JPH0840999A - Fluoroindane derivative - Google Patents

Abstract

PURPOSE:To provide a new compound having selective 5-HT reincorporation inhibitory effect, 5-HT2 receptor antagonistic effect and antidepressant and antianxiety activity, useful for therapy of depression, etc., and reduced in side effects. CONSTITUTION:This new compound is expressed by formula I (R<1> is, e.g. a piperidinyl which may be substituted at 1 position, pyrrolidinyl or a lower alkyl substituted with amino, diethylamino, etc., at omega position) or its salt, e.g. 1-ethoxycarbonyl-4-[(7-fluoro-4-indanyl)oxylpiperidine. This compound of formula I can be synthesized by reacting a compound of the formula, XR<1a> (R<1a> is an amino-protecting group; X is a halogen, mesyloxy, etc.) with an indanol compound of formula II and subsequently removing the protecting group. It is useful as a therapeutic agent effective for depression, depression symptoms, anxiety neurosis, psychosomatic disease, autonomic ataxia, anorexia or anxiety complaint and reduced in side effect. It is also useful as a therapeutic agent for reduction of spontaneity, atrabiliary mood, anxiety, impatience, hallucination, delusion, hypochondria, sleep disorder, etc., which are respectively symptoms related to cerebrovascular disease or Alzheimer's disease.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a fluoroindane derivative or a salt thereof having antidepressant activity and anxiolytic activity.

[0002]

2. Description of the Related Art At present, serotonin (5-H
T) has been reported to be involved [Shinbrain receptor, edited by Norio Ogawa, World Health News Agency (1991)],
Studies have been conducted on 5-HT reuptake inhibition or action with 5-HT receptors. Tricyclic compounds such as amitriptyline are widely used clinically as antidepressants. However, although amitriptyline also has 5-HT reuptake inhibition or 5-HT ₂ receptor antagonism, 5
-It has noradrenergic reuptake inhibitory action and anticholinergic action in addition to HT ₂ receptor antagonistic action, and also shows non-selective action, which is considered to cause side effects such as dry mouth and urinary retention. .

Therefore, those which selectively inhibit 5-HT reuptake or selectively act on 5-HT ₂ receptors are
It is suggested that the drug has few side effects. For example, fluoxetine has been clinically used as a drug that selectively inhibits 5-HT reuptake, and it has been reported to have effects such as anxiety induction and insomnia in the treatment process (Physician's Desk Reference, Medical Economic
S Company, Oradell, NJ (1990)]. Also, as a drug having a selective 5-HT ₂ receptor antagonistic action, for example, mianserin is known as an antidepressant drug. On the other hand, as a result of various studies, compounds that selectively combine 5-HT reuptake inhibitory action and 5-HT ₂ receptor antagonistic action are expected to be desirable as antidepressants [Cell, Biology to Pharmacology and Therapeu
tics., 488-504 (1990), Psychopathology, 22 [suppl 1] 2
2-36 (1989), J. Clin. Psychiatry, 52 , 34-38 (1991), P
sychopharmacol. Bull., 26 , 168-171 (1990), Br. J. P
harmacol., 100 , 793-799 (1990)]. This selective 5-HT reuptake inhibitory action and 5-HT ₂
Little drug is known to have both receptor antagonism, and trazodone is said to have both. However, its 5-HT reuptake inhibitory action is very weak, and it cannot be said that it is a drug having both actions, and it is reported that its antidepressant action and anxiolytic action are based on 5-HT ₂ receptor antagonistic action. Yes [Marek GJ et al., P
sychopharmacology, 109 , 2-11 (1992)]. In addition to the above-mentioned effects, trazodone has an α ₁ -receptor affinity, and side effects based on this have been reported.

[0004]

SUMMARY OF THE INVENTION The present invention is a selective 5-
It is an object of the present invention to provide a drug having an HT reuptake inhibitory action and a 5-HT ₂ receptor antagonistic action, which is useful for a medicine, particularly an antidepressant and anxiolytic action, and has few side effects.

[0005]

That is, the present invention provides a compound represented by the general formula (I)

[0006]

Embedded image (The symbols in the formula are as follows. R ¹ is a group represented by the following formula (II).

[0007]

[Chemical 6] A: a lower alkylene group which may be substituted with a hydroxy group R ² , R ³ : hydrogen atoms or lower alkyl groups which are the same or different and are dotted: R ² and R ³ are integrated with an adjacent nitrogen atom to form a ring atom 4 to Eight nitrogen-containing saturated heterocycles can be formed. Group represented by the following formula (III)

[0008]

[Chemical 7] Ring B: (i) a nitrogen-containing saturated hetero ring having 4 to 8 ring atoms or a bicyclic nitrogen-containing saturated bridge having 6 to 12 ring atoms, which contains 1 to 2 unsubstituted or substituted nitrogen atoms Telocycle (ii) A fluoroindane derivative represented by a cycloalkyl group having 4 to 8 ring atoms substituted with an amino group or a substituted amino group, m: 0 or 1, and the like below) or a salt thereof. Preferably, the ring B is

[0009]

Embedded image (The symbols in the formulas have the following meanings: X: a group represented by the formula —CH ₂ — or a group represented by the formula —NR ⁴ — Y: a group represented by the formula —NR ⁵ — or a formula —CHR ⁶ — R ⁴ and R ^{5 are the} same or different and each is a hydrogen atom, a lower alkyl group, an aralkyl group, an acyl group or a lower alkoxycarbonyl group R ⁶ : An amino group, a mono- or di-lower alkylamino group or a lower alkoxycarbonylamino group p: 0 or 1 q: an integer of 1 to 3).

The compound (I) of the present invention will be described in detail below. Unless otherwise specified in the definition of general formulas herein, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms. Specific examples of the "lower alkyl group" include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec.
-Butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1
-Methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1 , 2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1 , 1,2-trimethylpropyl group, 1,2,2
-Trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like. Preferably, it is a lower alkyl group having 1 to 3 carbon atoms, such as a methyl group, an ethyl group, a propyl group or an isopropyl group. Among the "lower alkylene groups which may be substituted with a hydroxy group" in A, "lower alkylene groups" include methylene group, ethylene group, methylmethylene group, trimethylene group, dimethylmethylene group, tetramethylene group, 1-methyl group. Trimethylene group, 2-methyltrimethylene group, pentamethylene group, 1-methyltetramethylene group, 2-methyltetramethylene group, 3-methyltetramethylene group, 4-methyltetramethylene group, 1,1-
Dimethyltrimethylene group, 2,2-dimethyltrimethylene group, 3,3-dimethyltrimethylene group, 1,3-dimethyltrimethylene group, 2,3-dimethyltrimethylene group, 1,2-dimethyltrimethylene group, 1,1,2-trimethylethylene group, hexamethylene group, 1,1-dimethyltetramethylene group, 2,2-dimethyltetramethylene group, preferably methylene group, ethylene group, trimethylene group, tetramethylene group is there.

The "hydroxy group-substituted lower alkylene group" is a group in which one hydroxy group is substituted at any position of the above lower alkylene group, and is hydroxymethylene group, hydroxyethylene group, 1-hydroxytrimethylene group. , 2-hydroxytrimethylene group, 1-hydroxytetramethylene group, 2-hydroxytetramethylene group,
3-hydroxytetramethylene group, 4-hydroxytetramethylene group, 1-hydroxypentamethylene group, 2-
Examples thereof include a hydroxypentimethylene group. "R ²
Examples of the “nitrogen-containing saturated heterocycle having 4 to 8 ring atoms formed by R ³ and R ³ integrally with the adjacent nitrogen atom” include groups represented by the following formulas.

[0012]

[Chemical 9] In ring B, "unsubstituted or substituted nitrogen atom 1 to 2
Examples of the "nitrogen-containing saturated hetero ring having 4 to 8 ring atoms" include the groups represented by the following formulas in addition to the nitrogen-containing saturated hetero ring having 4 to 8 ring atoms. Although the bond of the heterocycle shown in the following formulas 10 and 11 is represented by a carbon atom, it may be a bond from a nitrogen atom.

[0013]

[Chemical 10] As the substituent, any of the substituents does not impair the antidepressant activity and anxiolytic activity of the present invention, but preferably the lower alkyl group, aralkyl group (benzyl group, phenethyl group, etc.), acyl group (formyl group). Group, acetyl group, propionyl group, valeryl group, benzoyl group, etc.) and lower alkoxycarbonyl group (methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, tert-butoxycarbonyl group, etc.). One or two of these substituents can be substituted at any position on the ring. The "unsubstituted or substituted bicyclic nitrogen-containing saturated bridged heterocyclic ring having 6 to 12 ring atoms containing 1 to 2 nitrogen atoms" means ring atoms 6 to 12
And preferably 7 to 9 and specifically include those represented by the following formula.

[0014]

[Chemical 11] 1 to 3 of the above substituents can be substituted at any position. The “cycloalkyl group having 4 to 8 ring atoms substituted with an amino group or a substituted amino group” means a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, an amino group at an arbitrary position or It means a group substituted with a substituted amino group. As the substituent of the substituted amino group, any of the substituents does not impair the antidepressant activity and antianxiety activity of the present invention, but preferably, a lower alkyl group, an aralkyl group, which is a substituent on the B ring, Examples thereof include an acyl group and a lower alkoxycarbonyl group. Preferably, a lower alkyl group and a lower alkoquincarbonyl group are mentioned. These substituents can be substituted with 1 to 2 amino groups.

The compound (I) of the present invention can form a salt with an acid. Acids include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, propionic acid acetate, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid malic acid. , Citric acid, tartaric acid,
Examples thereof include acid addition salts with organic acids such as D-dibenzoyltartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid, and hydrochloride and fumaric acid salts are particularly preferable. Further, the compound of the present invention has an optical isomer depending on the kind of the group R ¹ and therefore has optical isomers, but the present invention includes all of these mixtures and isolated ones. Furthermore, the compounds of the present invention can form hydrates and solvates and polymorphs. (Production Method) The compound of the present invention can be produced by the method represented by the following reaction formula. First manufacturing method

[0016]

[Chemical 12]

(In the formula, R ^1a is a group in which the amino group in R ¹ is protected by a protecting group, and X represents a halogen atom, a mesyloxy group or a tosyloxy group. The same applies hereinafter) As a protecting group for an amino group, Is a commonly used protecting group, for example, trityl group, benzhydryl group, benzyl group, p-methoxybenzyl group, phthaloyl group, tert.
-Butyl group, ethoxycarbonyl group, benzyloxycarbonyl group, benzyloxycarbonyl group, tert-
Butylcarbonyl group and the like can be mentioned, with preference given to phthaloyl group, ethoxycarbonyl group and benzyl group. The above reaction may be carried out at room temperature or under heating with stirring the compound (IV) and the indanol compound (V) in the presence of a base in an inert solvent with stirring, or by reacting the indanol compound (V) in advance. After forming the sodium salt or potassium salt, the compound (IV) and an inert solvent are used as described above (step 1), and a conventional deprotection reaction, for example, a reduction reaction such as catalytic reduction or treatment with an acid or a base is performed. (Acid treatment method or base treatment method)
Can be obtained (second step). As the inert solvent in the first step, benzene, chloroform, DMF, DM
SO, ether, water, methanol, ethanol, etc. are mentioned. Examples of the base include sodium hydroxide, potassium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, butyllithium, potassium tert-butoxide and the like. As the base used in the base treatment method in the second step, sodium hydroxide, potassium hydroxide hydrazinemethylamine, etc. are used. Examples of the acid used in the acid treatment method include acetic acid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, sulfuric acid, hydrobromic acid-acetic acid and the like. This dearalkyl reaction is usually carried out in an organic solvent such as methanol, ethanol, acetone or the like or in water at room temperature or under heating (under reflux). Second manufacturing method

[0018]

[Chemical 13] (In the formula, A, X, R ² or R ³ are as described above.) In the above reaction, the di-substituted lower alkane (VII) and an amount of the indanol compound (V) corresponding to the reaction are used in the first production method. One step is performed in the same manner, and the lower alkyl-substituted indanol (VI
I) is obtained (first step), and the N-alkylation reaction (second step) is carried out using this compound (VII) with an amount of the substituted amine (VIII) corresponding to the reaction. The N-alkylation reaction may be carried out according to a conventional method. For example, the compound (V) may be potassium hydride, sodium hydride, potassium carbonate in an inert solvent such as benzene, chloroform, DMF, DMSO, ether, methanol or ethanol. , The compound (VII) in the presence of a base such as sodium hydroxide or potassium hydroxide is reacted at room temperature or with heating.

Third Production Method (N-Alkylation Reaction) In this production method, a compound having a primary amino group or a secondary amino group in the compound of the present invention is treated with a secondary amino group by a conventional N-alkylation reaction, A compound having a tertiary amino group is obtained. A compound having a primary amino group or a secondary amino group and an amount of an alkylating agent corresponding to the reaction thereof in an inert solvent (acetone, acetonitrile, tetrahydrophthene (TH
F), ether, DMF, etc.) in the presence of a base (potassium carbonate, sodium hydride, potassium hydride, etc.) at room temperature or under heating (or heating under reflux) with stirring. Examples of the alkylating agent include arylsulfonyloxy lower alkane, lower alkylsulfonyl oxine lower alkane, lower alkyl halide and the like. Preferred are lower alkyl halides such as methyl iodide, ethyl iodide, propyl iodide and isopropyl iodide.

(Alternative Method) (1) As an alternative method of the present N-alkylation reaction, the following method can be mentioned. This reaction is carried out in the presence of compound (V), a lower alkyl aldehyde corresponding to the reaction and sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride, and an inert solvent such as methanol, ethanol, THF or dioxane. It is carried out at room temperature to under stirring with heating. When carrying out the above reaction, it is preferable to add hydrochloric acid, acetic acid, formic acid or the like and carry out under acidic conditions. (2) Alkylation by reduction reaction In this reaction, the compound (V) and a corresponding amount of an acid halide (eg, acetyl chloride, propionyl chloride) are reacted in an inert solvent by an ordinary method to give an amide compound, and then a metal The reduction reaction is performed in the presence of a hydride (such as lithium aluminum hydride). Fourth manufacturing method

[0021]

Embedded image (In the formula, S is an integer of 0 to 5. The same applies hereinafter.) In the above reaction, the epoxide compound (X) and the corresponding amount of the amine (VIII) are reacted with an inert solvent (for example, methanol,
Ethanol, chloroform, benzene, toluene, etc.) at room temperature or under heating with stirring.

The compound of the present invention is extremely selective for 5-H.
Since it inhibits T reuptake and selectively has an antagonistic effect on 5-HT ₂ receptors, depression, depression, anxiety, psychosomatic disorders, autonomic imbalance, anorexia nervosa, Or as a therapeutic agent with few side effects for indefinite complaints, and peripheral symptoms in cerebrovascular disorders and Alzheimer's disease, such as decreased spontaneousness, depressed mood, anxiety / frustration,
It is useful as a therapeutic agent for hallucinations / delusions, hypochondria, sleep disorders, etc. Further, the compound of the present invention has blood viscosity improving action, anti-hypoxia action and anti-oxidant action, and is useful as a cerebral circulation / metabolic improving drug and a brain function improving drug, and also as an analgesic. Further, the compound of the present invention can be used for improving dementia in cerebral dysfunction and Alzheimer's disease. Hereinafter, the 5-HT reuptake inhibition test and the 5-HT ₂ receptor antagonism test showing the effect of the compound of the present invention will be described in detail.

1) 5-HT reuptake inhibition test In vitro test The 5-HT reuptake inhibition activity was determined by the test compound being 5-HT.
It was tested how to suppress the binding of [ ³ H] -citalopram to the reuptake site. D'amato RJ et al. J. Pharm
The method described in acol. Exp. Ther., 242 , 364 (1987) was used. 0.5 ml of a buffer containing about 1.0 nM [ ³ H] -citalopram, a rat cerebral cortical membrane preparation (about 0.4 mg protein amount) and a test compound was reacted at 25 ° C. for 60 minutes. Then, the bound labeled ligand and the free labeled ligand were separated by suction filtration. The specific binding amount to the 5-HT reuptake site was a value obtained by subtracting the nonspecific binding amount obtained by adding an excess amount of unlabeled fluoxetine (10 μM) from the total binding. The test compounds were evaluated by the IC _{50 of} each compound (concentration that reduces the amount of specific binding by 50%).
Was calculated and converted into a dissociation constant (Ki value). In vivo test 5-HT precursor, l-5-Hydroxytryptophan, was used to test the action (Naunyn-Schmiede).
berg's Archives of Pharmacology, 311 : 185-192,198
0). Male ICR mice weighing 30-40 g were used. The test drug was intraperitoneally administered, and 30 minutes later, 90 mg / kg of 1-5-hydroxytryptophan was intravenously administered, and observation was performed for 5 minutes after 5 minutes. The observation items are tremor, swinging,
There were three items of hindlimb abduction. Evaluation of the test drug was performed using the ED ₅₀ value required for the expression of each behavior.

2) 5-HT reuptake inhibition selectivity test [ ³ H] -5-
It was tested how to suppress the uptake of HT, [ ³ H] -noradrenaline and [ ³ H] -dopamine. The method described by Harada and Maeno in Biochem. Pharmacol., 28 , 2645 (1979) was used. Decapitating male Wistar rats,
The cerebral cortex and striatum were removed, and the cerebral cortex was adjusted for 5-HT and noradrenaline uptake, and the striatal synaptosome fraction was adjusted for dopamine uptake. Incubate each synaptosome for 3 minutes at 37 ° C, then [ ³ H]
-5-HT, [ ³ H] -noradrenaline and [ ³ H]-
Dopamine (10 ⁻⁷ M) was added to each, and the mixture was further incubated for 2 minutes and then ice-cooled (0 ° C.) to stop the reaction. After that, filtration was performed using a Whatman CF / B glass filter, and the radioactivity remaining on the filter was measured using a liquid scintillation counter. Non-specific activity used the thing incubated at 0 degreeC without adding a test drug. Evaluation of each test compound was carried out by calculating IC ₅₀ (concentration that reduces the amount of each radioligand uptake by 50%).

3) 5-HT ₂ receptor antagonistic activity test (in vi
(tro test) It tested how the test compound suppressed the binding of [ ³ H] -ketanserin. Leysen JE et al. Mol. Pharmaco
The method described in L., 21 , 301 (1982) was used. About 1.0
A total of 0.5 ml of a buffer solution containing nM [ ³ H] -ketanserin, a rat cerebral cortical membrane preparation (about 0.2 mg protein amount) and a test compound was reacted at 25 ° C. for 30 minutes. Then, the bound labeled ligand was separated by suction filtration. The specific binding amount to the 5-HT ₂ receptor was a value obtained by subtracting the nonspecific binding obtained by adding an excess amount of unlabeled metergoline (10 μM) from the total binding amount. The test compounds were evaluated by the IC ₅₀ value of each compound (specific binding amount was 50%).
The concentration to be reduced) was calculated and converted into a dissociation constant (Ki value).

(Test Results) From the above test, the compound of the present invention has an inhibitory effect on 5-HT reuptake (in vitro and in vivo).
o) and 5-HT ₂ receptor antagonistic activity (in vitro), and both effects were excellent. It also showed selective 5HT-reuptake inhibitory activity.

[0026]

[Table 1] Therefore, it is expected that the compound of the present invention does not cause side effects on the cardiovascular system (for example, acceleration of palpitations) or side effects such as dry mouth or urinary retention that compounds having a nonselective uptake inhibitory action have. A preparation containing one or more kinds of the compound of the present invention or a salt thereof as an active ingredient is prepared by using a carrier, an excipient and other additives usually used for preparation.
The carrier or excipient for the preparation may be solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol, etc. Examples include regular ones. The administration may be in the form of tablets, pills, capsules, granules, powders, liquids or the like, or injections such as intravenous injection and intramuscular injection, suppositories, and percutaneous parenteral administration. Good. The dose varies depending on age, weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually 1 to 1 per adult per day
1 in the range of 1000 mg, preferably 10-300 mg
It is orally administered once to several times a day. Of course, as described above, the dose varies depending on various conditions, so a dose smaller than the above dose range may be sufficient.

[0027]

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

Example 1 456 mg of 7-fluoro-4-indanol (3.0 m
6 mol of anhydrous dimethylformamide (DMF)
And 216 mg of sodium hydrogen (3.6 mg) under ice cooling.
mmol) was added, and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. This is then followed by 4- (1-ethoxycarbonyl) piperidinyl-p-toluenesulfonate 1.96.
g (6.0 mmol) was added, and the mixture was heated with stirring at 100 ° C. for 5 hours. After cooling to room temperature, water was added, the mixture was extracted with ethyl acetate and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 4:
1) and 1-ethoxycarbonyl-4-[(7-
Fluoro-4-indanyl) oxy] piperidine 534
mg (58%) was obtained as a colorless oil. Mass spectrum (m / z): 307 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.27 (3H, t, 7.11 Hz), 1.52-
2.30 (6H, m), 2.75-3.08 (4H,
m), 3.25-3.89 (4H, m), 4.15 (2
H, q, 7.11 Hz), 4.28-4.54 (1H,
m), 6.61 (1H, dd, J = 8.19, 4.86)
Hz), 6.77 (1H, dd, J = 8.19, 8.1)
9Hz)

Example 2 (A) 1-Ethoxycarbonyl-4-[(7-fluoro-4-indanyl) oxy] piperidine 267 mg
(0.87 mmol) is dissolved in 25 ml of ethanol,
To this, 8 ml of 38% aqueous potassium hydroxide solution was added, and the mixture was heated under reflux for 7 hours. After adding water, the mixture was extracted with methylene chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, and 197 mg (96%) of the obtained oily substance was added to 5 ml of ethanol.
And fumaric acid 97 mg (0.84 mmol)
Was added and heated until there was no precipitate. This was cooled to room temperature with stirring, and the precipitate was collected by filtration to obtain 4
259 mg (84%) of-[(7-fluoro-4-indanyl) oxy] piperidine fumarate was obtained as colorless crystals. Melting point 172-173 ° C. Elemental analysis value (as C ₁₈ H ₂₂ NO ₅ F) C (%) H (%) N (%) F (%) Theoretical value 61.53 6.31 3.99 5.41 Experimental value 61.46 6.30 3.94 5.29 Mass spectrum (m / z) 235 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.70-1.83 (2H , M), 1.96-2.
11 (4H, m), 2.78-2.91 (4H, m),
2.93-3.03 (2H, m), 3.07-3.22
(2H, m), 4.48-4.57 (1H, m), 6.
46 (2H, s), 6.84 (1H, dd, J = 8.7)
9,3.91 Hz), 6.89 (1H, dd, J = 8.
79, 8.79 Hz) (B) Hydrochloric acid was used instead of fumaric acid in the same manner as in (A) to give 4-[(7-fluoro-4-indanyl) oxy].
A piperidine hydrochloride was obtained. Melting point 217-219 ° C Elemental analysis value (as C ₁₄ H ₁₉ NOClF) C (%) H (%) N (%) Cl (%) F (%) Theoretical value 61.88 7.05 5.15 13.05 6.99 Experimental value 61.66 6.98 5.18 13.06 6.85 Mass spectrum (m / z): 235 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.81-1.87 (2H, m), 2.03-2.
10 (4H, m), 2.82-2.89 (4H, m),
3.02-3.07 (2H, m), 3.15-3.32.
(2H, m), 4.55-4.58 (1H, m), 6.
85 (1H, dd, J = 8.85, 3.97Hz),
6.90 (1H, dd, J = 8.85, 8.85H
z), 9.09 (2H, br)

Example 3 4-[(7-Fluoro-4-indanyl) oxy] -1
-Ethoxycarbonylpiperidine 267 mg (0.87
5 ml of anhydrous tetrahydrofuran (THF)
Lithium aluminum hydride 9
9 mg (2.61 mmol) was added. After heating under reflux for 2 hours in an argon atmosphere, cooling with ice, sodium sulfate 1
O-hydrate was added until there was no effervescence. Then, this was filtered and the filtrate was evaporated under reduced pressure to give a colorless oil (194 mg, 90
%) Was obtained. Dissolve this in 5 ml of ethanol,
After adding 1 ml of 4N-hydrochloric acid ethyl acetate solution, the solvent was distilled off under reduced pressure. The residue was recrystallized from diethyl ether: ethanol (10: 1) to give 4-[(7-fluoro-4-
Indanyl) oxy] -1-methylpiperidine hydrochloride was obtained. Melting point 199-201 ° C Elemental analysis value (as C ₁₅ H ₂₁ NOClF) C (%) H (%) N (%) Cl (%) F (%) Theoretical value 63.04 7.41 4.90 12.41 6.65 Experimental value 63.11 7.62 4.85 12.25 6.51 Mass spectrum (m / z): 249 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.82-2.25 (6H, m), 2.66-2.
85 (4H, m), 2.85-2.95 (3H, m),
2.98-3.15 (2H, m), 3.23-3.50
(2H, m), 4.35-4.57 (0.5H, m),
4.67 (0.5H, brs), 6.83-6.93
(2H, m), 10.89 (1H, br)

Example 4 1.50 g (5.52 mmol) of 4-[(7-fluoro-4-indanyl) oxy] piperidine hydrochloride was suspended in 20 ml of methylene chloride, and 1.85 ml of triethylamine (13. 2 mol), acetyl chloride 4
71 ml (6.62 mol) was added, and the mixture was stirred under an argon atmosphere for 1 hour. Then, water was added thereto, and the mixture was extracted with ethyl acetate, and washed with water, 1N-hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution, water and a saturated saline solution in this order. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain 1.61 g (quant.) Of 1-acetyl-4 [(7-fluoro-4-indanyl) oxy] piperidine as a yellow oil. Mass spectrum (m / z): 277 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.53 to 2.35 (6H, m), 2.11 (3)
H, s), 2.76-3.08 (4H, m), 3.23.
-3.87 (4H, m), 4.34-4.59 (1H,
m), 6.61 (1H, dd, J = 8.19, 5.13)
Hz), 6.77 (1H, dd, J = 8.19, 8.1)
9Hz)

Example 5 1-Acetyl-4 [(7-fluoro-4-indanyl)
Oxy] piperidine (1.53 g, 5.52 mmol) was subjected to the same procedure as in Example 3 to give 1-ethyl-4-[(7-fluoro-4-indanyl) oxy] piperidine hydrochloride (1.13 g, 68%) as colorless crystals. Got as. Melting point 204-206 ° C Elemental analysis value (as C ₁₆ H ₂₃ NOClF / 0.2H ₂ O) C (%) H (%) N (%) Cl (%) F (%) Theoretical value 63.34 7.77 4.62 11.68 6.26 Experiment Value 63.42 7.81 4.65 11.79 6.28 Mass spectrum (m / z): 263 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.19-1.32 (3H, m), 1 84-2.
24 (6H, m), 2.74-3.20 (8H, m),
3.24-3.40 (1H, m), 3.41-3.55
(1H, m), 4.38-4.48 (0.4H, m),
4.69 (0.6H, brs), 6.80-6.97
(2H, m), 10.70 (1H, br)

Example 6 4-[(7-Fluoro-indanyl) oxy] piperidine hydrochloride 1.50 g (5.52 mmol) and propionyl chloride were prepared in the same manner as in Example 4. 4-Indanyl) oxy] -1-propionylpiperidine (1.73 g, Quant.) Was obtained as a yellow oil. Mass spectrum (m / z): 291 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.16 (3H, t, J = 7.42Hz), 1.5
6-2.22 (6H, m), 2.37 (2H, q, J =
7.42Hz), 2.72-3.10 (4H, m),
3.20-3.98 (4H, m), 4.32-4.60
(1H, m), 6.65 (1H, dd, 8.82, 4.
59 Hz), 6.77 (1H, dd, 8.82, 8.8
2Hz)

Example 7 4-[(7-Fluoro-4-indanyl) oxy] -1
-1.61 g of propiolpiperidine (5.52 mmo
l)) was carried out in the same manner as in Example 3 to obtain 1.25 g (72%) of 4-[(7-fluoro-4-indanyl) oxy] -1-propylpiperidine hydrochloride as colorless crystals. Melting point 207-209 ° C Mass spectrum (m / z): 277 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.83-0.97 (3H, m), 1.64-1.
78 (2H, m), 1.94-2.25 (6H, m),
2.74-3.10 (8H, m), 3.35 (1.2
H, brd, J = 11.6Hz), 3.49 (0.8
H, brd, J = 11.0 Hz), 4.38-4.47.
(0.4H, m), 4.69 (0.6H, brs),
6.79-6.96 (2H, m), 10.45 (1H,
br)

Example 8 4-[(7-Fluoro-4-indanyl) oxy] -1
-To 1.0 g (3.68 mmol) of piperidine / hydrochloride, 20 ml of acetonitrile and 2.44 g of potassium carbonate (1
7.7 mmol), 1.32 ml of 2-iodopropane
(12.2 mmol) was added and the mixture was heated under reflux for 20 hours under an argon atmosphere. After cooling to room temperature, the insoluble matter was filtered, and the solvent of the filtrate was evaporated under reduced pressure. Dissolve the residue in ethyl acetate,
The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. 1.11 g of the obtained colorless oily substance.
(100%) was dissolved in methanol, 2 ml of 4N-hydrochloric acid ethyl acetate solution was added, and the solvent was distilled off again under reduced pressure. The residue was mixed with isopropanol-diisopropyl ether (1:
Recrystallized from the mixed solvent of 1) to give 4-[(7-fluoro-
4-Indanyl) oxy] -1- (1-methylethyl)
1.10 g (95%) of piperidine hydrochloride was obtained as colorless crystals. Melting point 234-236 ° C Mass spectrum (m / z): 277 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.27 (2.4H, d, J = 6.72Hz),
1.30 (3.6H, d, J = 6.72Hz), 1.9
0-2.12 (4H, m), 2.13-2.24 (2
H, m), 2.76-2.92 (4H, m), 3.00
-3.12 (2H, m), 3.20-3.41 (3H,
m), 4.41-4.49 (0.4H, m), 4.72
(0.6H, brs), 6.81-6.95 (2H,
m), 10.22 (0.4H, br), 10.39
(0.6H, br)

Example 9 332 mg of 7-fluoro-4-indanol (2.0 m
mol) and [(1-ethoxycarbonyl-3-piperidinyl) methyl] -p-toluenesulfonate 818m.
From g (2.4 mmol), the same procedure as in Example 1
693 mg of -ethoxycarbonyl-3-[(7-fluoro-4-indanyl) oxy] methyl] piperidine were obtained. Mass spectrum (m / z): 321 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 0.67-2.33 (7H, m), 1.25 (3
H, t, 7.29 Hz), 2.48-3.09 (6H,
m), 3.64-4.38 (4H, m), 4.13 (2)
H, q, J = 7.29 Hz), 6.55 (1H, dd,
J = 8.55, 3.96 Hz), 6.76 (1H, d
d, J = 8.55, 8.55 Hz)

Example 10 1-Ethoxycarbonyl-3-[[7-fluoro-4-
Indanyl) oxy] methyl] piperidine 693 mg
(2.0 mmol), the same procedure as in Example 2
[[7-Fluoro-4-indanyl) oxy] methyl]
262 mg (34%) of piperidine fumarate was obtained. Melting point 177-178 ° C. Elemental analysis value (as C ₁₉ H ₂₄ NO ₅ F) C (%) H (%) N (%) F (%) Theoretical value 62.45 6.62 3.83 5.20 Experimental value 62.31 6.60 3.77 5.15 Mass spectrum (m / z): 249 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.25-1.39 ( 1H, m), 1.57-1.
71 (1H, m), 1.73-1.87 (2H, m),
2.00-2.10 (2H, m), 2.10-2.23
(1H, m), 2.62-2.78 (2H, m), 2.
78-2.92 (4H, m), 3.18 (1H, br
d, J = 12.21 Hz), 3.30 (1H, brd,
J = 12.21 Hz), 3.82 (1H, dd, J =
9.77, 6.84 Hz), 3.90 (1H, dd, J
= 9.77, 5.85 Hz), 6.43 (2H, s),
6.74 (1H, dd, J = 8.79, 3.91H
z), 6.89 (1H, dd, J = 8.79, 8.30)
Hz)

Example 11 249 mg (1.0 mm) of an oily substance desalted from 3-[[(7-fluoro-4-indanyl) oxy] methyl] piperidine fumarate in the same manner as in Example 4.
189 μl (5.0 mmol) of formic acid and 189 μl (2.2 mmol) of 35% aqueous formaldehyde solution were added to ol) and heated and stirred at 80 ° C. for 5 hours. After cooling to room temperature,
A saturated aqueous sodium carbonate solution was added, and the mixture was extracted with ethyl acetate and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol, 1 ml of 4N-hydrochloric acid ethyl acetate solution was added, and the solvent was distilled off again under reduced pressure. The residue was recrystallized from diethyl ether-ethanol (5: 1) to give 3-[[(7-fluoro-4-indanyl) oxy] methyl] -1-methylpiperidine hydrochloride 247 mg (83%) as colorless crystals. Obtained. Melting point 180-182 ° C Elemental analysis value (as C ₁₆ H ₂₃ NOClF / 0.25H ₂ O) C (%) H (%) N (%) Cl (%) F (%) Theoretical value 63.15 7.78 4.60 11.65 6.24 Experiment Value 63.13 7.61 4.59 11.52 6.27 Mass spectrum (m / z): 263 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.23-1.31 (1H, m), 1 .81 (1
H, brs), 1.84 (2H, brs), 2.02-
2.10 (2H, m), 2.35 (1H, br), 2.
75 (3H, s), 2.80-2.90 (6H, m),
3.38 (1H, brd, J = 11.72Hz), 3.
47 (1H, brd, J = 11.23Hz), 3.81
(1H, dd, J = 9.77, 6.83Hz), 3.9
3 (1H, dd, J = 9.77, 4.88 Hz), 6.
75 (1H, dd, J = 8.79, 3.91Hz),
6.90 (1H, dd, J = 8.79, 8.79H
z), 10.62 (1H, br)

Example 12 345 mg (1.42 mmo of oily substance desalted from 3-[[(7-fluoro-4-indanyl) oxy] methyl] piperidine fumarate by the same method as in Example 4.
1-acetyl-3-from l)
406 mg (98%) of [[(7-fluoro-4-indanyl) oxy] methyl] piperidine was obtained as a yellow oil. Mass spectrum (m / z): 291 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.10-2.35 (7H, m), 2.09 (3
H, s), 2.73-3.26 (6H, m), 3.62.
-4.73 (4H, m), 6.55 (1H, dd, J =
9.0, 4.5 Hz), 6.78 (1H, dd, J =
9.0, 9.0 Hz)

Example 13 1-Acetyl-3-[[(7-fluoro-4-indanyl) oxy] methyl] piperidine 300 mg (1.0
3 mmol) was performed in the same manner as in Example 3 to obtain 1-ethyl-3.
237 mg (73%) of-[[(7-fluoro-4-indanyl) oxy] methyl] piperidine hydrochloride was obtained as yellow crystals. Melting point: 144-146 ° C. Elemental analysis value (as C ₁₇ H ₂₅ NOClF · 0.25H ₂ O) C (%) H (%) N (%) Cl (%) F (%) theoretical value 64.14 8. 07 4.40 11.14 5.97 Experimental value 64.04 8.07 4.43 11.35 5.80 Mass spectrum (m / z): 277 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.26 (3H, t, J = 7.28Hz), 1.2
2-1.35 (lH, m), 1.78-1.86 (3
H, m), 2.02-2.10 (2H, m), 2.37.
(1H, brs), 2.69-2.90 (6H, m),
3.06-3.20 (2H, m), 3.45 (1H, b
rd, J = 12.20 Hz), 3.52 (1H, br
d, J = 11.72 Hz), 3.84 (1H, dd, J
= 9.77, 6.35 Hz), 3.93 (1H, dd,
J = 9.77, 5.37 Hz), 6.75 (1H, d
d, J = 8.79, 3.91 Hz), 6.90 (1H,
dd, J = 8.79, 8.79 Hz), 10.35 (1
H, br)

Example 14 498 mg (2.0 mmol) of an oily substance desalted from 3-[[(7-fluoro-4-indanyl) oxy] methyl] piperidine hydrochloride by a conventional method and Example 4 from propionyl chloride. Do the same in 3-[[(7-fluoro-
580 mg (95%) of 4-indanyl) oxy] methyl] -1-propionylpiperidine was obtained as a yellow oil. Mass spectrum (m / z): 305 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 0.74-2.52 (7H, m), 1.14 (3
H, t, J = 7.56 Hz), 2.36 (2H, q, J
= 7.56 Hz), 2.57-3.25 (6H, m),
3.55-4.78 (4H, m), 6.54 (1H, d
d, J = 8.64, 3.96 Hz), 6.77 (1H,
dd, J = 8.64, 8.64 Hz)

Example 15 3-[[(7-Fluoro-4-indanyl) oxy] methyl] -1-propionylpiperidine 423 mg (1.
39 mmol) was carried out in the same manner as in Example 3-3-[[(7
-Fluoro-4-indanyl) oxy] methyl] -1-
202 mg (31%) of propylpiperidine fumarate
Was obtained as colorless crystals. Elemental analysis _{(C 18 H 26 NOF · 1.5C} 4 H 4 O 4 · 0.1H as _{2 O) C (%) H} (%) N (%) F (%) Theoretical values 61.68 6.95 3.00 4.07 Experimental value 61.69 7.20 2.89 4.02 Mass spectrum value (m / z): 291 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.87 (3H, t, J = 7.32Hz), 1.1
5-1.28 (1H, m), 1.51-1.81 (5
H, m), 2.02-2.09 (2H, m), 2.15
(1H, brs), 2.31-2.43 (2H, m),
2.64 (2H, t, J = 7.81Hz), 2.80-
2.89 (4H, m), 3.10 (1H, brd, J =
11.23 Hz), 3.21 (1H, brd, J = 1
1.23 Hz, 3.82 (1H, dd, J = 9.7)
7,6.84 Hz), 3.88 (1H, dd, J = 9.
77, 5.37 Hz), 6.56 (1.5 H, s),
6.73 (1H, dd, J = 8.79, 3.42H
z), 6.88 (1H, dd, J = 8.79, 8.79)
Hz)

Example 16 7-Fluoro-4-indanol 760 mg (5.0 m
mol) and (1-benzyl-3-pyrrolidino) methyl-
1.72 g (5.0 mmo of p-toluene sulfonate)
1) was carried out in the same manner as in Example 1 and 1-benzyl-3-
1.28 g (79%) of [[(7-fluoro-4-indanyl) oxy] methyl] pyrrolidine were obtained as an oil. Furthermore, 200 mg (0.615 mmo of this oily substance
1-benzyl-3-[[(7-fluoro-4-indanyl) was obtained by recrystallizing l) with 1 mg of fumaric acid as a 1: 1 salt using diethyl ether-ethanol. ) Oxy] methyl] pyrrolidine fumarate 155 mg was obtained as colorless crystals. Melting point: 117-119 ° C. Elemental analysis value (as C ₂₅ H ₂₈ NO ₅ F.0.1H ₂ O) C (%) H (%) N (%) F (%) Theoretical value 67.74 6.41 3. .16 4.29 Experimental value 67.65 6.39 3.23 4.12 Mass spectrum (m / z): 325 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1 .53-1.58 (1H, m), 1.94-2.
07 (3H, m), 2.55-2.65 (4H, m),
2.72-2.78 (3H, m), 2.84-2.88
(2H, m), 3.70 (2H, s), 3.86 (2
H, d, J = 6.35 Hz), 6.60 (2H, s),
6.73 (1H, dd, J = 8.79, 3.91H
z), 6.87 (1H, dd, J = 8.79, 8.79)
Hz), 7.26-7.34 (5H, m)

Example 17 1.08 g (3.32) 1-benzyl-3-[[(7-fluoro-4-indanyl) oxy] methyl] pyrrolidine
mmol) was dissolved in 30 ml of acetic acid, 1 g of 10% palladium carbon was added thereto, and the mixture was stirred at room temperature for 2.5 days in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure. After the residue was dissolved in 10 ml of ethanol, 4N-
1.5 ml of an ethyl acetate solution of hydrochloric acid was added, and the solvent was distilled off again under reduced pressure. The crude crystals obtained were recrystallized from ethanol, and 3
-[[(7-Fluoro-4-indanyl) oxy] methyl] pyrrolidine hydrochloride 458 mg (51%) was obtained as colorless crystals. Melting point: 157-158 ° C. Elemental analysis value (as C ₁₄ H ₁₉ NOFCl · 0.3H ₂ O) C (%) H (%) N (%) Cl (%) F (%) theoretical value 60.67 7. 13 5.05 12.79 6.85 Experimental value 60.55 6.91 5.07 13.68 6.84 Mass spectrometry value (m / z): 235 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d _6). , TMS internal standard) δ: 1.72-1.81 (1H, m), 2.02-2.
12 (3H, m), 2.66-2.74 (1H, m),
2.81-2.90 (4H, m), 2.97-3.01
(1H, m), 3.12-3.27 (2H, m), 3.
30-3.35 (1H, m), 3.96 (1H, dd,
J = 9.77, 7.33 Hz), 4.01 (1H, d
d, J = 9.77, 5.86 Hz), 6.76 (1H,
dd, J = 8.79, 3.41 Hz), 6.90 (1
H, dd, J = 8.79, 8.79 Hz), 9.52
(2H, br)

Example 18 3-[[(7-Fluoro-4-indanyl) oxy] methyl] pyrrolidine hydrochloride 380 mg (1.40 mmo)
The same procedure as in Example 11 was conducted from l) to obtain 149 mg (29%) of 1-methyl-3-[[(7-fluoro-4-indanyl) oxy] methyl] pyrrolidine fumarate as a colorless powder. Elemental analysis value (as C ₁₉ H ₂₄ NO ₅ F · 0.4H ₂ O) C (%) H (%) N (%) F (%) Theoretical value 61.25 6.71 3.76 5.10 Experiment Value 61.24 6.79 3.91 4.86 Mass spectrum (m / z): 249 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.69-1.74 (1H, m), 2.01-2.
10 (3H, m), 2.60 (3H, s), 2.65-
2.80 (1H, m), 2.80-2.89 (5H,
m), 2.99-3.04 (2H, m), 3.13-
3.18 (1H, m), 3.90 (1H, dd, J =
9.27, 9.27 Hz), 3.95 (1H, dd, J
= 9.27, 6.35 Hz), 6.51 (2H, s),
6.74 (1H, dd, J = 8.79, 3.91H
z), 6.88 (1H, dd, J = 8.79, 8.79)
Hz)

Example 19 172 mg (1.13) of 7-fluoro-4-indanol
mmol) and (3-quinuclidino) methyl-p-toluenesulfonate (333 mg, 1.13 mmol) were prepared in the same manner as in Example 1 and then converted into hydrochloride by the same method as in Example 2 to give 3-[[(( 7-Fluoro-4-indanyl) oxy] methyl] quinuclidine · hydrochloride 53 m
g (17%) was obtained as light brown crystals. Melting point: 117-179 ° C. Elemental analysis value (as C ₁₇ H ₂₃ NOClF.0.9H ₂ O) C (%) H (%) N (%) theoretical value 62.24 7.62 4.27 experimental value 62. 20 7.45 4.62 Mass spectrometry value (m / z): 275 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.67-1.77 (1H, m), 1.80-1.
91 (2H, m), 1.93-2.13 (4H, m),
2.79-2.82 (2H, m), 2.86-2.90
(2H, m), 2.93-2.99 (1H, m), 3.
11-3.29 (4H, m), 3.40-3.46 (2
H, m), 4.03 (2H, d, J = 7.32 Hz),
6.79 (1H, dd, J = 8.79, 3.42H
z), 6.92 (1H, dd, J = 8.79, 8.79)
Hz), 9.87 (1H, br)

Example 20 1.35 g (8.87) of 7-fluoro-4-indanol
mmol) and 2.04 g (5.91 mmol) of 3- (1-benzylpiperidino) -p-toluenesulfonate and the crude product obtained in the same manner as in Example 1 was added with 10 m of acetic acid.
1 g of 10% palladium hydroxide on carbon was dissolved in 1 and the mixture was stirred for 12 hours at room temperature under hydrogen atmosphere. The insoluble material was removed by filtration, the solvent was evaporated under reduced pressure, saturated sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate.
This was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. After dissolving the residue in methanol, 2 ml of 4N-hydrochloric acid in ethyl acetate was added,
The solvent was distilled off again under reduced pressure. The obtained yellow solid was washed with ether and recrystallized from isopropanol to give 3-[[(7-fluoro-4-indanyl) oxy] piperidine hydrochloride (600 mg, 37%) as colorless crystals. It was Melting point: 158-160 ° C. Elemental analysis value (as C ₁₄ H ₁₉ NOClF) C (%) H (%) N (%) Cl (%) F (%) theoretical value 61.88 7.05 5.15 13. 09 6.99 Experimental value 61.66 7.02 5.15 12.95 6.94 Mass spectrum value (m / z): 235 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ : 1.64-2.15 (6H, m), 2.80-2.
96 (4H, m), 2.98-3.30 (3H, m),
3.84-4.63 (2H, m), 6.76-6.96
(2H, m), 8.70-9.80 (2H, br)

Example 21 601 mg (3.95) of 7-fluoro-4-indanol
mmol) and 2- (1-benzylpiperidino) methyl
p-toluenesulfonic acid SCL 946 mg (2.64
mmol) in the same manner as in Example 1
203 mg (23%) of 2-[[(7-fluoro-4-indanyl) oxy] methyl] piperidine was obtained as a colorless oil. Mass spectrum (m / z): 339 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.07-2.43 (9H, m), 2.50-3.
25 (6H, m), 3.39 (1H, d, J = 13.9)
Hz), 3.91 (1H, dd, J = 9.72, 4.8)
6 Hz), 4.10 (1H, d, J = 13.91, 5.
04Hz), 4.18 (1H, dd, J = 9.72,
5.04 Hz), 6.50 (1H, dd, J = 8.3)
7.3.96 Hz), 6.74 (1H, dd, J = 8.
37.8.37 Hz), 7.07-7.75 (5H,
m)

Example 22 203 mg (0.60) of 1-benzyl-2-[[(7-fluoro-4-indanyl) oxy] methyl] piperidine
mmol) in the same manner as in Example 17 to give 2-[[(7
104 mg (61%) of -fluoro-4-indanyl) oxy] methyl] piperidine hydrochloride was obtained as colorless crystals. Melting point:> 250 ° C. Elemental analysis value (as C ₁₅ H ₂₁ NOClF) C (%) H (%) N (%) Cl (%) F (%) Theoretical value 63.04 7.41 4.90 12.41 6.65 Experimental value 62.83 7.46 4.86 12.47 6.40 Mass spectrum value (m / z): 249 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.44-1.69 (3H, m), 1.72-1.
83 (2H, m), 1.85-1.92 (1H, m),
2.01-2.12 (2H, m), 2.83-3.00
(5H, m), 3.21-3.37 (1H, m), 3.
45 (1H, brs), 4.07 (1H, dd, J = 1
0.38, 6.71 Hz), 4.14 (1H, dd, J
= 10.38, 4.27 Hz), 6.81 (1H, d
d, J = 8.54, 3.66 Hz), 6.92 (1H,
dd, J = 8.54, 8.54 Hz), 8.85 (1
H, dr), 8.96 (1H, dr)

Example 23 304 mg of 7-fluoro-4-indanol (2.0 m
mol) and 4- (1-ethoxycarbonylpiperidino)
Methyl-p-toluenesulfonate 1.02 g (3.0
mmol) in the same manner as in Example 1, and the obtained brown solid was recrystallized from n-hexane-ether to give 1-ethoxycarbonyl-4-[[(7-fluoro-4-indanyl) oxy. ] Methyl] piperidine 419 mg (65
%) As brown crystals. Mass spectrum (m / z): 321 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.26 (3H, t, J = 7.33Hz), 1.2
0-1.37 (2H, m), 1.82 (2H, brd,
J = 12.2 Hz), 1.91-2.01 (1H,
m), 2.04-2.17 (2H, m), 2.69-
3.00 (6H, m), 3.78 (2H, d, J = 6.
11 Hz), 4.14 (2H, q, J = 7.33H
z), 4.07-4.34 (2H, m), 6.55 (1
H, dd, J = 8.55, 3.66 Hz), 6.76
(1H, dd, J = 8.55Hz)

Example 24 1-Ethoxycarbonyl-4-[[(7-fluoro-4
-Indanyl) oxy] methyl] piperidine 321 mg
(1.00 mmol) and the same procedure as in Example 2
[[(7-Fluoro-4-indanyl) oxy] methyl] piperidine · hydrochloride 136 mg (48%) was obtained as colorless crystals. Melting point: 214-216 ° C. Elemental analysis value (as C ₁₅ H ₂₁ NOClF) C (%) H (%) N (%) Cl (%) F (%) Theoretical value 63.04 7.41 4.90 12. 41 6.65 Experimental value 62.89 7.42 4.86 12.55 6.55 Mass spectrum value (m / z): 249 (M ⁺ -HCl) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) ) Δ: 1.46-1.54 (2H, m), 1.89 (2
H, d, J = 12.21 Hz), 2.03 to 2.09
(3H, m), 2.80-2.83 (2H, m), 2.
86-2.92 (4H, m), 3.22-3.32 (2
H, m), 3.84 (2H, d, J = 5.91 Hz),
6.75 (1H, dd, J = 8.55, 3.66H
z), 6.89 (1H, dd, J = 8.55, 8.55)
Hz), 8.58 (1H, br), 8.88 (1H, b
r)

Example 25 1-Ethoxycarbonyl-4-[[(7-fluoro-4
-Indanyl) oxy] methyl] piperidine 250 mg
The same procedure as in Example 3 was performed from (0.78 mmol) 4-
[[(7-Fluoro-4-indanyl) oxy] methyl] -1-methylpiperidine hydrochloride 245 mg (90
%) As colorless crystals. Melting point: 164-166 ° C. Elemental analysis value (as C ₁₆ H ₂₃ NOClF · 0.6H ₂ O) C (%) H (%) N (%) Cl (%) F (%) theoretical value 61.87 7. 85 4.51 11.41 6.12 Experimental value 61.71 7.92 4.51 11.83 5.99 Mass spectrometry value (m / z): 263 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d _6). , TMS internal standard) δ: 1.52-1.63 (2H, m), 1.85-2.
01 (3H, m), 2.03 to 2.09 (2H, m),
2.72 (3H, s), 2.80-2.83 (2H,
m), 2.86-2.89 (2H, m), 2.90-
3.01 (2H, m), 3.36-3.49 (2H,
m), 3.84 (2H, d, J = 4.89 Hz), 6.
75 (-1H, dd, J = 8.55, 3.05Hz),
6.90 (1H, dd, J = 9.05, 8.55H
z), 10.15 (1H br)

Example 26 (1) 1.49 g of 7-fluoro-4-indanol
(9.80 mmol) and trans-4- (dibenzylamino) cyclohexyl-P-toluenesulfonate 2.
From 94 g (6.55 mmol), the same procedure as in Example 1 was performed, and the obtained crude product was dissolved in 20 ml of acetic acid to obtain 10%.
Palladium hydroxide-carbon (2 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 12 hours. The insoluble material was removed by filtration, the solvent was evaporated under reduced pressure, 10% aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with ethyl acetate. This was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol, 4N-hydrochloric acid and 3 ml of an ethyl acetate solution were added, and then the solvent was evaporated again under reduced pressure. 4-[(4-aminocyclohexyl) oxy] was obtained by washing the obtained light brown crystals with ether.
-7-Fluoroindane hydrochloride (cis: trans ≒
1: 3) 849 mg (45%) was obtained. (2) 4-[(4-aminocyclohexyl) oxy]-
7-Fluoroindan hydrochloride 823 mg (2.88 m
(mol) was suspended in 10 ml of methylene chloride, and 963 μl of triethylamine (6.91 mmo) was added thereto while cooling with ice.
l), 330 μl of ethyl chloroformate (3.46 mmo
1) was added, and the mixture was stirred at the same temperature for 2 hours. Next, water was added to this, and the mixture was extracted with ethyl acetate, washed with 1N-hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, water, and saturated saline in this order, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 7: 1), and trans-ethyl N- [4-[(7-fluoro-4-indanyl) was used.
Oxy] cyclohexyl] carbamate (A) 434m
g (47%) and cis-ethyl N- [4-[(7-
Fluoro-4-indanyl) oxy] cyclohexyl]
Carbamate (B) 434 mg (47%) and cis-
Ethyl N- [4-[(7-fluoro-4-indanyl) oxy] cyclohexyl] carbamate (B) 18
2 mg (20%) were obtained as colorless crystals.

Form A Mass spectrometric value (m / z): 321 (H ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.24 (3H, t, J = 7.29 Hz), 2. 7
2-7.05 (4H, m), 3.30-3.82 (1
H, m), 3.85-4.28 (1H, m), 1.00
-2.28 (10H, m), 4.11 (2H, q, J =
7.29 Hz), 4.30-4.67 (1H, m),
6.59 (1H, dd, J = 8.1, 4.0Hz),
6.76 (1H, dd, J = 8.1, 8.1Hz)

Form B mass spectrometric value (m / z): 321 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.24 (3H, t, J = 7.11 Hz), 1. Four
5-2.30 (10H, m), 2.74-3.09 (4
H, m), 3.36-3.81 (1H, m), 4.11.
(2H, q, J = 7.11Hz), 4.27-4.47
(1H, br), 4.47-4.87 (1H, br),
6.57 (-1H, dd, J = 8.8, 4.2Hz),
6.75 (1H, dd, J = 8.8, 8.8Hz)

Example 27 trans-ethyl N- [4-[(7-fluoro-4-
Indanyl) oxy] cyclohexyl] carbamate 4
30 mg (1.34 mmol) was hydrolyzed according to Example 2 to give trans-4-[(4-aminocyclohexyl)
Oxy] -7-fluoroindane 342 mg (quantitative)
Was obtained as an orange oil. 50 mg of this was converted to the hydrochloride according to the conventional method to obtain 55 mg of trans-4-[(4-aminocyclohexyl) oxy] -7-fluoroindane hydrochloride as colorless crystals. Mass spectrum (m / z): 249 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 0.77-2.32 (12H, m), 2.50-
3.10 (5H, m), 3.86-4.28 (1H,
m), 6.61 (1H, dd, J = 8.6, 4.0H
z), 6.75 (-1H, dd, J = 8.6, 8.6H)
z) Melting point:> 250 ° C. Elemental analysis value (as C ₁₅ H ₂₁ NOClF) C (%) H (%) N (%) Cl (%) F (%) Theoretical value 63.04 7.41 4.90 12 .41 6.65 Experimental value 63.07 7.43 4.94 12.34 − Mass spectrum (m / z): 249 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.36-1.52 (3H, m), 1.53-1.
78 (1H, m), 1.90-2.14 (6H, m),
2.74-2.81 (2H, m), 2.84-2.92
(2H, m), 3.06 (1H, brs), 4.11-
4.22 (1H, m), 6.83 (1H, dd, J =
9.28, 3.91 Hz), 6.87 (1H, dd, J
= 9.28, 9.28 Hz), 8.06 (2H, br)

Example 28 Cis-Ethyl N- [4-[(7-fluoro-4-indanyl) oxy] cyclohexyl] carbamate 180
131 mg (94 mg) of cis-4-[(4-aminocyclohexyl) oxy] -7-fluoroindane by hydrolyzing mg (0.56 mmol) according to Example 2.
%) As an orange oil. Mass spectrum (m / z): 249 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.04-2.32 (12H, m), 2.57-
3.19 (5H, m), 4.29-4.48 (1H,
m), 6.59 (1H, dd, J = 8.8, 5.1H)
z), 6.75 (-1H, dd, J = 8.8, 8.8H
z)

Example 29 trans-4-[(4-aminocyclohexyl) oxy] -7-fluoroindane 138 mg (0.55 mm)
ol) in the same manner as in Example 11 to obtain transformer-4-
[[4- (Dimethylamino) cyclohexyl] oxy]
-7-Fluoroindan hydrochloride 140 mg (81%)
Was obtained as colorless crystals. Melting point: 195-197 ° C. Elemental analysis value (as C ₁₇ H ₂₅ NOClF.0.25H ₂ O) C (%) H (%) N (%) Cl (%) F (%) theoretical value 64.14 8. 07 4.40 11.14 5.97 Experimental value 64.08 8.08 4.38 11.11 5.78 Mass spectrum (m / z): 277 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.34-1.47 (2H, m), 1.53-1.
67 (2H, m), 1.96-2.20 (6H, m),
2.69 (6H, s), 2.74-2.82 (2H,
m), 2.83-2.92 (2H, m), 3.14-
3.27 (1H, m), 4.12-4.23 (1H,
m), 6.81 (1H, dd, J = 8.79, 3.91)
Hz), 6.88 (1H, dd, J = 8.79, 8.7)
9Hz), 10.61 (1H, br)

Example 30 From 130 mg (0.52 mmol) of cis-4-[(4-aminohexyl) oxy] -7-fluoroindane, the same procedure as in Example 11 was carried out to obtain cis-4-[(4-dimethylamino). 142 mg (87%) of cyclohexyl] oxy] -7-fluoroindane hydrochloride was obtained as colorless crystals. Melting point: 194-197 ° C. Elemental analysis value (as C ₁₇ H ₂₅ NOClF · 0.25H ₂ O) C (%) H (%) N (%) Cl (%) F (%) theoretical value 64.14 8. 07 4.40 11.14 5.97 Experimental value 64.18 8.02 4.39 11.35 5.85 Mass spectrum (m / z): 277 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d _6). , TMS internal standard) δ: 1.50-1.79 (4H, m), 1.80-1.
94 (2H, m), 1.95-2.16 (4H, m),
2.71 (6H, s), 3.82-3.99 (4H,
m), 3.13-3.28 (1H, m), 4.56 (1
H, s), 6.79 (1H, dd, J = 8.79, 3.
91 Hz), 6.88 (1H, dd, J = 8.79,
8.79 Hz), 10.49 (1H, br)

Example 31 6.38 g (42.0) of 7-fluoro-4-indanol
mmol) and 2- (1,4-dibenzylpiperazino)
Methyl methanesulfonate 15.7 g (42.0 mmo
From l), in the same manner as in Example 1, 1,4-dibenzyl-
6.32 g (35%) of 2-[[(7-fluoro-4-indanyl) oxy] methyl] piperazine was obtained as a yellow oil. Furthermore, by converting this oily substance into a hydrochloride by the same method as in Example 4, 1,4-dibenzyl-
2-[[(7-Fluoro-4-indanyl) oxy] methyl] piperazine dihydrochloride was obtained as colorless crystals. Melting point: 187-189 ° C. Elemental analysis value (as C ₂₈ H ₃₃ N ₂ OCl ₂ F.0.6H ₂ O) C (%) H (%) N (%) Cl (%) F (%) theoretical value 65 .39 6.70 5.45 13.79 3.69 Experimental value 65.26 6.60 5.52 14.30 3.57 Mass spectrometry value (m / z): 430 (M ⁺ ) Nuclear magnetic resonance spectrum ( DMSO-d _6, TMS internal standard) δ: 1.96-2.11 (2H, m ), 2.63-5.
30 (15H, m), 6.79-6.90 (1H,
m), 6.93 (1H, dd, J = 8.55, 8.55)
Hz), 7.25-7.50 (6H, m), 7.50-
7.86 (4H, m)

Example 32 4.55 g (1 of 1,4-dibenzyl-2-[[(7-fluoro-4-indanyl) oxy] methyl] piperazine
0.6 mmol) and in the same manner as in Example 17,
[[(7-Fluoro-4-indanyl) oxy] methyl] piperazine dihydrochloride 3.45 g (100%) was obtained as colorless crystals. Melting point: 244-245 ° C. Elemental analysis value (as C ₁₄ H ₂₁ N ₂ OCl ₂ F.0.5H ₂ O) C (%) H (%) N (%) Cl (%) F (%) theoretical value 50 .61 6.67 8.43 21.34 5.72 Experimental value 50.60 6.47 8.59 22.04 5.70 Mass spectrum (m / z): 251 (M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 2.01-2.12 (2H, m ), 2.84-3.
01 (4H, m), 3.15-3.44 (3H, m),
3.46-3.57 (2H, m), 3.60-3.66
(1H, m), 3.90-4.00 (1H, m), 4.
25 (1H, dd, J = 10.99, 5.49Hz),
4.29 (1H, dd, J = 10.99, 4.27H
z), 6.83 (1H, dd, J = 8.55, 3.66)
Hz), 6.94 (1H, dd, J = 8.55, 8.5
5Hz), 9.97 (4H, br)

Example 33 2-[[(7-Fluoro-4-indanyl) oxy] methyl] piperazine dihydrochloride 1.35 g (4.00 mm)
12-ml of 1.4-dioxane and 12 ml of a 1N-sodium hydroxide aqueous solution were added to ol), and the mixture was further cooled with ice under di-t.
-Butyl dicarbonate 873 mg (4.00 mmo
l)) was added and the mixture was stirred at the same temperature for 2 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and 4-t-
Butoxycarbonyl-2-[[(7-fluoro-4-indanyl) oxy] methyl] piperazine 551 mg (3
9%) as a yellow oil. Mass spectrum (m / z): 350 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.47 (9H, s), 1.86-2.29 (4)
H, m), 2.54-3.24 (8H, m), 3.69
-4.29 (4H, m), 6.56 (1H, dd, J =
8.37, 3.69 Hz), 6.77 (1H, dd, J
= 8.37, 8.37 Hz)

Example 34 4-t-Butoxycarbonyl-2-[[(7-fluoro-4-indanyl) oxy] methyl] piperazine 387
mg (1.11 mmol) was dissolved in 5 ml of methylene chloride, and 201 μl of triethylamine (1.
44 mmol), 155 μl of benzoyl chloride (1.33
mmol) was added and the mixture was stirred at the same temperature for 1 hour. Next, water was added to this, extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Then, to the residue was added 4N-hydrochloric acid ethyl acetate solution 10
ml was added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. By distilling off the solvent under reduced pressure, 1
-Benzoyl-2-[[(7-fluoro-4-indanyl) oxy] methyl] piperazine 381 mg (97%)
Was obtained as a yellow oil. Further 160 mg (0.45
2 mmol) was converted to a fumarate by a conventional method to give 1-benzoyl-2-[[(7-fluoro-4-indanyl) oxy] methyl] piperazine fumarate 1
40 mg (66%) was obtained as colorless crystals. Melting point: 148-150 ° C. Elemental analysis value (as C ₂₅ H ₂₇ N ₂ O ₆ F) C (%) H (%) N (%) F (%) Theoretical value 63.82 5.78 5.95 4. 04 Experimental value 63.81 5.99 5.87 3.81 Mass spectrum (m / z): 354 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.98-2 10 (2H, m), 2.63-4.
52 (13H, m), 6.57 (2H, s), 6.50
-6.96 (2H, m), 7.31-7.54 (5H,
m)

Example 35 4-t-butoxycarbonyl-2-[[(7-fluoroindanyl) oxy] methyl] piperazine 158 mg
(0.45 mmol) and acetyl chloride 39 μl (0.5
4 mmol) in the same manner as in Example 34 to give the hydrochloride salt by a conventional method.
126 mg (85%) of [[(7-fluoro-4-indanyl) oxy] methyl] piperidine hydrochloride were obtained as colorless crystals. Melting point: 175-177 ° C. Elemental analysis value (as C ₁₆ H ₂₂ N ₂ O ₂ ClF.0.5H ₂ O) C (%) H (%) N (%) Cl (%) F (%) theoretical value 56 .89 6.86 8.29 10.49 5.62 experimental value 56.77 6.83 8.71 11.20 5.49 mass spectrometry value (m / z): 293 (M ⁺ +1) nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 1.98-2.18 (5H, m ), 2.67-2.
96 (5H, m), 2.96-3.12 (1H, m),
3.17-3.51 (3H, m), 3.85-4.96
(4H, m), 6.71-6.86 (1H, m), 6.
86-6.99 (1H, m), 9.57 (2H, br)

Example 36 210 mg of 1-benzoyl-2-[[(7-fluoro-4-indanyl) oxy] methyl] piperazine (0.6
From 0 mmol) to give 1-benzyl-2-[[(7-fluoro-4-indanyl) oxy].
174 mg (70%) of methyl] piperazine dihydrochloride was obtained as a yellow amorphous. Elemental analysis value (as C ₂₁ H ₂₇ N ₂ O ₂ ClF · 0.8H ₂ O) C (%) H (%) N (%) Cl (%) F (%) Theoretical value 58.96 6.746 0.55 16.58 4.44 Experimental value 59.15 7.05 6.92 16.51 4.33 Mass spectrometry value (m / z): 340 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS) Internal standard) δ: 1.97-2.15 (2H, m), 2.79-2.
98 (4H, m), 2.65-4.90 (12H,
m), 6.77-7.00 (2H, m), 7.22-
7.50 (3H, m), 7.50-7.79 (2H,
m), 9.55-10.30 (br, 2H)

Example 37 1.52 g (10.0) of 7-fluoro-4-indanol
(mmol) was dissolved in 25 ml of acetone, and N-
(3-Bromopropyl) phthalimide 3.22 g (1
2.0 mmol), potassium carbonate 2.07 g (15.0
mmol) was added and the mixture was heated with stirring for 8 hours. Then, the solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 50 ml of ethanol is added to the residue.
1 ml of hydrazine monohydrate was added to this, and 3
Heated to reflux for hours. After cooling to room temperature, the insoluble matter was removed by filtration, and the solvent was evaporated under reduced pressure. Silica gel column chromatography (chloroform: methanol = 1)
0: 1), 4- (3-aminopropoxy) -7
-1.21 g (58%) of fluoroindane (A) was obtained as a pale yellow oil. Of this, 139 mg (0.665
mmol) to give a fumarate in the same manner as in Example 4, whereby 4- (3-aminopropoxy) -7-
156 mg of fluoroindan fumarate (B) was obtained as colorless crystals. Compound A Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.74-2.29 (4H, m), 2.48-3.
25 (8H, m), 4.01 (2H, t, J = 5.99)
Hz), 6.56 (1H, dd, J = 8.61, 4.0)
1 Hz), 6.76- (1H, dd, J = 8.61,
8.61 Hz) B compound mp: 162-164 ° C. Elemental analysis (C ₁₆ H ₂₀ N0 as _{5 F) C (%) H} (%) N (%) F (%) Theoretical values 59.07 6.20 4 .31 5.84 Experimental value 59.08 6.15 4.35 5.93 Mass spectrum value (m / z): 210 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1 .93-2.10 (4H, m), 2.73-3.
00 (6H, m), 4.03 (2H, t, J = 6.12)
Hz), 6.41 (2H, s), 6.74 (1H, d
d, J = 8.79, -3.41 Hz), 6.89 (1
H, dd, J = 8.79, 8.30 Hz)

Example 38 From 230 mg (1.10 mmol) of 4- (3-aminopropoxy) -7-fluoroindane, the same procedure as in Example 11 was carried out, and then a fumarate was prepared by a conventional method.
4- (3-Dimethylaminopropoxy) -7-fluoroindane fumarate, 133 mg (34%), was obtained as colorless crystals. Melting point: 113-115 ° C. Elemental analysis value (as C ₁₈ H ₂₄ N 0 ₅ F) C (%) H (%) N (%) F (%) theoretical value 61.18 6.85 3.96 5.38 experiment Value 61.04 6.77 3.96 5.36 Mass spectrum (m / z): 237 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.87-1.94 (2H, m), 2.01-2.
09 (2H, m), 2.34 (6H, s), 2.62
(2H, t, J = 7.32Hz), 2.79-2.82
(2H, m), 2.85-2.89 (2H, m), 3.
98 (2H, t, J = 6.35Hz), 6.55 (2
H, s), 6.73 (1H, dd, J = 8.79, 3.
91 Hz), 6.88 (1H, dd, J = 8.79,
8.79Hz)

Example 39 1) 1.52 g (1) of 7-fluoro-4-indanol
0.0 mmol) to 3N-sodium hydroxide aqueous solution 10
ml, 1.3-dibromopropane 10.1 ml (100
mmol) was added and the mixture was heated with stirring at 80 ° C. for 24 hours.
After cooling to room temperature, water was added, the mixture was extracted with ether, washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1).
(3-Bromopropoxy) -7-fluoroindane 1.
Obtained 63 g (60%) as a colorless oil. Mass spectrum (m / z): 247 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.92-2.45 (4H, m), 2.75-3.
08 (4H, m), 3.60 (2H, t, J = 6.53)
Hz), 4.07 (2H, t, J = 5.76Hz),
6.59 (1H, dd, J = 8.19, 3.96H
z), 6.78 (1H, dd, J = 8.19, 8.19)
Hz)

2) To 220 mg (0.806 mmol) of 4- (3-bromopropoxy) -7-fluoroindane was added 25 ml of a 40% methylamine methanol solution, and 6
The mixture was heated and stirred at 0 ° C for 5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1 to 5: 1) to obtain 152 mg of a colorless oil. By converting this into a hydrochloride by a conventional method, 4- (3-methylaminopropoxy) -7-fluoroindane hydrochloride 76 mg, (3
6%) as colorless crystals. Melting point: 162-164 ° C. Elemental analysis value (as C ₁₃ H ₁₉ NOC1F.0.2H ₂ O) C (%) H (%) N (%) Cl (%) F (%) theoretical value 59.29 7. 42 5.32 13.46 7.21 Experimental value 59.10 7.29 5.33 15.69 7.10 Mass spectrum (m / z): 223 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d _6). , TMS internal standard) δ: 2.01-2.10 (4H, m), 2.57 (3
H, s), 2.80-2.84 (2H, m), 2.86
-2.90 (2H, m), 3.04 (2H, t, J =
7.57 Hz), 4.04 (2H, t, J = 6.86H
z), 6.75 (1H, dd, J = 8.79, 3.42)
Hz), 6.91 (1H, dd, J = 8.79, 8.3)
0Hz), 8.73 (1H, br)

Example 40 4- (3-Aminopropoxy) -7-fluoroindane 400 mg, triethylamine 343 μl, propionyl chloride 200 μl, lithium aluminum hydride 108
In the same manner as in Examples 3 and 4, using mg, 4- [3-
(Propylamino) propoxy] -7-fluoroindane hydrochloride (360 mg) was obtained. Melting point: 156-158 ° C. Elemental analysis value (as C ₁₅ H ₂₃ NOFCl) C (%) H (%) N (%) Cl (%) F (%) theoretical value 62.60 8.05 4.87 12. 32 6.60 Experimental value 62.21 8.07 4.83 12.08 6.45 Mass spectrum value (m / z): 251 (M ⁺ ) Infrared absorption spectrum (KBr) cm ⁻¹ : 1469,1
244 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.92 (3H, t, J = 8.0 Hz), 1.67.
(24, tt, J = 7.5, 7.5 Hz), 1.98-
2.14 (4H, m), 2.81-2.89 (6H,
m), 3.02 (2H, br), 4.05 (2H, t,
J = 6.0 Hz), 6.76 (1H, dd, J = 9.
5,3.5 Hz), 6.90 (1H, dd, J = 9.
5,9.5Hz)

Example 41 4- [3- (Diethylamino) propoxy] -7-fluoroindane odor was obtained in the same manner as in Example 39 using 230 mg of 4- (3-bromopropoxy) -7-fluoroindane and 3 ml of diethylamine. 227 mg of hydrohydrate
Obtained. Melting point: 120-123 ° C. Elemental analysis value (as C ₁₆ H ₂₅ NOFBr · 0.2H ₂ O) C (%) H (%) F (%) Br (%) N (%) theoretical value 54.93 7. 32 4.00 5.43 22.84 Experimental value 54.91 7.27 3.94 5.34 22.33 Mass spectrum (m / z): 265 (M ⁺ ) Infrared absorption spectrum (KBr) cm ^-1 1494,1
242 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.22 (6H, t, J = 10.0 Hz), 2.0
3-2.13 (4H, m), 2.83 (2H, t, J =
7.5 Hz), 2.88 (2H, t, J = 7.5H
z), 3.15-3.24 (6H, m), 4.05 (2
H, t, J = 6.0 Hz, 6.77 (1H, dd, J
= 9.5, 3.5 Hz), 6.91 (1H, dd, J =
9.5, 9.5Hz)

Example 42 To 273 mg (1.0 mmol) of 4- (3-bromopropoxy) -7-fluoroindane was added 1 ml of piperidine, and the mixture was stirred at room temperature for 1 hour. Water was added, the mixture was extracted with methylene chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 260 mg of a colorless oil. By converting this into a hydrochloride by a conventional method, 1- [3-[(7-fluoro-4-indanyl) oxy] propyl] piperidine · hydrochloride 162m
g (52%) was obtained as colorless crystals. Melting point: 176-178 ° C. Elemental analysis value (as C ₁₈ H ₂₅ NOClF.0.8H ₂ O) C (%) H (%) N (%) Cl (%) F (%) theoretical value 63.54 7. 88 4.12 10.42 5.58 Experimental value 63.62 8.03 4.38 11.19 5.83 Mass spectrometry value (m / z): 277 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d _6). , TMS internal standard) δ: 1.31-1.45 (1H, m), 1.65-1.
85 (5H, m), 2.02-2.10 (2H, m),
2.10-2.19 (2H, m), 2.79-2.93
(6H, m), 3.10-3.20 (2H, m), 3.
40-3.50 (2H, m), 4.03 (2H, t, J
= 5.86 Hz), 6.76 (1H, dd, J = 8.7)
9, 3.90 Hz), 6.91 (1H, dd, J = 8.
79, 8.79 Hz), 9.91 (1H, br)

Example 43 1.5 g of 7-fluoro-4-indanol, 3.33 g of bromobutylphthalimide and 2.05 g of potassium carbonate,
1.8 g of 4- (4-aminobutoxy) -7-fluoroindane hydrochloride was obtained by the same method as in Example 37 using 2 ml of hydrated hydrazine. Melting point: 121-124 ° C Mass spec (m / z): 223 (M ⁺ ) Infrared absorption spectrum (KBr) cm ^-1 : 1946,1
248 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.67-1.78 (4H, m), 2.05 (2
H, tt, J = 5.0, 5.0 Hz), 2.79-2.
89 (6H, m), 3.96 (2H, t, J = 7.5H
z), 6.75 (1H, dd, J = 10.0, 5.0H
z), 6.89 (1H, dd, J = 10.0, 10.0
Hz)

Example 44 4- (4-aminobutoxy) -7-fluoroindane 1
4- [4- (Dimethylamino) butoxy] -7-fluoroindane hydrochloride was prepared in the same manner as in Example 38 by using 50 mg, formic acid 2 ml and formaldehyde 2 ml.
1 mg was obtained. Melting point: 69-72 ° C. Elemental analysis value (as C ₁₅ H ₂₃ NOFCl · 0.9H ₂ O) C (%) H (%) N (%) Cl (%) F (%) theoretical value 59.26 8. 22 4.61 11.66 6.25 Experimental value 59.31 8.13 4.64 11.87 6.48 Mass spectrum (m / z): 251 (M ⁺ ) Infrared absorption spectrum (KBr) cm ^-1 : 1488, 1
246 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.71-1.88 (4H, m), 2.05 (2
H, tt, J = 4.5, 4.5 Hz), 2.72 (6
H, S), 2.81-2.89 (4H, m), 3.08
(2H, t, J = 9.0 Hz), 3.97 (2H, t,
J = 7.5 Hz), 6.75 (1H, dd, J = 11.
0, 5.0 Hz), 6.87 (1H, dd, J = 11.
0, 11.0 Hz)

Example 45 4- (4-aminobutoxy) -7-fluoroindane 2
00 mg was dissolved in 5 ml of acetone, 143 μl of ethyl iodide and 250 mg of potassium carbonate were added thereto, and the mixture was heated under reflux for 8 hours. 20 ml of saturated saline was added to the reaction solution, extraction was performed 3 times with 10 ml of ether, the ether solution was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Dissolve the obtained oil in 10 ml of ether and stir 4N
A solution of hydrochloric acid in ethyl acetate was added. The precipitated salt is filtered, washed with ether, and dried to give 4-
85 mg of [4- (diethylamino) butoxy] -7-fluoroindane hydrochloride was obtained. Melting point: 111-114 ° C. Mass spectrum (m / z): 279 (M ⁺ ) Infrared absorption spectrum (KBr) cm ⁻¹ : 1496,1
248 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.22 (6, t, J = 7.0 Hz), 2.05
(2H, tt, J = 4.5,4.5Hz), 2.81-
2.89 (6H, m), 3.04-3. 11 (4H,
m), 3.95-4.00 (2H, m), 6.75 (1
H, dd, J = 8.5, 4.0 Hz), 6.89 (1
H, dd, J = 8.5, 8.5 Hz)

Example 46 In the same manner as in Examples 39 and 40, using 300 mg of 7-fluoro-4-indanol, 3.7 ml of ethylene bromide and 10 ml of 40% methylamine in methanol,
340 mg of [2- (methylamino) ethoxy] -7-fluoroindane hydrochloride was obtained. Melting point: 174-177 ° C. Elemental analysis value (as C ₁₂ H ₁₇ NOFCl) C (%) H (%) N (%) Cl (%) F (%) theoretical value 58.66 6.97 5.70 14. 43 7.73 Experimental value 58.44 7.03 5.69 14.28 7.87 Mass spectrum (m / z): 209 (M ⁺ ) Infrared absorption spectrum (KBr) cm ⁻¹ : 1946,1
246 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.06 (2H, tt, J = 7.0, 7.0H
z), 2.61 (3H, s), 2.87-2.91 (4
H, m), 3.28 (2H, t, J = 5.0Hz),
4.25 (2H, t, J = 5.0Hz), 6.81 (1
H, dd, J = 10.0, 5.0 Hz), 6.92 (1
H, dd, J = 10.0, 10.0 Hz)

Example 47 4- [2- (methylamino) ethoxy] -7-fluoroindane (160 mg) was used in the same manner as in Example 11 to give 4
168 mg of-[2- (dimethylamino) ethoxy] -7-fluoroindane hydrochloride was obtained. Melting point: 178-181 ° C. Elemental analysis value (as C ₁₃ H ₁₉ NOFCl) C (%) H (%) N (%) Cl (%) F (%) theoretical value 60.11 7.37 5.39 13. 65 7.31 Experimental value 59.74 7.79 5.40 13.84 7.19 Mass spectrum value (m / z): 223 (M ⁺ ) Infrared absorption spectrum (KBr) cm ⁻¹ : 1494,1
246 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.06 (2H, tt, J = 7.0, 7.0H
z), 2.83 (6H, s), 2.85-2.93 (4
H, m), 3.48 (2H, t, J = 5.5Hz),
4.36 (2H, t, J = 5.5Hz), 6.82 (1
H, dd, J = 8.5, 4.0 Hz, 6.93 (1
H, dd, J = 8.5, 8.5 Hz)

Example 48 To 10 ml of a 40% methylamine / methanol solution, 250 mg (1.20 mmol) of 4- (2,3-epoxypropoxy) -7-fluoroindane was added at room temperature, and the mixture was stirred at the same temperature for 5 hours. did. Then, the solvent was distilled off under reduced pressure, and the residue was converted to a fumarate by a conventional method to give 195 mg (46%) of 7-fluoro-4- (3-methylamino-2-hydroxypropoxy) indane-fumarate. Obtained as colorless crystals. Melting point: 182-184 ° C. Elemental analysis value (as C ₁₅ H ₂₀ NO ₄ F.0.25H ₂ O) C (%) H (%) N (%) F (%) theoretical value 59.69 6.854 .64 6.29 Experimental value 59.87 6.72 4.77 6.28 Mass spectrum (m / z): 239 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1 96-2.10 (2H, m), 2.47 (3
H, s), 2.50 (1H, s), 2.71-2.97.
(6H, m), 3.84-3.97 (2H, m), 3.
99-4.10 (1H, m), 6.39 (1H, s),
6.74 (1H, dd, J = 8.79, 3.42H
z), 6.89 (1H, dd, J = 8.79, 8.79)
Hz)

[0079]

[Table 2]

[0080]

[Table 3]

[0081]

[Table 4]

[0082]

[Table 5]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 31/445 AEN 31/495 C07C 217/34 7457-4H 217/52 7457-4H 217/56 7457 -4H 217/74 7457-4H 271/24 9451-4H 271/28 9451-4H C07D 207/08 207/12 211/22 211/42 211/46 241/04 295/08 Z 453/02 (72) Invention Person Yaichi Shinichi 8-10 Kamitatsushinmachi, Tsuchiura-shi, Ibaraki No. 302 Sanraizu Wakaba (72) Inventor Tokio Yamaguchi 6-16-3 Ryoke, Urawa-shi, Saitama City Core No. 402

Claims (2)

[Claims] 1. A compound of the general formula (I) (The symbols in the formula are as follows. R ¹ is a group represented by the following formula (II): A: a lower alkylene group which may be substituted with a hydroxy group R ² , R ³ : hydrogen atoms or lower alkyl groups which are the same or different and are dotted: R ² and R ³ are integrated with an adjacent nitrogen atom to form a ring atom 4 to Eight nitrogen-containing saturated heterocycles can be formed. A group represented by the following formula (III): Ring B: (i) a nitrogen-containing saturated heterocycle having 4 to 8 ring atoms or a bicyclic nitrogen-containing saturated heterocycle having 6 to 12 ring atoms, which contains 1 to 2 unsubstituted or substituted nitrogen atoms (ii) A fluoroindane derivative represented by a cycloalkyl group having 4 to 8 ring atoms substituted with an amino group or a substituted amino group, m: 0 or 1), or a salt thereof. 2. The ring B is (The symbols in the formulas have the following meanings: X: a group represented by the formula —CH ₂ — or a group represented by the formula —NR ⁴ — Y: a group represented by the formula —NR ⁵ — or a formula —CHR ⁶ — R ⁴ and R ^{5 are the} same or different and each is a hydrogen atom, a lower alkyl group, an aralkyl group, an acyl group or a lower alkoxycarbonyl group R ⁶ : An amino group, a mono- or di-lower alkylamino group or a lower alkoxycarbonylamino group p: 0 or 1 q: an integer of 1 to 3), The fluoroindane derivative or a salt thereof according to claim 1.