriers include, for example,
Calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of the present invention is a pharmaceutically acceptable liquid carrier, for example,
It can be dissolved or suspended in water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. Liquid carriers include other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers. Agents or osmotic pressure regulators can be included. Suitable examples of liquid carriers for oral and parenteral administration include water (in particular, additives such as those mentioned above, for example, containing a cellulose derivative, preferably sodium carboxymethylcellulose solution), alcohol (for example, monohydric alcohol). And polyhydric alcohols such as glycols) and their derivatives, and oils such as fractionated coconut oil and peanut oil. For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Aseptic liquid carrier,
Used as a sterile liquid composition for parenteral administration.

The liquid pharmaceutical composition which is a sterile solution or suspension can be used by, for example, intramuscular, intraperitoneal or subcutaneous injection. In addition, the sterile solution can also be administered intravenously. Oral administration may be either liquid or solid composition form.

[0028] Preferably the pharmaceutical composition is in unit dosage form, for example a tablet or capsule. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active component; can do. 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.

In order to obtain consistency of administration, the compositions of the invention are preferably in unit dose form. Suitable unit dosage forms include tablets, capsules, and powders in sachets or vials. Such unit dosage form is 0.1% of the compound of the invention.
˜100 mg, preferably 2 to 50 mg. A further preferred unit dosage form contains 5-25 mg of the compound of the invention. The compound of the present invention is about 0.01
It can be administered orally in a dosage range of -100 mg / kg, preferably in a dosage range of 0.1-10 mg / kg. Such compositions may be administered 1 to 6 times per day, more typically 1 to 4 times per day.

The present invention also provides a method for producing a compound of formula (I). Such a method has the formula (II):

[0031]

[Chemical 5]

[0032] [In the formula, Ar has the same meaning as above] A compound represented by the formula (III):

[0033]

[Chemical 6]

[Wherein R ₁ , R ₂ and R ₃ have the same meanings as defined above], and if necessary, the compound is isolated as a pharmaceutically acceptable salt thereof.

In general, the compounds of formula (I) are conveniently synthesized as described below.

According to the present invention, compounds of formula (I) may be prepared according to Scheme I below.

[0037]

[Chemical 7]

Thus, the Journal of Organic Chemistry (J. Org. Chem.),
1996, 61, 3849, represented by formula (II) according to the method described by Abdel-Magid, Carson, Harris, Maryanoff and Shah. The compound was treated with the compound of formula (III) at 23 ° C. in dichloroethane.
) Is reacted with acetic acid to obtain a compound of formula (I).

According to the present invention, the compound of formula (II) may be prepared according to scheme II below.

[0040]

[Chemical 8]

Thus, Journal of Medicinal Chemistry (J. Med. Chem.),
1997, 40,250, as described by Wustrow et al., Formula (IV)
The compound of formula (V) is reacted with 1,4-cyclohexanedione monoethylene ketal and potassium hydroxide at 65 ° C. in methanol to obtain a compound of formula (V). Hydrogenation to a compound of formula (VI) can be achieved by treatment with H ₂ and 5% Pd / C in a suitable solvent (eg alcohol, but not limited to EtOH). . Hydrolysis to the compound of formula (III) is
It can be carried out with 1N HCl in a 1: 1 mixture of F and water.

According to the present invention, compounds of formula (II) may be prepared according to Scheme III below.

[0043]

[Chemical 9]

Thus, the compound of formula (VII) is treated with a suitable solvent (eg chloroform,
THF or alcohol, but not limited to MeOH) in (Boc) ₂ O
To give a compound of formula (VIII). The conversion to the compound represented by formula (IX) is performed by ANGEDANDTE Chemie International Edition in
According to the method of Buchwald et al. In Anew. Chem. Int. Ed. Engl., 1995, 34, 1348, aryl bromide, catalytic amount of Pd ₂ dba ₃ , catalyst in toluene at 80 ° C. It can be realized by treating with a large amount of BINAP and NaOt-Bu. Deprotection to give a compound of formula (II) can be achieved by treatment with TFA in CH ₂ Cl ₂ at 23 ° C.

The present invention further provides the compounds of the present invention for use as an active therapeutic substance. The compounds of formula (I) are especially useful for the treatment of diseases affected by disorders of serotonin.

The present invention further provides methods of treating depression and anxiety in mammals, including humans. Such methods consist of administering to the affected mammal an effective amount of a compound or pharmaceutical composition of the invention.

The following examples are provided to illustrate rather than limit the invention. EXAMPLES The 5-HT transporter affinities of the compounds of this invention were established according to standard pharmaceutically acceptable test methods, using representative compounds, as follows.

Rat Brain ³ H-Paroxetine Binding Assay (RB 5-HT Transporter): The following assay was used to measure the compound's 5-HT transporter affinity. A protocol similar to that used by Cheetham et al. (Neuropharmacology, 1993, 32,737) was used. Briefly, precortical membranes prepared from male SD rats were incubated with ³ H-paroxetine (0.1 nM) at 25 ° C. for 60 minutes. All tubes contained vehicle, test compound (1-8 concentrations), or saturating concentrations of fluoxetine (10 μM) that defined specific binding. All reactions are stopped by the addition of ice-cold Tris buffer and then rapidly filtered using Tom Tech filter equipment to separate the conjugate from free ³ H-paroxetine. The radioactivity of the conjugate was determined by Wallac 1205 beta plate (B
It was quantified using an eta plate (registered trademark) counter. IC ₅₀ values were determined using non-linear regression analysis and using the method of Cheng and Prusoff (Biochem. Pharmacol., 1973, 22, 3099).
This was converted to a K _i value. IC _{50 Ki} = ―――――――――――――――― Radioligand concentration / (1 + KD)

Inhibition of ³ H-5-HT Uptake by Cells with Human 5-HT Transporter (HC 5-HT Transporter) Human carcinoma cell lines with low endogenous levels of 5-HT transporter (Jar (J
ar) cells) are seeded in 96-well plates and treated with staurosporine at least 18 hours before the assay. [Staurosporine greatly increases expression of the 5-HT transporter. ] On the day of the assay, vehicle, excess fluoxetine,
Alternatively, test compounds are added to various wells on the plate. It was then added ³ H-5-HT in all wells and incubated for 5 min at 37 ° C.. The wells were then washed with ice cold 50 mM Tris-HCl (pH 7.4) buffer, aspirated and free ³ H.
-Remove 5-HT. Then 25 μl of 0.25 M NaOH was added to each well to lyse the cells and 75 μl of scintillation cocktail (Microsint (Micr
oscint ^™ ) 20) and then Packard's Top Count
t) Quantify with the instrument. Tubes with excipients represent all possible uptake, radioactivity counted in tubes with fluoxetine representing non-specific binding / uptake is subtracted from all possible uptake to give all possible Get specific uptake. This non-specific binding (usually in low numbers) is then subtracted from the counts obtained in wells with different test compounds (or different concentrations of test drug) to give specific uptake in the presence of drug. obtain. Specific uptake was then expressed as% of control value and analyzed using non-linear regression analysis (Prizm) to determine IC _{5
Calculate 0} value. If the compound is active in inhibiting 5-HT uptake, the counts are close to those obtained with fluoxetine.

[0050]   The results of these two assays are shown in Table I below.

[0051]

[Table 1]

Accordingly, the compounds of the present invention have a substantial affinity for the 5-HT transporter and can be administered orally, parenterally or by inhalation to a patient in need thereof. , Useful for treating diseases affected by disorders of the nervous system affected by serotonin, such as depression and anxiety.

[0053]   The following examples illustrate the invention.

[0054]   Example 1   3- {4- [4- (2-methoxy-phenyl)-[1,4] diazepin-1-yl] -cyclohe
Kisil} -1H-Indole   Process 1   3- (1,4-dioxa-spiro [4.5] dec-7-en-8-yl) -1H-indole   Indole (22.6 g, 190 mmol) 1,4-cyclohexanedione mono
Ethylene ketal (22.8 g, 145 mmol) and KOH (4.6 g, 80 m).
Limol) was heated to reflux in 50 mL of MeOH for 6 hours. The reaction mixture to 23 ° C.
Upon cooling, a solid precipitated and was collected by vacuum filtration. Add this solid to 3 x 30 mL H _Two Wash with O to give 33.3 g (130.5 mmol, 90% yield) of the title compound as white.
Obtained as a colored solid. MS (ES) m / z (relative intensity): 256 (M⁺+ H, 100)
.

Step 2 3- (1,4-Dioxa-spiro [4.5] dec-8-yl) -1H-indole 3- (1,4-dioxa-spiro [4.5] in 100 mL EtOH. Deca-7-
En-8-yl) -1H-indole (10.0 g, 39.2 mmol) and 10% P
A mixture of d / C (1.0 g) was placed under 40 psi H ₂ and shaken at 23 ° C. for 3 hours. The Pd / C was removed by filtration and the solvent was evaporated. Flash chromatography (CH ₂ Cl ₂ / MeOH) gave 8.66 g (33.7 mmol, 86% yield) of the title compound as a white solid. MS (ES) m / z (relative intensity)
: 258 (M ⁺⁺ H, 100).

Step 3 4- (1H-Indol-3-yl) -cyclohexanone 8.66 g (33.7 mmol) of 3- (1,4-dioxa-spiro [4.5] dec-8-yl)- To a 23 ° C. solution of 1H-indole and 200 mL of THF was added 200 mL of 1N HCl. After stirring for 12 hours, the organics were evaporated and the resulting slurry was extracted with 2 x 150 mL EtOAc. 2 x 1 of combined organics
Wash with 00 mL 1 N NaOH, dry over MgSO ₄ , filter and evaporate to give an off-white solid. By flash chromatography on silica gel, eluting with hexane / EtOAc (1/1), 5.89 g (27.
The title compound (6 mmol, yield 82%) was obtained as a white solid. Melting point 123
~125 ℃; MS (ES) m / z ( relative ^{intensity): 214 (M + + H} , 100).

Step 4 [1,4] Diazepan-1-carboxylic acid tert-butyl ester To 5.0 g (50 mmol) homopiperazine in 200 mL MeOH at 0 ° C. 11.93 g (54.7 mmol) (Boc) ₂ O and 100 mL Me
The solution of OH was added dropwise over 1 hour. After heating the mixture to 23 ° C, 50 ° C
Heated for 3 hours. After cooling to 23 ° C., the reaction mixture obtained was filtered over Celite.
Filtered in e) and evaporated the solvent to a volume of 100 mL. 3 this solution
Extract with 100 mL of 1 N citric acid and combine the aqueous layers with 1 x 100 mL of EtO.
After washing with Ac, the aqueous solution was basified to pH = 11 with solid Na ₂ CO ₃ . The resulting slurry was extracted with 3 × 100 mL of EtOAc and the combined organics were dried over Na ₂ SO ₄ , filtered and evaporated to give 3.2 g (15.9 mmol, 32% yield) of the title compound. Was obtained as a light yellow oil. ¹ H NMR
(300 MHz, CDCl ₃ ): δ 1.46 (s, 9H), 1.70-1.85 (m, 2H)
, 2.81-2.96 (m, 4H), 3.37-3.53 (m, 4H); IR (KBr, cm ^{- 1} ): 3348w, 1690s; MS (ES) m / z (relative intensity ): 201 (M ⁺ + H,
100).

Step 5 4- (2-Methoxy-phenyl)-[1,4] diazepan-1-carboxylic acid tert-butyl ester 1.6 g (7.99 mmol) of [1,4] diazepan-1-carboxylic acid To the acid tert-butyl ester, 1.09 mL (1.64 g, 8.79 mmol) of 2-bromoanisole,
37 mg (0.04 mmol) Pd ₂ dba ₃ , 75 mg (0.12 mmol) (
±) -BINAP, 1.08 g (11.19 mmol) NaOt-Bu, 20 mL toluene were added and the resulting slurry was heated to 80 ° C. for 20 hours. After cooling to 23 ° C., the reaction mixture was filtered through Celite and evaporated to leave a dark brown oil. 2.17 g (7.08 g) by flash chromatography on silica gel, eluting with CH ₂ Cl ₂ / EtOAc (1 / 0-40 / 1-20 / 1).
The title compound was obtained as a light yellow oil (mmol, 89% yield). ¹ H N
MR (300 MHz, CDCl ₃ ): δ 1.45 and 1.47 (single line, 9H-rotomer), 1.91-2.07 (m, 2H), 3.16-3.31 (m, 4H) ), 3.47-3.6
5 (m, 4H), 3.85 (s, 3H), 6.72-6.96 (m, 4H); IR (KBr, c
m ⁻¹ ): 1691s; MS (ES) m / z (relative intensity): 307 (M ⁺ + H, 100)
. Elemental analysis calcd _{(as C 17 H 26 N 2 O 3} ): C, 66.64; H
, 8.55; N, 9.14. Found: C, 66.18; H, 8.54; N, 8.80.
.

Step 6 1- (2-Methoxy-phenyl)-[1,4] diazepane 2.03 g (6.62 mmol) of 4 in 30 mL of CH ₂ Cl ₂ at 23 ° C.
To-(2-Methoxy-phenyl)-[1,4] diazepan-1-carboxylic acid tert-butyl ester was added 5 mL of trifluoroacetic acid. After stirring for 30 minutes at 23 ° C., an additional 4 mL of trifluoroacetic acid was added. After 1 hour in total, 200 m of the reaction solution
Poured into L saturated aqueous NaHCO ₃ solution and extracted with 3 × 100 mL EtOAc. The combined organics were washed with 1 × 200 mL H ₂ O, 1 × 200 mL brine, dried over Na ₂ SO ₄ , filtered and evaporated to 1.01 g (4.90 mmol, 74% yield). To give the title compound as a yellow oil. ¹ H NMR (3
00 MHz, CDCl ₃ ): δ1.99 (5 main lines, J = 4.5 Hz, 2H), 2.82 (b
rs, 1H), 3.06 (t, J = 4.4Hz, 2H), 3.08-3.13 (m, 2H), 3
.29-3.36 (m, 4H), 3.84 (s, 3H), 6.83-6.96 (m, 4H); IR
^{(KBr, cm -1): 3335w} ; MS (ES) m / z ( relative intensity): 207 ^(M + +
H, 100).

[0060]   Process 7   3- {4- [4- (2-methoxy-phenyl)-[1,4] diazepan-1-yl] -cyclohe
Kisil} -1H-Indole   150 mg (0.727 mmol) of 1- (2-methoxy-phenyl)-[1,4] diaze
Bread and 155 mg (0.727 mmol) of 4- (1H-indol-3-yl) -shi
To clohexanone, 7 mL of 1,2-dichloroethane, 0.06 mL (66 mg, 1
0.091 mmol of HOAC, 231 mg (1.091 mmol) of NaBH (OA
c)_ThreeWas added and the resulting mixture was stirred at 23 ° C. for 19 hours. Then reaction mix
The product was quenched by adding 2 mL of 1N NaOH, saturated NaHCO 3.
_ThreePoured into aqueous solution. 2 x 50 mL CH_TwoCl_TwoOrganic matter extracted and combined with
To Na_TwoSO_FourDried over, filtered and evaporated to give a yellow oil.
EtOAc / MeOH: concentrated NH_FourElute with OH (10/1: 0% to 10/1: 0.5%)
Flash chromatography on silica gel to give 227 mg (0.5
The title compound (6 mmol, 77% yield) was obtained as a white foam. The hydrochloride is
The title compound was dissolved in 10 mL EtOAc and 0.6 mL (0.6 mmol) 1M.
 HCl / Et_TwoPrepared by treating with O. White solid precipitates from solution
And collected. Melting point 148 to 160 ° C; IR (KBr, cm^-1): 3407w, 2
529 m; MS (ES) m / z (relative intensity): 404 (M⁺+ H, 100). Elemental analysis
Result: Calculated value (C₂₆H₃₃N_ThreeO_Three・ HCl ・ C_FourH₈O_Two・ 2H_Two(As O)
: C, 63.87; H, 8.22; N, 7.45. Found: C, 63.87; H, 7
.85; N, 8.43.

Example 2 8- {4- [4- (1H-Indol-3-yl) -cyclohexyl]-[1,4] diazepane
-1-yl} -quinoline Step 1 4-quinolin-8-yl- [1,4] diazepan-1-carboxylic acid tert-butyl ester The title compound uses 8-bromoquinoline instead of 2-bromoanisole. Prepared according to the method of Step 5 of Example 1 except for the above. Yield: 68%; ¹ H N
MR (300 MHz, CDCl ₃ ): δ1.41 and 1.47 (s, 9H-rotomers
), 2.05-2.19 (m, 4H), 3.52-3.87 (complex m, 6H), 7.13 (d
d, J = 1.4,7.4Hz, 1H), 7.27-7.41 (m, 3H), 8.07 (d, J =
7.4 Hz, 1 H), 8.83 (d, J = 1.4 Hz, 1 H); IR (KBr, cm ⁻¹ ):
1689s; MS (ES) m / z ( relative ^{intensity): 328 (M + + H} , 100). As a result of elemental analysis, calculated value (as C ₁₉ H ₂₅ N ₃ O ₂ ): C, 69.70; H, 7.70;
N, 12.83. Found: C, 70.21; H5 7.63; N5 12.17.

Step 2 8- [1,4] diazepan-1-yl-quinoline The title compound was replaced by 4- (2-methoxy-phenyl)-[1,4] diazepan-1-carboxylic acid tert-butyl ester. 4-quinolin-8-yl- [1,4] diazepan-1-
Prepared according to the method of Step 6 of Example 1 except that carboxylic acid tert-butyl ester was used. Yield: 100%; ¹ H NMR (300 MHz, CDCl ₃ ):
δ2.05 (5 lines, J = 6.2Hz, 2H), 3.11 (t, J = 5.7Hz, 2H), 3
.31 (t, J = 5.6Hz, 2H), 3.68 (t, J = 6.0Hz, 2H), 3.75 (t
, J = 6.0 Hz, 2H), 4.47 (brs, 1H), 7.09 (dd, J = 1.4, 7.4)
Hz, 1H), 7.28-7.39 (m, 3H), 8.02 (dd, J = 1.5, 7.5Hz,
1H), 8.78 (d, J = 1.4 Hz, 1H); IR (KBr, cm ^-1 ): 3309w
; MS (ES) m / z ( relative ^{intensity): 228 (M + + H} , 60).

Step 3 8- {4- [4- (1H-Indol-3-yl) -cyclohexyl]-[1,4] diazepan
-1--yl} -quinoline The title compound was 8- (2-methoxy-phenyl)-[1,4] diazepan instead of 8-
Prepared according to the method of step 7 of example 1 except that [1,4] diazepan-1-yl-quinoline was used. Yield: 65%. The hydrochloride salt was formed according to the method of Step 7 of Example 1. Melting point 152-165 ° C; IR (KBr, cm ^-1 ): 3406w, 3
245w, 2671; MS (ES) m / z ( relative ^{intensity): 425 (M + + H} , 100).
As a result of elemental analysis, calculated value (as C ₂₈ H ₃₂ N ₄ .HCl.C ₄ H ₈ O ₂ .1.5H ₂ O): C, 66.71; H, 7.70; N, 9.72. Found: C, 66.5
4; H, 7.39; N, 11.19.

Example 3 3- {4- [4- (2-Methoxy-phenyl)-[1,4] diazepan-1-yl] -cyclohexyl} -5-fluoro-1H-indole Step 1 4- (5 -Fluoro-1H-3-indolyl) -cyclohex-3-ene-ethylene ketal The title compound was prepared according to the method of Step 1 of Example 1 except that 5-fluoroindole was used instead of indole. Yield: 86%. Melting point 153 ~
155 ° C.

Step 2 4- (5-Fluoro-1H-3-indolyl) -cyclohexanone ethylene ketal The title compound is 3- (1,4-dioxa-spiro [4.5] dec-7-en-8-yl ) -1
4- (5-Fluoro-1H-3-indolyl) -cyclohexa-instead of H-indole
Prepared according to the method of Step 2 of Example 1 except that 3-ene-ethylene ketal was used. Yield: 82%. Melting point 183-185 [deg.] C.

Step 3 4- (5-Fluoro-1H-3-indolyl) -cyclohexanone The title compound was converted to 3- (1,4-dioxa-spiro [4.5] dec-8-yl) -1H-indole. Prepared according to the method of step 3 of example 1 except that 4- (5-fluoro-1H-3-indolyl) -cyclohexanone ethylene ketal was used instead.
Yield: 91%. Melting point 112-114 [deg.] C.

Step 4 3- {4- [4- (2-Methoxy-phenyl)-[1,4] diazepan-1-yl] -cyclohexyl} -5-fluoro-1H-indole 1- (2-methoxy- Phenyl)-[1,4] diazepane (103 mg, 0.5 mmol)
4- (5-Fluoro-1H-3-indolyl) -cyclohexanone (116 mg, 0.5
5 mL of 1,2-dichloroethane and 159 mg (0.75 mmol)
NaBH (OAc) ₃ in 2 mL of a 20 mL scintillation vial at 23 ° C.
Stir for 1 hour. The reaction was quenched with 2 mL of 1N NaOH, the vial was capped, shaken and the organic layer (bottom layer) was removed with an automatic pipette. The organics were transferred to a Speed Vac and pumped overnight to give 169 mg (0.4 mmol, 80% yield) of the title compound as an off-white solid. MS (ES)
m / z (relative ^{intensity): 422 (M + + H} , 100).

Example 4 3- {4- [4- (2-Methoxy-phenyl)-[1,4] diazepan-1-yl] -cyclohexyl} -5-cyano-1H-indole Step 1 4- (5 -Cyano-1H-3-indolyl) -cyclohex-3-ene-ethylene ketal The title compound was prepared according to the method of Step 1 of Example 1 except that 5-cyanoindole was used instead of indole. Yield: 50%; melting point 158-1
60 ° C.

Step 2 4- (5-Cyano-1H-3-indolyl) -cyclohexanone ethylene ketal The title compound is 3- (1,4-dioxa-spiro [4.5] dec-7-en-8-yl ) -1
4- (5-cyano-1H-3-indolyl) -cyclohexa-3 instead of H-indole
Prepared according to the method of Step 2 of Example 1 except that -ene-ethylene ketal was used. Yield: 95%; mp 153-155 ° C.

3- (4-oxo-cyclohexyl) -1H-indole-5-carbonitrile The title compound is 3- (1,4-dioxa-spiro [4.5] dec-8-yl) -1H-indole. Prepared according to the method of Step 3 of Example 1 except that 4- (5-cyano-1H-3-indolyl) -cyclohexanone ethylene ketal was used instead of. Yield: 81%; melting point 162-164 [deg.] C.

Step 4 3- {4- [4- (2-Methoxy-phenyl)-[1,4] diazepan-1-yl] -cyclohexyl} -5-cyano-1H-indole The title compound is 4- ( According to the method of Step 4 of Example 3 except that 3- (4-oxo-cyclohexyl) -1H-indole-5-carbonitrile was used in place of 5-fluoro-1H-3-indolyl) -cyclohexanone. Prepared. Yield: 60%;
MS (ES) m / z (relative ^{intensity): 429 (M + + H} , 100).

Example 5 3- {4- [4- (2-Methoxy-phenyl)-[1,4] diazepan-1-yl] -cyclohexyl} -6-fluoro-1H-indole Step 1 3- (1 , 4-Dioxa-spiro [4.5] dec-7-en-8-yl) -6-fluoro-1H
-Indole The title compound was prepared according to the method of Step 1 of Example 1 except that 6-fluoroindole was used instead of indole. Yield 96%; melting point 196-1
97 ° C.

Step 2 3- (1,4-Dioxa-spiro [4.5] dec-8-yl) -6-fluoro-1H-indole The title compound is 3- (1,4-dioxa-spiro [4 .5] Dec-7-En-8-yl) -1
3- (1,4-dioxa-spiro [4.5] dec-7-ene-8- instead of H-indole
Prepared according to the method of Step 2 of Example 1 except that yl) -6-fluoro-1H-indole was used.

Step 3 4- (6-Fluoro-1H-indol-3-yl) -cyclohexanone The title compound is 3- (1,4-dioxa-spiro [4.5] dec-8-yl) -1H- According to the method of Step 3 of Example 1 except that 3- (1,4-dioxa-spiro [4.5] dec-8-yl) -6-fluoro-1H-indole was used instead of indole. Prepared. Yield: 60%; MS (ES) m / z ( relative ^{intensity): 429 (M + + H} , 100).

Step 4 3- {4- [4- (2-Methoxy-phenyl)-[1,4] diazepan-1-yl] -cyclohexyl} -6-fluoro-1H-indole The title compound is 4- ( Prepared according to the method of Step 4 of Example 3 except that 4- (6-fluoro-1H-3-indolyl) -cyclohexanone ethylene ketal was used instead of 5-fluoro-1H-3-indolyl) -cyclohexanone. did. Yield: 38
%; MS (ES) m / z ( relative ^{intensity): 422 (M + + H} , 100).

Example 6 8- {4- [4- (5-Fluoro-1H-indol-3-yl) -cyclohexyl]-[1,
4] diazepan-1-yl} -quinoline The title compound is 8- (2-methoxy-phenyl)-[1,4] diazepan instead of 8-
Prepared according to Step 4 of Example 3 except that [1,4] diazepan-1-yl-quinoline was used. Yield: 43%; MS (ES) m / z (relative intensity): 443 (M ⁺ + H)
, 100).

Example 7 8- {4- [4- (5-Cyano-1H-indol-3-yl) -cyclohexyl]-[1,4]
Diazepan-1-yl} -quinoline The title compound was 8- (2-methoxy-phenyl)-[1,4] diazepan instead of 8-
Using [1,4] diazepan-1-yl-quinoline, 3- (4-oxo-cyclohexyl) -1H-indole-5-in place of 4- (5-fluoro-1H-3-indolyl) -cyclohexanone Prepared according to Step 4 of Example 3 except that carbonitrile was used. Yield 92%; MS (ES) m / z ( relative ^{intensity): 450 (M + + H} , 100).

Example 8 8- {4- [4- (6-Fluoro-1H-indol-3-yl) -cyclohexyl]-[1,
4] diazepan-1-yl} -quinoline The title compound is 8- (2-methoxy-phenyl)-[1,4] diazepan instead of 8-
Using [1,4] diazepan-1-yl-quinoline, 4- (6-fluoro-1H-indol-3-yl) instead of 4- (5-fluoro-1H-3-indolyl) -cyclohexanone
Prepared according to step 4 of example 3 except that cyclohexanone was used.
89% yield; MS (ES) m / z ( relative ^{intensity): 443 (M + + H} , 100).

Example 9 3- {4- [4- (3-trifluoromethyl-phenyl)-[1,4] diazepan-1-yl]
-Cyclohexyl} -5-fluoro-1H-indole Step 1 4- (3-Trifluoromethyl-phenyl)-[1,4] diazepan-1-carboxylic acid ter
t-Butyl ester The title compound was prepared according to the method of Step 5 of Example 1 except that 1-bromo-3-trifluoromethylbenzene was used instead of 2-bromoanisole.
Yield: 73%; ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.33 and 1.4.
3 (s, 9H-rotomer), 1.95-2.03 (m, 4H), 3.22 (t, J = 4.2H)
z, 2H), 3.34 (t, J = 4.2Hz, 2H), 3.53-3.64 (m, 4H), 6.
79-6.91 (m, 2H), 7.25-7.33 (m, 2H); IR (KBr, cm ^-1 ):
1693s; MS (ES) m / z ( relative ^{intensity): 345 (M + + H} , 100). Elemental analysis: Calculated _{(as C 17 H 23 F 3 N 2} O 2): C, 59.29; H, 6.7
3; N, 8.13. Found: C, 59.24; H, 6.68; N, 8.11.

Step 2 1- (3-Trifluoromethyl-phenyl)-[1,4] diazepane The title compound is 4- (2-methoxy-phenyl)-[1,4] diazepane-1-carboxylic acid tert- Instead of butyl ester, 4- (3-trifluoromethyl-phenyl)-[1,
4] Prepared according to the method of Step 6 of Example 1 except that diazepan-1-carboxylic acid tert-butyl ester was used. Yield: 91%; ¹ H NMR (300 MHz
, CDCl ₃ ): δ1.77 (brs, 1H), 1.92 (5 main lines, J = 5.9 Hz, 2H)
, 2.84 (t, J = 5.8Hz, 2H), 3.04 (t, J = 5.4Hz, 2H), 3.5
6-3.62 (m, 4H), 6.77-6.88 (m, 3H), 7.29 (d, J = 7.7Hz,
1H); IR (KBr, cm ^-1 ): 3286w; MS (ES) m / z (relative intensity): 2
45 (M ⁺⁺ H, 60). Result of elemental analysis: Calculated value (as C ₁₂ H ₁₅ F ₃ N ₂ ).
: C, 59.01; H, 6.19; N, 11.47. Found: C, 58.56; H,
6.03; N, 10.98.

Step 3 3- {4- [4- (3-trifluoromethyl-phenyl)-[1,4] diazepan-1-yl]
-Cyclohexyl} -5-fluoro-1H-indole The title compound was 1- (2-methoxy-phenyl)-[1,4] diazepan instead of 1-
Prepared according to step 4 of example 3 except that (3-trifluoromethyl-phenyl)-[1,4] diazepane was used. Yield: 86%; MS (EZ) m / z (relative intensity)
: 460 (M ⁺⁺ H, 100).

Example 10 3- {4- [4- (3-trifluoromethyl-phenyl)-[1,4] diazepan-1-yl]
-Cyclohexyl} -5-cyano-1H-indole The title compound was 1- (2-methoxy-phenyl)-[1,4] diazepan instead of 1-
Using (3-trifluoromethyl-phenyl)-[1,4] diazepane, instead of 4- (5-fluoro-1H-3-indolyl) -cyclohexanone, 3- (4-oxo-cyclohexyl) -1H- Prepared according to step 4 of example 3 except that indole-5-carbonitrile was used. Yield: 80%; MS (ES) m / z (relative intensity): 467 (
M ⁺ + H, 100).

Example 11 3- {4- [4- (3-trifluoromethyl-phenyl)-[1,4] diazepan-1-yl]
-Cyclohexyl} -6-fluoro-1H-indole The title compound was 1- (2-methoxy-phenyl)-[1,4] diazepan instead of 1-
Using (3-trifluoromethyl-phenyl)-[1,4] diazepane, 4- (6-fluoro-1H-indole-3 instead of 4- (5-fluoro-1H-3-indolyl) -cyclohexanone Prepared according to Step 4 of Example 3 except that -yl) -cyclohexanone was used. Yield: 64%; MS (ES) m / z (relative intensity): 460 (M ⁺ + H)
, 100).

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI Theme Coat (Reference) A61P 25/24 A61P 25/24 25/28 25/28 25/30 25/30 25/32 25/32 C07D 403/08 C07D 403/08 (81) Designated countries 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, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, 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, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Richard・ Eric Mushaw United States 19406 King of Prussia, Pennsylvania, Apartment Bee-509, West DeKalb Pike No. 251F Term (Reference) 4C063 AA01 BB05 CC36 DD06 DD14 EE01 4C086 AA01 AA02 AA03 AA04 BC53 GA07 MA02 MA05 NA14 ZA05 ZA12 ZA15 ZA81 ZC39

Claims (14)

[Claims] 1. The formula: [In the formula, Ar is aryl having 5 to 14 carbon atoms; arylalkyl (wherein the aryl portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 6 carbon atoms); or heteroaryl having 5 to 10 ring atoms. (Wherein the heteroatom is one or more of oxygen, nitrogen and sulfur selected from the same or different)
); Wherein the aryl or heteroaryl moiety is: alkyl having 1 to 12 carbons (which may be substituted with halogen, hydroxy, nitro, amino or cyano), alkoxy having 1 to 12 carbons, 1 carbon ~ 6 thioalkyl, C1-6 perfluoroalkyl, hydroxy, nitro, halogen, amino and optionally substituted with 1 to 3 substituents different from each other selected from cyano; R ₁ and R ₂ independently represents hydrogen; alkyl having 1 to 12 carbons (which may be substituted with halogen, hydroxy, nitro, amino or cyano); or cycloalkyl having 3 to 10 carbons (halogen, 1 carbon) ~ 6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, hydroxy, Substituted with nitro, amino, cyano, carboxy, C2-7 alkoxycarbonyl, C2-7 alkylcarbonyl, C3-13 alkoxycarbonylalkyl or C2-7 alkylcarbonyloxy. R ₃ is hydrogen; alkyl having 1 to 12 carbons (which may be substituted with halogen, hydroxy, nitro, amino or cyano); cycloalkyl having 3 to 10 carbons (halogen, 1 carbon) To C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, C1 to C6 haloalkoxy, hydroxy, nitro, amino, cyano, carboxy, C2 to C7 alkoxycarbonyl, carbon C2-C7 alkylcarbonyl, C3-C13 alkoxycarbonylalkyl or C2-C7 Optionally substituted with carbonylcarbonyloxy); halogen; alkoxy group having 1 to 12 carbon atoms; haloalkyl having 1 to 12 carbon atoms; hydroxy; nitro; nitrile; amino; cyano; carboxy; alkoxy having 2 to 12 carbon atoms Carbonyl; alkylcarbonyl having 2 to 12 carbons; aminocarbonyl or alkylaminocarbonyl having 2 to 12 carbons], or a pharmaceutically acceptable salt thereof. 2. Ar is a monocyclic, bicyclic or tricyclic aryl- or aryl-alkyl, wherein aryl has 6 to 14 carbon atoms and is substituted as defined in claim 1. Optionally alkyl is C1-4) or Ar is a monocyclic or bicyclic heteroaryl, which may be substituted as defined in claim 1; The compound shown. 3. Ar is furanyl, thiophene, pyrrole, imidazole, oxazole, thiazole, isoxazole, pyrazole, isoxazole,
Isothiazole, oxadiazole, triazole, thiadiazole, quinolizine, quinoline and isoquinoline (each of which has 1 to 12 carbon atoms, -CF ₃ ,
The compound according to claim 1 or 2, which may be substituted with 1 to 3 groups selected from alkoxy having 1 to 12 carbons and halogen. 4. Ar is phenyl, benzyl, naphthalene, anthracene, phenanthrene, indene or indacene (each is alkyl having 1 to 12 carbon atoms,
The compound according to claim 1 or 2, which is selected from CF ₃ , optionally substituted with 1 to 3 groups selected from C 1-12 alkoxy and halogen. 5. A compound represented by formula (I) according to any one of claims 1 to 4, wherein Ar may be substituted with one or more alkoxy having 1 to 4 carbon atoms or perfluoromethyl. . 6. The method according to claim 1, wherein R ₁ and R ₂ are each independently selected from halogen, alkyl having 1 to 6 carbons or cycloalkyl having 3 to 8 carbons. A compound of formula (I). 7. R ₃ is hydrogen, halogen, cyano, CONH ₂ or COOH
The compound of formula (I) according to any one of claims 1 to 6. 8. Ar having 5 or 6 carbon atoms, which may be substituted, or an aryl group having 5 to 10 carbon atoms, which may be substituted; R ₁ and R ₂ are independently H, Linear alkyl having 1 to 8 carbons or 3 carbons
A branched-chain alkyl having 8 to 8; R ₃ is H, a linear alkyl having 1 to 8 carbons, a branched alkyl having 3 to 6 carbons, a cycloalkyl having 3 to 8 carbons, halogen, and 1 to 6 carbons. Alkoxy, carbon number 1
~ 6 haloalkyl, C1-6 haloalkoxy, hydroxy, nitro, nitrile, amino, cyano, carboxy, C2-6 alkoxycarbonyl,
The compound according to claim 1, which is an alkylcarbonyl having 2 to 6 carbon atoms, an aminocarbonyl and an alkylaminocarbonyl having 2 to 6 carbon atoms, which is represented by the formula (I) or a pharmaceutically acceptable salt thereof. . 9. Ar is an aryl group having 6 carbon atoms or a heteroaryl group having 5 to 10 carbon atoms; R ₁ and R ₂ are independently H, linear alkyl having 1 to 3 carbon atoms or 3 carbon atoms.
A branched chain alkyl of -6; R ₃ is H, halogen, cyano, CONH ₂ or CO ₂ H, or a pharmaceutically acceptable salt thereof, of formula (I). Compound of. 10. The following: 3- {4- [4- (2-methoxy-phenyl)-[1,4] diazepan-1-yl] -cyclohexyl} -1H-indole; 8- {4- [4-- (1H-Indol-3-yl) -cyclohexyl]-[1,4] diazepan
3- {4-yl} -quinoline; 3- {4- [4- (2-methoxy-phenyl)-[1,4] diazepan-1-yl] -cyclohexyl} -5-fluoro-1H-indole; 3- { 4- [4- (2-Methoxy-phenyl)-[1,4] diazepan-1-yl] -cyclohexyl} -5-cyano-1H-indole; 3- {4- [4- (2-methoxy-phenyl] )-[1,4] Diazepan-1-yl] -cyclohexyl} -6-fluoro-1H-indole; 8- {4- [4- (5-fluoro-1H-indol-3-yl) -cyclohexyl]- [1,
4] diazepan-1-yl} -quinoline; 8- {4- [4- (5-cyano-1H-indol-3-yl) -cyclohexyl]-[1,4]
Diazepan-1-yl} -quinoline; 8- {4- [4- (6-fluoro-1H-indol-3-yl) -cyclohexyl]-[1,
4] diazepan-1-yl} -quinoline; 3- {4- [4- (3-trifluoromethyl-phenyl)-[1,4] diazepan-1-yl]
-Cyclohexyl} -5-fluoro-1H-indole; 3- {4- [4- (3-trifluoromethyl-phenyl)-[1,4] diazepan-1-yl]
-Cyclohexyl} -5-cyano-1H-indole; or 3- {4- [4- (3-trifluoromethyl-phenyl)-[1,4] diazepan-1-yl]
-Cyclohexyl} -6-fluoro-1H-indole; and a pharmaceutically acceptable salt thereof. 11. A medicament comprising the compound according to claim 1 defined in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Composition. 12. A method for treating depression in a mammal, which comprises a pharmaceutically effective amount of the compound or a pharmaceutically acceptable compound thereof according to any one of claims 1 to 10, to a mammal in need thereof. A method comprising administering a salt as defined above. 13. A method for treating anxiety in a mammal, which comprises a pharmaceutically effective amount of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable compound thereof, to a mammal in need thereof. A method comprising administering a salt. 14. A process for preparing a compound of formula (I) as defined in claim 1, comprising formula (II): [Wherein Ar has the same meaning as in claim 1], and a compound represented by the formula (III): [Wherein R ₁ , R ₂ and R ₃ have the same meanings as in claim 1] and are isolated, if necessary, as a pharmaceutically acceptable salt thereof.