WO2002018367A1

WO2002018367A1 - Tetrahydrobenzindole derivatives capable of binding to 5-ht7 receptor and metabolically stable

Info

Publication number: WO2002018367A1
Application number: PCT/JP2001/007573
Authority: WO
Inventors: Chika Kikuchi; Masao Koyama; Kazuyuki Fuji; Masayo Okuno; Toyokazu Hiranuma
Original assignee: Meiji Seika Kaisha, Ltd.
Priority date: 2000-08-31
Filing date: 2001-08-31
Publication date: 2002-03-07
Also published as: AU2001282595A1; JP2004231514A

Abstract

Compounds represented by the following general formula (I) or pharmacologically acceptable salts thereof. These compounds are useful in preventing or treating diseases caused by failures in central and peripheral serotonin regulation, for example, mental diseases (manic-depressive psychosis, anxiety, schizophrenia, epilepsy, sleep disorder, biorhythm disorder, migraine, etc.), circulatory diseases (hypertension, etc.) and digestive function failures, wherein R1 represents hydrogen or halogeno; R2 represents hydroxy or halogeno; and R3 represents hydrogen or halogeno, provided that the case where R?1 and R3¿ are both hydrogen is excluded.

Description

Specification

Background of the Invention Tetrahydrobenzindole Derivatives with 5-HT ₇ Receptor Binding Capability and Metabolically Stable

Field of the invention

The present invention relates to a tetrahydropentzuindole derivative having a selective binding ability to a serotonin receptor in a living body and having high metabolic stability, and a pharmaceutical composition comprising the same.

Profile:

In today's society, the environment around us is changing rapidly, making it increasingly difficult to adapt. The parts that cannot cope with the social environment become stress and accumulate in our bodies, which may eventually cause abnormalities not only in physical functions but also in mental functions. In the treatment of mental dysfunction, the importance of pharmacotherapy together with psychotherapy is increasing, and the development of useful drugs is progressing.

Since the effect of serotonin (5-HT) on the central nervous system was suggested, the classification and distribution of serotonin receptors has been gradually clarified. And the detailed analysis of serotonin receptors using recent molecular biological techniques, 5-HT! And its subtypes, 5-HT ₂ and its _{subtypes, 5-HT 3, 5- HT} 4, 5- certain such HT _6, 5-HT ₇ is made, 14 kinds of serotonin receptors have been proposed [RD Ward et euroscience, 64, 1105-1111, 1995] .

Than to show high affinity for both receptors Several schizophrenia drugs of 5-HT _6, 5 one HT _7, including clozapine, these receptors are closely to the effectiveness of schizophrenia drugs [BL Roth et al., J. Pharmacorol. Exp. Ther., 268, 1403-1410, 1994].

In addition, the 5-HT7 receptor is thought to play an important role in controlling circadian rhythms in humans, suggesting its involvement in sleep disorders and biological rhythm disorders [TW Lovenberg et al. Neuron, 11, 449-458, 1993]. Moreover, control over the 5-HT ₇ receptor density in rat suprachiasmatic nuclei was reduced by given continuous projection of several depression drugs, 5-HT ₇ receptor is expressed Ya circadian rhythms of antidepressant action Has been suggested to be involved [UL Mullins et al., Neurosychopharmacology, 21, 352-367, 1999]. .

It is widely found not only in the brain of humans and animals but also in smooth muscle tissues, such as the spleen, stomach, ileum, small intestine, and coronary blood vessels [AJ Sleight, DN & P, 214-223, 1997]. It is assumed that the function is fulfilled. Therefore, the creation of a substance that acts on the 5-HT7 receptor is extremely useful for studying physiological functions in these organs and for treating and preventing diseases caused by abnormal functions in these organs.

The present inventors have already found the quality ones having strong ability to bind to 5-HT ₇ receptor in vivo. That invention related to the present inventors (W098 / 00400, EP97928490, WO 99/33804, EP1057814, WO 99 Z54303, EP 1081136) According to the novel binding strongly against the 5-HT ₇ receptors in vivo The present invention provides a novel tetrahydrobenzindole derivative and a pharmaceutical composition comprising the compound.

As described above, although the novel tetrahydronaphthalene base Nzuindoru derivatives which bind strongly to 5-HT ₇ receptor in the living body is provided, not necessarily satisfactory with stability to the metabolism. Summary of the Invention

The present inventors have now found that the introduction of a halogen atom or a hydroxyl group into the aromatic ring portion of the tetrahydrobenzindole derivative significantly enhances metabolic stability, and has completed the present invention.

That is, an object of the present invention is to provide a tetrahydrobenzindole derivative having a selective binding ability to a serotonin receptor in a living body and having high metabolic stability, and a medicament comprising the compound. I do.

The compound according to the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof It is.

(In the above formula,

R ¹ represents a hydrogen atom or a Hagengen atom,

R ² represents a hydroxyl group or a halogen atom,

R ³ represents a hydrogen atom or a halogen atom,

However, this does not apply when both R ¹ and R ³ are hydrogen atoms. )

The compounds according to the invention bind to human 'serotonin 5- H ΊΝ receptor subtypes expressed in clonal cell lines ^[3 H] - 5 CT strongly and selectively inhibit, also evident from the below test examples Thus, it is remarkably stable against metabolism as compared with known compounds. Thus, the compounds according to the invention may be used for diseases caused by abnormal central and peripheral serotonin control functions, such as mental disorders (manic depression, anxiety, schizophrenia, epilepsy, sleep disorders, biological rhythm disorders, migraines, etc.), circulation, It is useful for the prevention or treatment of systemic diseases (such as hypertension) and gastrointestinal dysfunction.

The pharmaceutical composition according to the invention comprises the compound according to the invention or a pharmacologically acceptable salt thereof, and optionally a pharmaceutical additive.

The present invention also provides the use of a compound according to the present invention for the manufacture of a medicament for use in the prevention or treatment of mental illness.

The present invention further provides a method for preventing or treating a psychiatric disorder, comprising the step of administering a therapeutically effective amount of a compound according to the present invention to a mammal, including a human. Detailed description of the invention ''

"Halogen atom" means each atom of fluorine, chlorine, bromine and iodine, and "base" used as a catalyst means sodium hydroxide, potassium carbonate, triethylamine and the like. R ¹ is preferably a hydrogen atom, a fluorine atom, a chlorine atom, or a bromine atom, and more preferably a fluorine atom, a chlorine atom, or a bromine atom.

R ² is preferably a hydroxyl group, a fluorine atom, a chlorine atom or a bromine atom, more preferably a fluorine atom, a chlorine atom or a bromine atom, and particularly preferably a chlorine atom.

R ³ is preferably a hydrogen atom, a fluorine atom, a chlorine atom, or a bromine atom, and more preferably a hydrogen atom.

Preferred compounds of the formula (I) include those in which R ¹ and R ² may be the same or different and are a fluorine atom, a chlorine atom or a bromine atom.

Another preferred group of compounds include those wherein R ¹ is a fluorine, chlorine or bromine atom and R ² is a hydroxyl group.

A more preferred compound group includes compounds in which R ¹ is a fluorine atom, a chlorine atom, or a bromine atom, and R ² is a chlorine atom.

Further preferred compound groups include: compounds in which R ¹ is a fluorine atom, a chlorine atom or a bromine atom, R ² is a chlorine atom, and R ³ is a hydrogen atom. In the present invention, among the compounds of the formula (I), specific examples of preferred compounds are as follows.

2a- (4- (4- (4-fluorophenyl) 1-1,2,3,6-tetrahydridopyridine-11-yl) butyl) -16-chloro-1a, 3,4,5- Tetrahide Mouth Bends [cd] Indole-1 (1H) On

2 a- (4— (4— (4-chlorophenyl) -1,2,3,6-tetrahydropyridine-11-yl) butyl) -1-6-cyclo-1,2 a, 3,4,5- Tetrahydrobenz [cd] indole-1 (1H) on,

2a- (4- (4- (4-bromophenyl) -1 1,2,3,6-tetrahydropyridine-1 1-yl) butyl) 1 6-chloro-2a, 3,4,5-tetrahydrobenz [cd ] Indore One 2 (1H) On,

2a- (4- (4- (4-fluorophenyl) -1, 2,3,6-tetrahydrid pyridine-11-yl) butyl) -1,6-dichloro-1 2a, 3,4,5 —Te Trahydrobenz [cd] Indoneil 2 (1H) on,

2a- (4- (4-phenyl-1,1,2,3,6-tetrahydropyridine-1-yl) butyl) 1,6,8-dichloro-2a, 3,4,5-tetrahydrobenz [cd] Indore One 2 (1H) On,

2a— (4- (4-phenyl-1,2,3,6-tetrahydropyridine-11-yl) butyl) 1,6,8-difluoro-2a, 3,4,5-tetrahydrobenz [cd ] India 1 Rue 2 (1H) On, and

2a- (4- (4- (4-Monofluorophenyl-1,2,3,6-tetrahydropyridine-11-yl) butyl) 1-6-Hydroxy-2a, 3,4,5-tetrahydrobe [Cd] Indore One 2 (1H) On.

The compound represented by the formula (I) has an asymmetric carbon at one place, and optical isomers based on the asymmetric carbon exist. In addition to optical isomers in pure form, any mixtures of optical isomers, racemates, etc. are all included in the scope of the present invention, and any of those substances may be used as an active ingredient of the medicament of the present invention. Good.

The compounds according to the invention are characterized in that they have an affinity for the serotonin 5-HT7 receptor. Therefore, the compound according to the present invention is useful for preventing or treating mental disorders such as manic depression, anxiety, schizophrenia, epilepsy, sleep disorders, biological rhythm disorders, or migraine involving the serotonin 5-HT? Receptor. Useful for

The compounds of the formula (I) according to the invention can be prepared starting from compounds of the formula (II).

First, by subjecting a compound of the formula (II) to a conventionally known aromatic nucleophilic substitution reaction, a compound of the formula (III) wherein RR ³ has the same meaning as defined in the above formula (I) You. ].

(II) (III)

Preferred examples of halogenation include disulfide in the presence and absence of a suitable catalyst. The reaction is carried out in a solvent such as carbon, carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, and acetic acid at 0 ° C to heating under reflux. In addition to fluorine, chlorine, bromine, and iodine as halogenating agents, non-fluorinated compounds such as 1-fluoropyridinium triflate, 1-fluoro 2,6-dichloropyridinium tetrafluoroborate, etc. N-fluoro-N-alkylsulfonamides such as substituted or substituted N-fluoropyridinium salts, N-fluoro-N-propyl-p-toluenesulfonamide, N-fluorobenzenesulfone N-fluorosulfonimides such as imide, sodium hypochlorite N-promosuccinimide, sulfuryl chloride, etc. are used.

The introduction of hydroxyl groups is carried out by converting the acyl group introduced by the Friedel-Crafts reaction, which is an aromatic nucleophilic substitution reaction, by a chemical reaction. The Friedel-Crafts reaction is carried out in the presence of a catalyst in a solvent such as carbon disulfide, chloroform, dichloromethane, 1,2-dichloroethane, or nitrobenzene at 0 ° C to heating under reflux. Examples of the acylating agent include acyl halides such as acetyl chloride and propyl chloride, as well as acid anhydrides such as acetic anhydride and carboxylic acids such as acetic acid and propionic acid. Preferred catalysts include Lewis acids such as aluminum chloride, iron chloride, boron trifluoride, tin chloride and zinc chloride, as well as protonic acids such as hydrogen fluoride, sulfuric acid and polyphosphoric acid.

The acyl group introduced by the Friedel-Crafts reaction is reacted with a peroxide such as m-chloroperbenzoic acid or pertrifluoroacetic acid, and if necessary, in the presence of an acid catalyst such as trifluoroacetic acid. An oxygen atom is inserted between the ring and the carbonyl group to convert to an acyloxy group, and further, to a hydroxyl group by hydrolysis.

The compound of formula (II) can be produced by the method described in WO98 / 4000.

Then, the compound of the formula (III) is converted to a compound of the formula (IV) wherein R ¹ has the same meaning as defined in the formula (I). ] In the presence of a base with a secondary amine represented by the formula (1) to convert into a compound of the formula (I).

This reaction is carried out in the absence of a solvent or after being diluted with an inert solvent, and proceeds in the range of room temperature to heating in the presence or absence of an acid absorbent. Examples of the inert solvent used include dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, and the like. Examples of the acid absorbent include salts of alkali metals, carbonates (eg, sodium carbonate, potassium carbonate, etc.), and bicarbonate. Salts (sodium bicarbonate, potassium bicarbonate, etc.), trialkylamines, pyridine bases, etc. are used, and secondary amine itself used as a raw material can be used in excess to serve as an acid absorbent. .

The compound of the formula (IV) can be produced by using a commercially available product or by dehydrating a corresponding commercially available piperidinol compound with an acid.

Among the compounds of formula (III), specific examples of the preferred compounds are as follows _c

2a— (4-Promooptyl) -1-6-hydroxy-2a, 3,4,5-tetrahydrobenz [cd] indole-1 (1H) one,

2a- (4-Promooptyl) -1-6-chloro mouth 2a, 3,4,5-tetrahydrobenz [cd] indole-1 (1H) one,.

2a- (4-bromobutyl) -6-bromo-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one,

2 a— (4-Promooptyl) 1-fluoro-2a, 3,4,5-tetrahydr benzobens [cd] India 1 2. (1H) on,

2 a- (4—Promooptyl) —6,8—dichloro-2a ύ, 4,5—Tetra hydrobenz [cd]

2 a- (4-Bromobutyl) —6,8-dibromo-1 2a, 3 4,5-tetrahydrobenz [cd] indole-1 (1H) one, and

2a— (4-bromobutyl) —6,8-difluoro-2a, 3,4,5-tetra Lahydrobenz [cd] Indole-1 (1H) on.

Among the compounds of the formula (IV), specific examples of preferred compounds are as follows. 4-phenyl-1,2,3,6-tetrahydro-pyridine,

4- (4-fluorophenyl) 1-1,2,3,6-tetrahydro-pyridine, 4- (4-chlorophenyl) 1-1,2,3,6-tetrahydro-pyridine, and

4- (4-Promophenyl) 1-1,2,3,6-tetrahydro-pyridine. Purification of the target compound from the reaction mixture in the synthesis of the compound according to the present invention is carried out by a method commonly used in synthetic chemistry, i.e., the reaction is carried out with ice and an organic solvent that is not arbitrarily miscible with water, such as benzene, toluene, and the like. Partition and extract into ethyl acetate, butyl acetate, methyl isobutyl ketone, chloroform, dichloromethane, etc., and concentrate and crystallize. If necessary, fractional purification by column chromatography using, for example, alumina or silica gel is also performed.

Representative compounds of the present invention are specifically and specifically described in the working examples of the present specification. Therefore, based on the above-mentioned general production method and the description of the examples described below, the starting compounds, the reaction reagents, the reaction conditions, and the like are appropriately selected and disclosed in the examples as necessary. By making appropriate modifications or alterations to the method, those skilled in the art can produce any of the compounds encompassed by the above general formula (I). The compounds according to the present invention are amines and exist as bases. Therefore, it forms salts with many inorganic and organic acids, and this property is used in the production of pure substances and in the form of delivery as pharmaceuticals. That is, by making it acidic at the time of production, it is solubilized in, for example, a polar solvent such as water, extracted and purified, and isolated as a salt having favorable physicochemical properties. It can be in the form of an acceptable salt.

Possible salt forms include acid addition salts with inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid and sulfuric acid, or aliphatic monocarboxylic acids, dicarboxylic acids, hydroxyalconic acids, hydroxyalkanediacids, There are salts derived from non-toxic organic acids such as amino acids and also aromatic acids, aliphatic and aromatic sulfonic acids. Examples of such acid salts include hydrochloride, hydrobromide, nitrate, sulfate, bisulfate, phosphorus Monohydrogen acid, dihydrogen phosphate, acetate, propionate, tartrate, oxalate, malonate, succinate, fumarate, maleate, mandelate, benzoate, benzoate Examples include butyrate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, lactate, malate, and glycolate. The above-mentioned acid addition salts are preferable as pharmacologically acceptable medicaments. That is, it is advantageous in the formulation from the viewpoint of the dissolution rate in water, and is also advantageous from the viewpoint of dispersibility and absorption when administered to the human body.

The medicament provided by the present invention is characterized by comprising at least one compound represented by the formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. The medicament according to the present invention can be administered to humans and non-human animals by any of oral and parenteral (for example, intravenous, intramuscular, subcutaneous, rectal, transdermal) administration routes. . As the medicament of the present invention, the above-mentioned substance which is an active ingredient may be administered as it is, but generally, a pharmaceutical composition is prepared and administered using one or more pharmaceutical additives. It is preferable that the dosage form is appropriate for the administration route. Specifically, oral preparations include tablets, capsules, powders, granules, syrups, and the like. Parenteral preparations include injections such as intravenous injections and intramuscular injections, rectal preparations, and oily seats. And aqueous suppositories.

These various preparations can be produced by conventional methods using commonly used preparation additives, for example, excipients, disintegrants, binders, lubricants, coloring agents and the like. Excipients include, for example, lactose, pudose, corn starch, sorbitol, crystalline cellulose, and disintegrants, for example, starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin, etc. For example, dimethylcellulose, polyvinyl alcohol, polyvinylether, methylcellulose, ethylcellulose, gum arabic, gelatin, hydroxypropylcellulose, polyvinylpyrrolidone, etc., and as a lubricant, for example, talc, magnesium stearate, polyethylene glycol, Hardened vegetable oils and the like can be mentioned. In addition, the above injection can be produced by adding a buffer, a pH adjuster, a stabilizer and the like as necessary.

The content of the compound according to the present invention in the pharmaceutical composition varies depending on its dosage form, Usually, it is 0.1 to 50% by weight, preferably about 0.1 to 20% by weight in the whole composition. The dose is appropriately determined depending on the individual case in consideration of the patient's age, weight, sex, difference in disease, degree of symptoms, and the like. Usually, the dose is 0.1 to 0.1 mg / day; The preferred dose is 0.1 to 30 mg, which is administered once or several times a day. Example

The present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited to these examples.

Example 1: 2a- (4-Promobutyl) -6-chloro-2a, 3,4,5-tetrahydrobenz Ccd] indole-2 (1H) one

2a- (4-Promooptyl) -2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one (1.5 g, 5.0 mmo 1) prepared according to Example 1 of WO 98/00400 The residue was dissolved in methylene (30 ml), sulfuryl chloride (420 ml, 5.3 mmol) was added, and the mixture was stirred at 0 ° C for 1.5 hours. Water was added to the reaction solution, and the reaction product was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure.The obtained substance was separated and purified by silica gel column chromatography to obtain 1.5 g of the above-mentioned target substance ( 4.4 t ol, yield 87%).

Ή-NMR (CDCla) δ 1.19-1.54 (3Η, m), 1.69-1.90 (4H, m), 1.90-2.00 (1H, m), 2.08-2.20 (2H, m), 2.70-2.84 (2H, m ), 3.32 (2H, t, J = 7.1Hz), 6.64 (1H, d, J = 8.0Hz), 7.61 (1H, d), 7.31 (1H, brs); MW 342.66 (CuHnN OBrCl); Mass spectrum EI m / z 341, 343, 345 (M) ⁺

Example 2: 2a- (4- (4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridin-1-yl) butyl) -6-chloro-2a, 3,4 , 5-tetrahydrobenz [cd] indole-2 (1H) on

2a- (4-bromobutyl) -6-chloro-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one (340mg, l.Ommol), 4- (4-fluorophenyi) ) -1,2,3,6-tetrahydropyridine hydrochloride (240fflg, 1.1 mmol) and potassium carbonate (350 mg, 2.5 mmol) in anhydrous N, N-dimethylformamide (4 ml) at 60 ° C Stir for 3 hours Was. Ethyl acetate is added to the reaction mixture, which is washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.The substance obtained is separated and purified by silica gel column chromatography. As a result, 27 Omg (0.60 recommended ol, yield 60%) of the above-mentioned target compound was obtained.

Ή-thigh (CDCL) δ 1.06-1.19 (1H, m), 1.23-1.53 (4H, m), 1.71-2.00 (3H, m), 2.07-2.20 (2H, m), 2.30-2.42 (2H, m ), 2.46-2.53 (2H, m), 2.59-2.67 (2H, m), 2.71-2.81 (2H, m), 3.04-3.11 (2H, m), 5.96 (1H, brs), 6.62 (1H , d, J = 8.0Hz), 6.95 one 7.00 (2H, m), 7.15 (1H, d), 7.25 - 7. 34 (3H, m); layer _{_{38.97 (C 26 H 2 0C1F)}} ; Masusu Bae spectrum EI m / z 438: 44 0 (Intensity ratio = 3: 1) (M) ⁺

The obtained free compound was dissolved in methanol, hydrochloric acid was added dropwise, and the solvent was distilled off under reduced pressure to obtain a hydrochloride.

MW 475.44 (C ₂₆ H2 ₉ N ₂ OCLF); mass spectrum TSP m / z 439,441 (M-C1) + Example 3: 2a- (4- (4- (4- (4-methylphenyl) -1) -1,2 , 3,6-tetrahydropyridine-tolyl) butyl) -6-chloro-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one

4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride was replaced with 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride Others were synthesized in the same manner as in Example 2 (yield 64%).

Ή-NMR (CDCL) δ 1.06-1.18 (1H, m), 1.30-1.53 (4H, m), 1.71-2.00 (3H, m), 2.08-2.20 (2H, m), 2.30-2.42 (2H, m ), 2.47-2.53 (2H, m), 2.59-2.66 (2H, m), 2.73-2.85 (2H, m), 3.04-3.11 (2H, m), 6.02 (1H, brs), 6.62 (1H , D, J = 8.0Hz), 7.15 (1H, d), 7.26 (1H, br s), 7.26-7.28 (4H, m); MW 455.43

; Mass spectrum EI m / z

454, 456, 458 (M) ⁺

_{_{MW 491.89 (C 26 H 2 0C1}} 3); mass spectrum TSP m / z 455, 457, 459 (M-C1) + Example 4: 2a- (4- (4- ( 4- bromophenyl) _-1, _ 2, _ 3, _ 6-tetrahydropyridine- Tril) butyl) -6-chloro-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) on

(1) 4- (4-Promophenyl) -4-piperidinol (2.0 g, 7.8 mmol) was dissolved in trifluoroacetic acid (20 ml) and heated under reflux for 17.5 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in chloroform, and washed with 1N aqueous sodium hydroxide solution and saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.8 g of 4- (4-bromophenyl) -1,2,3,6-tetrahydropyridine (7.6 described, yield 97%).

Ή-NM (CDC1 δ 2.42 (2H, br s), 3.10 (2H, t, J = 5.8Hz), 3.50-3.54 (2H, m), 6.13 (1H, br s), 7.25 (2H, d, J = 8.8Hz), 7.44 (2H, m); MW 238.13 (CnHnNBr); Mass spectrum EI m / z 237: 239 (Intensity ratio = 1: 1) (Μ) ^÷

(2) Instead of 4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride, 4- (4-bromophenyl) -1,2,3 obtained in (1) Synthesized in the same manner as in Example 2 except that 6-tetrahydropyridine was used (yield 70%).

'H-NMR (CDCL) δ 1.06-1.18 (1H, m), 1.29-1.64 (4H, m), 1.72-1.99 (3H ₃ m), 2.08-2.20 (2H, m), 2.30-2.40 (2H, m), 2.46-2.52 (2H, m), 2.60-2.66 (2H, m), 2.71-2.82 (2H, m), 3.04-3.10 (2H, m), 6.03 (1H, brs), 6.62 (1H , d, J = 8.3Hz), 7.15 (1H, d), 7.22 - 7.26 (3H, m) 7.42 (2 H, d, J = 8.5Hz); MW 499.88 (C 26 H 2 OBrCl); Masusu Bae vector EI m / z 49 8, 500, 502 (M) ⁺

The obtained prepolymer was dissolved in methanol and hydrochloric acid was added dropwise, and then the solvent was distilled off under reduced pressure to obtain a hydrochloride.

MW 536.34 (C _{2 S} H ₂₃ N _z OBrCl ₂ ); mass spectrum TSP m / z 499, 501, 503 (MC ιγ

Example 5: 2a- (4- (4-phenyl-1,2,3,6-tetrahydropyridine-; 1-yl) butyl) -6-chloro-2a, 3,4,5-tetrahydroben [Cd] Indole-2 (1H) on

Same as Example 2 except that 4- (phenyl) -1,2,3,6-tetrahydropyridine hydrochloride was used instead of 4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride It was synthesized by the same method (yield 64%).

_{Ή-NMR (CDC1 3) δ} 1.06 - 1.19 (1H, m), 1.30 - 1.41 (2H, m), 1.41 - 1.55 (2H, m), 1.72 - 2.00 (3H, in), 2.09 - 2.20 (H, m), 2.32-2.43 (2H, m), 2.51-2.59 (2H, m), 2.61-2,69 (2H, m), 2.72-2.82 (2H, m), 3.06-3.15 (2H, m ), 6.03 (1H, brs), 6.63 (1H, d, J = 8.0Hz), 7.14-7.41 (7H ₅ m); MW 420.98 (C2M2OCI); mass spectrum FAB m / z 421: 423 (strength ratio) : 3

: 1) (M + n

_{_{MW 457.45 (C2 6 H 3 oN20CL}} ); mass spectrum TSP m / z 421: 423 (intensity ratio: 3: 1) (M- C1) +

Example 6: 2a- (4-bromobutyl) -6,8-dichloro-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one

2a- (4-bromobutyl) -2a, prepared according to Example 1 of WO 98/00400

3,4,5-Tetrahydrobenz [cd] indole-2 (1H) one (3.1 g, lOmmol) was dissolved in methylene chloride (30 ml), sulfuryl chloride (3 ml) was added, and the mixture was stirred at room temperature for 2.5 hours. . Water was added to the reaction solution, and the reaction product was extracted with a port form. The organic layer is washed with saturated saline, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure.The substance obtained is separated and purified by silica gel column chromatography to obtain the target compound 3. ol, yield 99%).醒 -wake (CDCls) δ 1.22 ― 1.40 (2Η, m), 1.41-1.55 (1H, m), 1.68-2.00 (5H, m) ₅ 2.05-2.19 (2H, m), 2.66-2.81 (2H, m ), 3.33 (2H, t, J = 6.8Hz),

7.19 (1H, s), 7.44 (1H 5 br s); MW 377.11 (CuHuNOBrCL); Masusu Bae transfected Le EI m / z 375, 377, 379, 381 (Μ) ÷

Example 7: 2a- (4- (4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridin-1-yl) butyl) -6,8-dichloro-2a, 3, 4, 5-tetrahydrobenz [cd] indole-2 (1H) on

2a- (4-Promobutyl) -6-chloro-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one in place of 2a- (4-bromobutyl) -6,8 Dichloro-2a, 3, 4, It was synthesized in the same manner as in Example 2 except that 5-tetrahydrobenz [cd] indole-2 (1H) one was used (yield: 58%).

Ή-NMR (CDCL) δ 1.10-1.21 (1H, m), 1.29-1.61 (4H, m), 1.71-2.00 (3H, m), 2.08-2.18 (2H, m), 2.32-2.43 (2H, m ), 2.47-2.54 (2H, m), 2.60-2.69 (2H, m), 2.70-2.78 (2H, ι) ₃ 3.06-3.12 (2H, m), 5.97 (1H, brs), 6.99 (2H , t, J = 8.8Hz), 7.18 (1H, s), 7.26 - 7.34 (3H, m); MW473.4 2 (C 26 HnN 2 OFCl 2); mass spectrum EI m / z 472: 474: 476

(Intensity ratio: 9: 6: 1) (M) ⁺

_{_{MW 509.88 (C 26 H 28 N}} 2 OFCl 3); mass spectrum TSP m / z 473: 475: 477 ( intensity index ratio: 9: 6: 1) ( M ~ C1) +

Example 8: 2a- (4- (4-phenyl-1,2,3,6-tetrahydropyridine-; 1-yl) butyl) -6,8-dichloro-2a, 3,4,5-tetrahydro Penz [cd] Indole -2 (1H) on

2a- (4-Promobutyl) -6-chloro-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one in place of 2a- (4-promobutyl) -6,8 Replace dichloro-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one with 4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride Synthesized in the same manner as in Example 2 except that phenyl-1,2,3,6-tetrahydropyridine hydrochloride was used (yield 7750).

Ή-NMR (CDCL) δ 1.08-1.21 (1H, m), 1.29-1.64 (4H, m), 1.72-2.00 (3H, m), 2.08-2.20 (2H, m), 2.32-2.45 (2H, m ), 2.52-2.60 (2H, m), 2.62-2.80 (4H, m), 3.08-3.14 (2H, m), 6.03 (1H, brs), 7.19-7.38 (7H, m); MW 455.43 _{_{_{(C 26 ¾ 8 N 2 OCL}}} ); mass spectrum EI m / z 454: 456: 458

(Intensity ratio: 9: 6: 1) (M) +

The obtained monolith was dissolved in methanol, hydrochloric acid was added dropwise, and the solvent was distilled off under reduced pressure to obtain a hydrochloride.

_{_{MW 491.89 (C IM 2 OC1 3}} ); Masusu Bae spectrum TSP m / z 455: 457: 459 ( intensity Degree ratio: 9: 6: 1) (M-C1) ⁺

Example 9: 2a- (4-bromobutyl) -6-fluoro-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one and 2a- (4-bromobutyl) -6,8 -Difluoro-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one

2a- (4-bromobutyl) -2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one (3.1 g) prepared according to Example 1 of WO 98/4000 , LOmmol), and 1-fluoro-2,6-dichloropyridinium tetrafluoroborate (7.6 g, 30 mol) were dissolved in chloroform (60 ml), and the mixture was heated under reflux for 14 hours. The reaction mixture was added to chloroform, washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.The resulting substance was separated and purified by silica gel column chromatography. 530 mg (1.7 mmol, 17% yield) of 2a- (4-bromobutyl) -6-fluoro-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one, 2a- ( 770 mg (2.2 mol, yield 2) of 4-bromobutyl) -6,8-difluoro-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one was obtained.

2a- (4-Promobutyl) -6-fluoro mouth-2a, 3,4,5-tetrahydrobenz "cdl indole-2 (1H) one

_{Ή-NMR (CDC1 3) ό} · 1.18 - 1.52 (3Η, m), 1.70 - 1.96 (5H 5 m), 2.06 - 2.18

(2H, m), 2.64-2.75 (1H, m), 2.77-2.88 (1H, m), 3.32 (2H, t, J = 6.8Hz), 6.61-6.71 (1H, m), 6.80-6.88 (1H MW 326.21 (CuHnNOBrF); Mass spectrum EI m / z 325: 327 (Intensity ratio: 1: 1) (M) +

2a- (4-Bumobutyl) -6,8-difluoro-2a, 3,4,5-tetrahydrobenz "cd" Indole-2 (1H) one

Ή-NMR (CDCL) δ 1.17-1.53 (3Η, m), 1.70-1.96 (5H, m), 2.02-2.18 (2H ₅ m), 2.59-2.69 (1H, m), 2.76-2.86 (1H, m ), 3.33 (2H, t, J = 6.8Hz), 6.71 (1H, t, J = 10.0Hz), 7.46 (1H, br s); MW 344.20 (C "HuN0BrF 2); Ma Susupe spectrum EI m / z 343: 345 (Intensity ratio: 1: 1) (M) ⁺

Example 10 0: 2a- (4- (4-phenyl-1,2,3,6-tetrahydropyridine-tolyl) butyl) -6-fluoro mouth-2a, 3,4,5-tetrahydrobenz [ cd] Indole-2 (1H) _ ON 2a- (4-bromobutyl)-6-chloro- 2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) Instead of 2a- (4-bromobutyl) -6-fluoro- 2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one is replaced by 4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride Synthesized in the same manner as in Example 2 except that phenyl-1,2,3,6-tetrahydropyridine hydrochloride was used (yield: 60%).

Ή-NMR (CDCL) δ 1.06-1.18 (1H, m) ₅ 1.28-1.55 (4H, m), 1.73-1.95 (3H, in), 2.07-2.17 (2H, m), 2.31-2.42 (2H, m ), 2.50-2.58 (2H, m), 2.60-2.74 (3H ₅ m), 2.77-2.87 (1H, m), 3.06-3.13 (2H, m), 6.03 (1H, brs), 6.60 (1H , dd, J = 3.4Hz, 8.3Hz ), 6.82 (1H, dd, J = 10.0Hz), 7.20 - 7.3 8 (6H, m); MW 404.53 (C 26 9 N 2 OF); mass spectrum EI m / z

404 (M) ⁺

MW 440.99 (CHHSONZOCIF); Mass spectrum TSP m / z 405 (M-C1) ⁺

Example 11 1: 2a- (4- (4-phenyl-1,2,3,6-tetrahydropyridine-; [-yl) butyl) -6,8-difluoro mouth-2a, 3,4,5- Tetrahydrobenz [cd] indonyl -2 (1H) on

2a- (4-Bromobutyl) -6-chloro-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one in place of 2a- (4-bromobutyl) -6,8 Difluoro mouth-2a, 3,4,5-tetrahydrobenz [cd] Indole-2 (1H) one replaced with 4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride The compound was synthesized in the same manner as in Example 2 except that 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride was used (yield: 58%).

_{Ή-NMR (CDC1 3) δ} 1.05 - 1.19 (1H, m), 1.28 - 1.40 (2H, m), 1.43 - 1.56 (2H, m), 1.74 - 1.94 (3H, m), 2.07 - 2.17 (2H, m), 2.32-2.43 (2H, m), 2.51-2.58 (2H, in), 2.58-2.69 (3H,), 2.74-2.84 (1H, m), 3.07-3.13 (2H, m), 6.03 (1H, br s), 6.69 (1H, t, J = 9.9Hz), 7.20 - 7.40 (6H, m); MW 422.52 (C 26 ¾ 0F 2); mass spectrum EI m / z 422 (M) + The obtained monolith was dissolved in methanol, hydrochloric acid was added dropwise, and the solvent was distilled off under reduced pressure to obtain a hydrochloride.

_{_{MW 458.98 (C 26 IM 2 0C1F}} ; mass spectrum TSP m / z 423 (M- C1) +

Example 12: 2a- (4-bromobutyl) -6-hydroxy-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one

6-acetoxy-2a- (4-bromooptyl) -2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one (160 mg, 0.44 w / w) prepared according to Example 70 of WO 98/00400 ol) was dissolved in methanol (5 ml), sodium methoxide (270 ml, 13 ol) was added, and the mixture was stirred at 0 ° C for 0.5 hour. 5N Hydrochloric acid (0.25 ml) was added to the reaction mixture, and the solvent was distilled off under reduced pressure.The residue was dissolved in chloroform and washed with 0.1N hydrochloric acid and brine, and the solvent was distilled off under reduced pressure. The substance thus obtained was separated and purified by silica gel column chromatography to obtain 90 mg (0.28 mol, yield: 635) of the target compound.

Ή-NMR (CDC) δ 1.30-1.52 (3H, m), 1.70-1.98 (5H, m), 2.07-2.19 (2H ₅ m), 2.60-2.80 (2H, m), 3.31 (2H, t, J = 6.8Hz), 4.66 (1H ₃ s), 6.52- 6.62 (2H, m), 7.23 (1H, br s); MW 324.22 (CuH ₁₈ N0 ₂ Br); Mass spectrum

FAB m / z 324: 326 (Intensity ratio 1: 1) (M + H) ⁺

Example 13 3: 2a- (4- (4- (4-fluorophenyl-1,2,3,6-tetrahydropyridin-1-yl) butyl) -6-hydroxy-2a, 3,4, 5-tetrahydrobenz [cd, indole-2 (1H) on

2a- (4-Promobutyl) -6-chloro-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one in place of 2a- (4-bromobutyl) -6-hydroxy- It was synthesized in the same manner as in Example 2 except that 2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one was used (yield 71%).

Ή-((CDC1 ₃ ) δ 1.06-1.19 (1H,), 1.28-1.54 (4H, m), 1.70-1.96 (3H, m), 2.05-2.18 (2H, m), 2.30-2.41 (2H, m ), 2.46-2.54 (2H, m), 2.57-2.78 (4H, m), 3.05-3.12 (2H, m), 5.96 (1H, br s), 6.52 (1H ₃ t, J = 8.3 Hz ), 6.57 (1H, d) 6.98 (2H, t, J = 8.8Hz), 7.21-7.33 (3H, m); MW420.53

_{_{_{(C 26 H Z9 N 2 0}}} 2 F); mass spectrum EI m / z 420 (M) + The obtained monolith was dissolved in methanol, hydrochloric acid was added dropwise, and the solvent was distilled off under reduced pressure to obtain a hydrochloride.

_{_{MW 456.99 (C 26 H 3 .N}} 2 0 2 C1F); Masusu Bae spectrum TSP m / z 421 (M- C1) ÷

Test results showing the usefulness of typical examples of the compounds of the present invention are shown below. Test Example 1: Binding affinity tests with 5-HT ₇ receptor

Cultured cells expressing human seotonin 5-HT, receptor subtype are harvested in Atsushi buffer (50 mM Tris-HCl pH7.4 containing lOmM MgCL, and 0.5 mM EDTA), and homogenized with a Pouniyu type homogenizer. After homogenization, the membrane fraction was centrifuged at 39,000 g for 20 minutes at 4 ° C. The obtained pellet was resuspended by adding 1 ml of Atsushi buffer per cell for one culture dish having a diameter of 10 cm and re-homogenized.

The binding experiments were performed with a final concentration of 1 ηΜ [Ή] -5CT (carboxamide tryptamine) and a test substance of 1 to: ΙΟΟΟηΜ (in the examples, compounds represented by the general formula (I) of the present invention). A final suspension volume of 300/1 was added by adding 100〃1 of the fraction suspension, and the mixture was incubated at 37 ° C for 30 minutes. The incubation was stopped by rapid filtration over a GF / B filter and washed with 6 ml of cold 50 iM Tris-HCl (pH 7.4). Radioactivity was measured in the liquid scintillation count. Non-specific binding was determined with 10 zM metergoline, and specific binding was calculated from the difference. _ICse was determined from the inhibition curve of each compound, and the binding inhibition constant Ki was calculated from this.

Test Example 2: 5-affinity binding affinity test

The rat cerebral cortex was homogenized in 10 volumes of 0.32M sucrose solution, and the supernatant obtained by centrifugation at 900 × g for 10 minutes was further centrifuged at 500 × g for 20 minutes. The obtained precipitate was resuspended in 50 mM Tris-HCl (pH 7.4) buffer and centrifuged at 39,900 xg for 20 minutes, and the obtained precipitate was used as a P2 fraction.

The P2 fraction was incubated for 15 minutes at 37 ° C. in 50 mM Tris-HCl (pH 7.4) buffer containing InM [Ή] keinserin and a compound according to the present invention. After the reaction, the Whatman GF / B Glass Fill Filtered in the evening. The radioactivity of the fill was measured at the liquid scintillation county. Non-specific binding was determined using 10 zM kerosene, and specific binding was calculated from the difference. IC ₅ »was determined from the inhibition curve of each compound, and the binding inhibition constant Ki was calculated from this. And Ki for 5-HT _2, the Ki and the ratio of 5-HT ₇ obtained from Test Example 1 are shown in Table 1. As can be seen from Table 1, the compound of the present invention was found to bind strongly and selectively to the 5-11 receptor.

table 1

Test compound

(n M)

Example 2 2 1 6 9 8 4.5

Example 3 7> 1 0 0 0> 1 4 2

Example 4 1 1.6> 1 0 0 0> 8 6

Compound A 9.00 9 2 1 0

Compound B 3.7 6 4 17.3

Compound C 9.05 56.1

Compound A, Compound B and Compound C in the table are the following compounds described in WO 98/400, EP 979 280 490, and Compound A is a tetrahydropenzindole derivative. A compound in which a substituent is not introduced into the aromatic ring portion. Compound A: 2a- (4- (4-phenyl-1,2,3,6-tetrahydropyridine-1-yl) butyl) -2a, 3,4,5-tetrahydrobenz [cd] indole-2 ( 1H)-ON

Compound: B: 2a- (4- (4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridin-1-yl) butyl) -2a, 3,4,5-tetrahydrobenz [cd ] India 1-2 (1H)-ON

Compound C: 6-Hydroxy-2a- (4- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) butyl) -2a, 3,4,5-tetrahydrobenz [cd] India Il-2 (1H) -on Test Example 3 Metabolic rate test

For the human liver 9,000 × g supernatant (S9) fraction, Pooled HepatoSNine ^1M (Pooled human liver S9 fraction; HBI ver. 1.0) purchased from Human Biologies International [HBI] (AZ, USA) was used. Nicotinamide adenine dinucleotide reduced form generation system (lOmM glucose 6-phosphate (G-6-P), lm-nicotinamide adenine dinucleotide oxidized form (? -NADP +), incubated at 37 ° C for 5 minutes, 0.7U / Reaction solution containing 100 mM G-6-P dehydrogenase 6 mM magnesium chloride hexahydrate, 6 mM magnesium chloride hexahydrate (lOOniM phosphate buffer solution (pH 7.4), Im ethylene diamine tetraacetic acid (EDTA) The test substance was added to a final concentration of 25 mM to 2 sodium, 4 mg / mL liver S9 fraction) to initiate the reaction. After the reaction at 37 ° C for a predetermined time (0, 10, 30 or 60 minutes), Ν, Ν-dimethylformamide was added to stop the reaction. The reaction solution was subjected to centrifugation to perform protein reduction, and the amount of the test substance remaining in the obtained supernatant was measured by high performance liquid chromatography. In addition, under the above conditions, after adding Ν, Ν-dimethylformamide, the reaction solution to which the test substance was added was measured to obtain the initial amount of the test substance.

From these measurements, the initial rate (maximum rate) of the metabolic reaction was calculated as the metabolic rate.

Compound according to the present invention, compound Α: 2a- (4- (4-phenyl-1,2,3,6-tetrahydropyridine-1-yl) butyl) -2a, 3,4,5-tetrahydrobenz [cd Indole-2 (1H) -one and compound B: 2a- (4-. (4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridin-1-yl) butyl) -2a, The metabolic rates of 3,4,5-tetrahydrobenz [cd] indole-2 (1H) -one were as shown in Table 2. The compounds according to the present invention were found to have significantly higher metabolic stability than compounds A or B.

Two

Metabolic rate Metabolic rate ratio

/ Compound A

Test compound Z Compound B

(pmol / min / mg / protein) (%) Example 2 92.5 52.8 70.8 Example 3 51 29.1

Example 4 23.1 13.2

Example 13 80.6 61.7 Compound A 175.2 *

Compound B 130.6

(*: Measured 5 times and the average is shown)

Claims

The scope of the claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof.

(In the above formula,

R ¹ represents a hydrogen atom or a Hagengen atom,

R ² represents a hydroxyl group or a halogen atom,

R ³ represents a hydrogen atom or a halogen atom,

However, this does not apply when both R ¹ and R ³ are hydrogen atoms. )

2. The compound or a salt thereof according to claim 1, wherein R ¹ and: R ^{2, which} may be the same or different, are a fluorine atom, a chlorine atom, or a bromine atom.

3. The compound according to claim 1, wherein R ¹ is a fluorine atom, a chlorine atom, or a bromine atom, and R ² is a hydroxyl group, or a salt thereof.

4. The compound or a salt thereof according to claim 1, wherein R ¹ is a fluorine atom, a chlorine atom, or a bromine atom, and R ² is a chlorine atom.

5. The compound or a salt thereof according to claim 1, wherein R ¹ is a fluorine atom, a chlorine atom, or a bromine atom, R ² is a chlorine atom, and R ³ is a hydrogen atom.

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6, further comprising a pharmaceutical additive.

8. The pharmaceutical composition according to claim 5, which is used for prevention or treatment of a mental illness.

9. The pharmaceutical composition according to claim 8, wherein the psychiatric disorder is selected from the group consisting of manic depression, anxiety, schizophrenia, epilepsy, sleep disorders, biological rhythm disorders, and migraine.

10. Use of a compound according to any one of claims to! 5 or a pharmacologically acceptable salt thereof for the manufacture of a medicament for use in the prevention or treatment of mental illness c.

11. The use according to claim 10, wherein the mental illness is selected from the group consisting of manic depression, anxiety, schizophrenia, epilepsy, sleep disorders, biorhythm disorders, and migraine.

12. A method comprising administering to a mammal, including a human, a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof. How to prevent or treat the disease.

13. The method of claim 12, wherein the mental illness is selected from the group consisting of manic depression, anxiety, schizophrenia, epilepsy, sleep disorders, biorhythm disorders, and migraine.