JPH05125024A - New aryloxyalkylamine derivative or its salt - Google Patents

Abstract

PURPOSE:To provide a new aryloxyalkylamine derivative having remarkably excellent selective affinity to 5-HT1A receptor and useful as a treating agent for symptoms relating to central neruous system such as anxiety, depression, disorder of memory, etc. CONSTITUTION:The aryloxyalkylamine derivative of formula I [(A is group of formula II or formula III); R<1>, R<2>, R<5> and R<6> are H or lower alkyl; R<3> and R<4> are H, lower alkyl, lower alkoxy, lower alkylthio or OH (R'' and R' are not H at the same time); R<7> is lower alkoxy; (n) is 1-5; (m) is 1-4] or its salt, e.g. N-[2-(8-chromanyloxy) ethyl]-p-methoxyphenetylamine. The compound of formula I can be produced e.g. by reacting a compound of formula IV (X is eliminable group such as halogen or methylsulfonyloxy) with a compound of formula V (Y is H or protecting group such as benzyl) and optionally removing the protecting group.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to pharmaceuticals, especially 5-HT _1A.
The present invention relates to a novel aryloxyalkylamine derivative or a salt thereof, which has a selective affinity for a receptor and is therefore useful as a therapeutic agent for a condition involving the central nervous system such as anxiety, depression, and memory disorder.

[0002]

2. Description of the Related Art Recently, the neurotransmitter serotonin (5-hydroxytryptamine: hereinafter abbreviated as 5-HT) has been used for several years to improve appetite, memory, thermoregulation, sleep, sexual behavior, anxiety, It has been shown to be directly or indirectly associated with many physiological phenomena, including depression and hallucinatory behavior [Glenon (Glenon, RA, J. Med . Chem. 3
0, 1 (1987)]].

It is recognized that there are multiple types of 5-HT receptors. These receptors are 5-H
Classified as T ₁ , 5-HT ₂ and 5-HT ₃ receptors, the first 5-HT ₁ is further subclassed as 5
-HT _1A , 5-HT _1B , 5-HT _1C and 5-HT _1D . Among the subclasses of 5-HT ₁ above,
The 5-HT _1A receptor is considered to be involved in diseases of the central nervous system such as anxiety and depression. Therefore, a compound having an affinity for the 5HT _1A receptor is involved in the central nervous system. It is considered to be effective in treating or preventing various diseases.

Conventionally, typical compounds having a selective affinity for the 5-HT _1A receptor are buspirone (Buspirone; compound described in Merck Index 11th edition, page 229) and vinospilone (M. Hibert et a
L., Br. J. Pharmacol, 1988, 93 , page 2, MDL 73005.
As EF, the compound described as Example 9 in JP-A-61-246180 and the like are known. Such compounds are thought to have potential for the treatment of anxiety, depression, schizophrenia, impaired food intake, learning and cognitive impairment, Alzheimer's disease, or hypertension and migraine, among others. Buspirone is already on the market as an anxiolytic.

[0005]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention
As a result of repeated research on the T _1A receptor and creation of various compounds and proceeding with screening, the novel aryloxyalkylamine derivative has a markedly superior selective affinity for the 5-HT _1A receptor. This has led to the completion of the present invention.

Regarding the aryloxyalkylamine derivative, it is reported in JP-A-1-501393, but the compound of the present invention is a novel compound having different kinds of substituents in the aryloxy group. .. Also,
The publication only describes the action as a fungicide and does not describe the affinity for the 5-HT receptor at all.

[0007]

That is, the present invention provides a novel aryloxyalkylamine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[0008]

[Chemical 3]

(Where A is the following general formula (II)

[0010]

[Chemical 4]

R ¹ , R ² , R ⁵ and R ⁶ are the same or different and are a hydrogen atom or a lower alkyl group,
R ³ and R ⁴ are the same or different and each is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group or a hydroxy group (provided that both R ³ and R ⁴ are hydrogen atoms), and R ⁷ is , A lower alkoxy group, n is an integer of 1 to 5, and m is an integer of 1 to 4. )

The compound of the present invention will be described in detail below. In the present specification, the term "lower" means a straight or branched hydrocarbon chain having 1 to 6 carbon atoms. Therefore, as the "lower alkyl group", for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group are specifically mentioned. 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, Examples include 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like.

The "lower alkoxy group" includes methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy (aluminoxy) group, Examples include isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group and hexyloxy group. The "lower alkylthio group" is a group in which a hydrogen atom of a thiol group (-SH) is substituted with the "lower alkyl group", and specifically, for example, methylthio group, ethylthio group, propylthio group, isopropyl group. Thio group, butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, 2
-Methylbutylthio group, 1,2-dimethylputylpropylthio group, hexylthio group, isohexylthio group, 1-
Methylpentylthio group, 2-methylpentylthio group, 3
-Methylpentylthio group, 1,1-dimethylbutylthio group, 1,2-dimethylbutylthio group, 2,2-dimethylbutylthio group, 1,3-dimethylbutylthio group, 2,3
Dimethylbutylthio group, 3,3-dimethylbutylthio group, 1-ethylbutylthio group, 2-ethylbutylthio group, 1,1,2-trimethylpropylthio group, 1,2,
2-trimethylpropylthio group, 1-ethyl-1methylpropylthio group, 1-ethyl-2-methylpropylthio group and the like can be mentioned.

The compound of the present invention may contain an asymmetric carbon atom depending on the kind of the substituent. Therefore, the compound of the present invention includes a mixture of various optical isomers and an isolated one. The compound (I) of the present invention may form an acid addition salt. Also, depending on the type of substituent, it may form a salt with a base. As such salt, specifically,
Hydrochloric acid, hydrobromic acid, hydroiodic acid, mineral acids such as sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, Organic acids such as tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, acid addition salts with acidic amino acids such as aspartic acid and glutamic acid, inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, methylamine, ethylamine, ethanol Examples thereof include organic bases such as amines, salts with basic amino acids such as lysine and ornithine, and ammonium salts.

(Production Method) The compound of the present invention and a salt thereof can be produced by utilizing various synthetic methods by utilizing the characteristics based on the basic skeleton or the kind of the substituent. The typical manufacturing method is illustrated below. First manufacturing method (1)

[0016]

[Chemical 5]

(In the formula, A, R ¹ , R ² , R ³ , R ⁴ and n have the above-mentioned meanings, and X is a halogen atom or a methylsulfonyloxy group, a trifluoromethylsulfonyloxy group, paratoluenesulfonyl. This means a leaving group such as an oxy group, and Y means a hydrogen atom or a protecting group or activating group such as a benzyl group or an acyl group.) This production method is represented by (IIIa) and (IVa) in the above formula. The compound represented by (I) in the above formula is reacted by reacting with a suitable solvent or without solvent in the presence or absence of a base, and optionally removing the protecting group (group represented by Y in the above formula (IVa)). ) Is a method for obtaining the compound of the present invention. As the solvent, hydrocarbons such as methanol and ethanol, or tetrahydrofuran, dioxane, acetoniryl, dimethylformamide (DM
A solvent inert to the reaction such as F) or dimethyl sulfoxide is appropriately used, or the reaction can be performed without a solvent.
When the reaction is carried out in the presence of a base, organic bases such as triethylamine and pyridine, inorganic bases such as sodium carbonate and potassium carbonate, sodium hydride or n-
Butyllithium or the like is preferably added, and when the base is a liquid, the base may be used as a solvent. The reaction is preferably carried out at -78 ° to under heating (reflux), particularly at room temperature to under heating (reflux). (2)

[0018]

[Chemical 6]

(In the formula, A, X, Y, R ¹ , R ² , R ³ , R ⁴
And n have the meanings given above. ) This manufacturing method uses the formula (II
This is a method for obtaining the compound (I) of the present invention by reacting the compounds represented by Ia ') and (IVa'). This reaction is carried out under the same conditions as in (1) above. Second manufacturing method (1)

[0020]

[Chemical 7]

(In the formula, A, Y, R ¹ , R ² , R ³ , R ⁴ and n have the above-mentioned meanings.) This production method is carried out according to the above formula (IIIb).
And a compound represented by (IVb) are dehydrated and condensed, and then reduced, that is, treated by a reaction known as so-called reductive amination, and then, if necessary, a protecting group is removed to give (I) in the above formula. A method of obtaining the indicated compounds of the present invention. Dehydration condensation can be carried out in alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, hydrocarbon solvents such as toluene, and halogenated hydrocarbon solvents such as 1,2-dichloroethane. Temperature conditions are preferably room temperature or under heating (under reflux),
At that time, dehydration may be performed using a dehydrating agent such as an azeotropic dehydrator or a molecular sieve. The reduction can be carried out in the same solvent as in the above dehydration condensation. In this manufacturing method,
The dehydration condensation product of the intermediate of the compound of the present invention may be isolated and reduced, or the two reactions of dehydration condensation and reduction may be carried out continuously or simultaneously. As the reducing agent, a reducing agent such as sodium borohydride or sodium cyanoborohydride is appropriately used, and catalytic hydrogenation is performed under normal pressure or pressure in the presence of a noble metal catalyst such as palladium carbon or platinum oxide. Good. The reduction reaction is preferably carried out at 0 ° or under heating (under reflux). (2)

[0022]

[Chemical 8]

(In the formula, A, Y, R ¹ , R ² , R ³ , R ⁴ and n have the above-mentioned meanings.)
b ') and (IVb') are reacted to obtain the compound (I) of the present invention. This reaction is carried out under the same conditions as in (1) above. Third manufacturing method (1)

[0024]

[Chemical 9]

(In the formula, A, R ² , R ³ , R ⁴ and n have the above-mentioned meanings.) In the compound (I) of the present invention, R ¹ is a hydrogen atom. The obtained compound can be obtained by reducing the amide derivative represented by the above formula (Ia ′) which is the starting compound. As the reducing agent, a reducing agent such as borane, lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride or the like is appropriately used. This reaction is preferably carried out in a solvent such as ethers such as ether, tetrahydrofuran, dimethoxyethane, etc., hydrocarbons such as benzene, toluene etc. under ice cooling or heating (under reflux). Further, the amide derivative (Ia ′) which is a raw material compound is obtained by reacting a corresponding carboxylic acid or its derivative with an amine derivative.
It can be synthesized by coupling using a coupling reaction such as acid chloride method, mixed acid anhydride method, azide method, DCC method and the like. (2)

[0026]

[Chemical 10]

(In the formula, A, R ¹ , R ³ , R ⁴ and n have the above-mentioned meanings.) In the compound (I) of the present invention, R ² is a hydrogen atom. The obtained compound can be obtained by reducing the amide derivative represented by the above formula (Ib ′) which is the starting compound. This reaction is carried out in the same manner as (1) above.

【The invention's effect】

The compounds of the present invention have an affinity for the 5-HT receptor, and in particular, a very high affinity for the 5-HT _1A receptor, which is a subtype of the 5-HT receptor. .. Therefore, the compounds of the present invention can be used in the treatment of various diseases involving the 5-HT nervous system. Such disorders include, for example, anxiety, tension and depression, neuropsychiatric disorders such as schizophrenia, sexual dysfunction, food intake disorders,
Examples include sleep disorders, motion sickness, and drug dependence. Furthermore, they can be used for treatment of stroke, cerebral ischemia, cognitive impairment, learning / memory impairment, Alzheimer's disease and the like. Furthermore, they can be used for cardiovascular disorders such as migraine and hypertension. Furthermore, since some of the compounds included in the present invention have an affinity for the adrenergic α receptor, the compounds can be used as therapeutic agents for dysuria and hypertension and cerebral circulation improving agents. Hereinafter, the affinity of the compound of the present invention for the 5-HT _1A receptor and the anxiolytic action will be described by posting experimental examples.

Experimental Example 1 Affinity for 5-HT _1A Receptor 1) Experimental Method Affinity for 5-HT _1A was determined by the method of Peroutka (J. Neu.
Rochem. 47 , 529 (1986)), it was determined by measuring the displacement of tritium-labeled 8-OH-DPAT using a rat hippocampus specimen, and expressed as a Ki value. The Ki values of the above-mentioned buspirone used as the compound of the present invention and the control compound are shown in Table 1 below. 2) Experimental results

[0030]

[Table 1]

As a result, the compound of the present invention was a control compound.
5-HT compared to certain buspirone_1AFor the receptor
It was found that the affinity was extremely strong. For this reason
The compound of the present invention is 5-HT Various diseases involving the nervous system
Have a better effect in the prevention or treatment of
Can be expected.

[Experimental Example 2] Anxiolytic action 1) Experimental method The anxiolytic action of the compound of the present invention was examined using the social interaction in rats as an index (J. Neurosci. Methods.,
2 , 219 (1980)). Anxiety relief is shown as an increase in social interaction time. The drug was intraperitoneally administered to male Wistar rats that had been handled for several days in advance,
After 30 minutes, place two animals in a cage for testing and
It was observed for 0 minutes. During that time, the time during which the rat had active social interactions such as sniffing, following, and grooming was measured. The total number of seconds of social interaction in 10 minutes was calculated and expressed as the increase rate (%) of the drug administration group to the drug non-administration group. Table 2 shows the anxiolytic effect of the compound of the present invention and the above-mentioned buspirone as a control, and diazepam widely used as an anxiolytic drug at the time of intraperitoneal administration of 1 mg / kg, respectively (in the table, * indicates not Regarding the numerical value of the administration group to the administration group, it was shown that there is a significant difference at a risk rate of 5% or less, *
* Also indicates that there is a significant difference at a risk rate of 1% or less). 2) Experimental results

[0033]

[Table 2]

As a result, among the compounds of the present invention, the compounds of Examples 1 and 12 have a markedly higher rate of increase in social interaction time and a stronger anxiolytic effect as compared with the control compounds diazepam or buspirone. It was discovered. Therefore, the compound of the present invention can be expected to have more excellent effects on various mental disorders such as anxiety, depression, and memory disorders.

A pharmaceutical composition containing, as an active ingredient, one or more compounds of the compound represented by the general formula (I) or a salt thereof is a carrier, an excipient or other additives usually used for formulation. Is prepared using. Carriers and excipients for formulation include solid or liquid non-toxic pharmaceutical substances. Examples of these include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol and the like, and other commonly used ones.

For administration, tablets, pills, capsules, granules,
It may be in any form of oral administration such as powder and liquid preparation, or parenteral administration such as injection such as intravenous injection and intramuscular injection, suppository and transdermal administration. The dose is appropriately determined depending on the individual case in consideration of symptoms, age of the subject, sex, etc., but usually, in the case of oral administration, it is 0.1 to 1000 mg per day for an adult,
It is preferably about 1 to 500 mg, and once,
Alternatively, it is administered in 2 to 4 divided doses.

[0037]

EXAMPLES The present invention will be described in more detail with reference to the following examples. The raw material compound of the present invention also includes a novel substance, and its production method is shown in Reference Example. In addition, a series of processes for the production method of the starting material compound and the production method of the compound of the present invention will be described with reference to Examples.

Reference Example 1 1.5 g of 8-chromanol was added to 1,2-dibromoethane 1
Dissolve in 0 ml, 3m sodium hydroxide aqueous solution 10m
1 and tetrabutylammonium hydrogen sulfate (TBAH
S) 170 mg was added, and the mixture was stirred at 70 ° C. 2 hours later,
1,2-Dibromoethane and 5 ml of a 3N aqueous sodium hydroxide solution were added, and the mixture was further stirred for 2 hours. After cooling, the reaction mixture was extracted with dichloromethane, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to dryness to obtain 2.6 g of white crystals of 8- (2-bromoethoxy) chroman.

Physicochemical properties Mass spectrometric value (EI, m / z): 256 (M⁺), 258
(M⁺+2) Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ: 1.8-2.1 (2H, m, C3-H₂), 2.
79 (2H, t, C4-H ₂), 3.63 (2H, t,
CH₂Br), 4.24, 4.30 (4H, tx2, C
2-H₂, OCH ₂ CH₂Br), 6.74 (3H, m) of Reference Example 2 and Reference Example 3 by the same method as in Reference Example 1.
The compound was synthesized.

Reference Example 2 7- (2-Bromoethoxy) -2,3-dihydrobenzofuran

Physicochemical properties Mass spectrometric value (EI, m / z): 242 (M ⁺ ), 244
(M ⁺ +2) Nuclear magnetic resonance spectrum (CDCl _3, TMS internal standard) δ: 3.22 (2H, t , C3-H 2), 3.62
(2H, t, CH ₂ Br), 4.36 (2H, t, OC
_{H 2), 4.62 (2H,} t, C2-H 2), 6.7-
6.9 (3H, m)

Reference Example 3 7- (2-Bromoethoxy) -2,3-dihydro-2,
2-dimethylbenzofuran

Physicochemical properties Mass spectrometric value (EI, m / z): 270 (M ⁺ ), 272
(M ⁺ +2) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.50 (6H, s, CH ₃ × 2), 3.02
(2H, s, C3-H 2), 3.62 (2H, t, CH 2
Br), 4.37 (2H, t , OCH 2 C H 2 Br),
6.77 (3H, m)

Reference Example 4 700 mg of 8-chromanol, 7 ml of acetone, 520 mg of chloroacetone, 970 mg of potassium carbonate and 100 mg of potassium iodide were mixed and heated under reflux for 5 hours,
Chloroacetone (260 mg) and potassium carbonate (320 mg) were added, and the mixture was further refluxed for 2 hours. After cooling, the solid was filtered off, the filtrate was concentrated and subjected to column chromatography, eluting with a mixed solvent of hexane-ethyl acetate (85:15) to give (8-chromanyloxy) acetone 710m.
g was obtained.

Physicochemical properties Mass spectrometric value (EI, m / z): 206 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.9-2.2 (2H, m, C3 ') -H _{2), 2.}
28 (3H, s, CH ₃ ), 2.80 (2H, t, C
_{4'-H 2), 4.27 (} 2H, t, C2'-H 2),
_{4.56 (2H, s, COCH 2} O), 6.5-6.8
(3H, m)

Reference Example 5 (1) 1.0 g of 8-chromanol, 10 ml of acetone,
Chloroacene (600 mg), potassium carbonate (1.38 g) and potassium iodide (100 mg) were mixed and heated under reflux for 5 hours. After cooling, the insoluble solid was filtered off, the filtrate was concentrated and subjected to column chromatography, using hexane-ethyl acetate (9:
By elution with the mixed solvent of 1), 1.18 g of (8-chromanyloxy) acetonitrile was obtained.

Physical and chemical properties Mass spectrometric value (EI, m / z): 189 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.7-1.9 (2H, m, C3 ') -H _2),
2.55 (2H, t, C4'- H 2), 4.01 (2
_{H, t, C2'-H 2} ), 4.54 (2H, s, CH 2 C
N), 6.5-6.6 (3H, m)

(2) Lithium aluminum hydride 760
mg suspension in 10 ml of tetrahydrofuran, under ice cooling,
980 mg of 100% sulfuric acid was added dropwise. 1.16 g of (8-chromanyloxy) acetonitrile obtained in (1)
A tetrahydrofuran solution (10 ml) of was added dropwise, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution to stop the reaction, an aqueous sodium hydroxide solution was added, and the mixture was extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain 1.16 g of colorless oily 2- (8-chromanyloxy) ethylamine.

Physicochemical properties Mass spectrometric value (EI, m / z): 193 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.6 (2H, br s, NH ₂ ), 1 .8-
2.1 (2H, m, C3'- H 2), 2.79 (2H,
_{t, C4'-H 2),} 3.08 (2H, t, CH 2 N),
4.02,4.24 (4H, t × 2, C2'-H 2, O
_{C H 2 CH 2 N),} 6.6-6.8 (3H, m)

Reference Example 6 (1) 98% chlorosulfuric acid was cooled to -20 ° C., and N- (p
3.0 g ethyl-methoxyphenethyl) carbamate was added in small portions. After stirring for 2 hours while maintaining the temperature below -5 ° C, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 2.52 g of ethyl N- [3- (chlorosulfonyl) -4-methoxyphenethyl] carbamate as a white solid.

Physicochemical properties Mass spectrometric value (EI, m / z): 321 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.22 (3H, t, OCH ₂ CH ₃ ) , 2.82
(2H, t, NCH ₂ CH ₂ Ar), 3.42 (2H,
m, NC H ₂ CH ₂ Ar), 4.04 (3H, s, OCH
_{3), 4.10 (2H, q} , OC H 2 CH 3), 4.64
(1H, brs, NHCO), 7.04 (1H,
d), 7.50 (1H, dd), 7.74 (1H, d)

(2) 8.96 g of ethyl N- [3- (chlorosulfonyl) -4-methoxyphenethyl] carbamate obtained in the above (1) was dissolved in 180 ml of methylene chloride and, under ice cooling, trimethylsilane iodide was added. 28.2 g was gradually added. After stirring at room temperature for 20 hours, saturated sodium hydrogen carbonate solution and then sodium thiosulfate were added to the reaction solution until iodine disappeared. This was extracted with methylene chloride, the obtained organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated, the obtained residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of methylene chloride-methanol (20: 1) to give a colorless oil. This was crystallized from hexane-ethyl acetate to obtain 5.50 g of ethyl 3,3'-dithiobis [N- (4-methoxyphenethyl) carbamate] as a white powder.

Physicochemical properties Mass spectrometry value (EI, m / z): 508 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.21 (6H, t, OCH ₂ CH ₃ ) , 2.70
(4H, t, NCH ₂ CH ₂ Ar), 3.32 (4H,
m, NC H ₂ CH ₂ Ar), 3.87 (6H, s, OCH
_{3), 4.07 (4H, q} , OC H 2 CH 3), 4.76
(2H, brs, NHCO), 6.78 (2H,
d), 7.02 (2H, dd), 7.38 (2H, d)

(3) 3.03 g of ethyl 3,3'-dithiobis [N- (4-methoxyphenethyl) carbamate] obtained in (2) above, 20 ml of benzene, 5 m of methanol
1 was mixed, and tri (n-butyl) phosphine 3.57 g
15 ml of a methanol solution of was added dropwise, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, 40 ml of acetone, 2.4 g of potassium carbonate and 1.5 g of methyl iodide were added to the residue, and the mixture was heated under reflux for 3 hours. The insoluble material was filtered off, the filtrate was concentrated and then dissolved in chloroform, diluted hydrochloric acid, water, 1N sodium hydroxide,
The extract was washed with saturated brine in that order and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of hexane-ethyl acetate (1: 1) to give N- [4-methoxy-3- (methylthio) phenethyl] as a colorless oil. ] 3.08 g of ethyl carbamate was obtained.

Physicochemical properties Mass spectrometric value (EI, m / z): 269 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.23 (3H, t, OCH ₂ CH ₃ ) , 2.42
_{(3H, s, SC H 3} ), 2.75 (2H, t, NCH 2
CH ₂ Ar), 3.40 (2H, m, NC H ₂ CHA
r), 3.87 (3H, s, OCH ₃ ), 4.11 (2
H, q, OC H ₂ CH ₃ ), 4.64 (1H, br s,
NHCO), 6.7-7.1 (3H, m)

(4) 3.08 g of ethyl N- [4-methoxy-3- (methylthio) phenethyl] carbamate obtained in (3) above was mixed with 20 ml of ethanol and 50 ml of 4N potassium hydroxide for 20 hours. Heated to reflux. After cooling, ether was added and the mixture was extracted with 1N hydrochloric acid. The hydrochloric acid layer was neutralized with sodium hydroxide and back-extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off to give colorless oily 4-methoxy-3- (methylthio). ) 1.97 g of phenethylamine were obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.43 (3H, s, SC H ₃ ), 2.71 (2
_{H, t, NCH 2 C H} 2 Ar), 2.94 (2H, br,
NC H ₂ CH ₂ Ar), 3.87 (3H, s, OC
_{H 3), 6.7-7.1 (3H,} m)

Reference Example 7 (1) 5 ', 6', 7 ', 8'-tetrahydro-1'-
Hydroxy-2'-acetonaphthone 2.5 g, dimethyl sulfate 2.5 g, potassium carbonate 3.6 g, acetone 25 m
1 was mixed and heated to reflux overnight. After cooling, insoluble matter is filtered off,
The filtrate was concentrated and then subjected to silica gel column chromatography, and eluted with a mixed solvent of hexane-ethyl acetate (98: 2) to give colorless oils 5 ', 6', 7 ',
2.1 g of 8'-tetrahydro-1'-methoxy-2'-acetonaphthone was obtained.

Physical and chemical properties Mass spectrometric value (EI, m / z): 204 (M⁺) Nuclear magnetic resonance spectrum (CDCl ₃, TMS internal standard
Quasi) δ: 1.7-1.9 (4H, m, C6'-H₂, C
7'-H₂), 2.60 (3H, s, COCH₃), 2.
6-2.9 (4H, m, C5'-H₂, C8'-H₂),
3.72 (3H, s, OCH₃), 6.88 (1H,
d), 7.26 (1H, d)

(2) 5 ', 6'obtained in (1) above,
2.05 g of 7 ', 8'-tetrahydro-1'-methoxy-2'-acetonaphthone was dissolved in 25 ml of toluene,
While cooling with ice, 4.58 g of trifluoroacetic acid and then 3.47 g of m-chloroperbenzoic acid were gradually added. After stirring at 5 ° C. for 60 hours, dilute aqueous ammonia was added, and the mixture was extracted with ether. After distilling off the solvent, 15 ml of methanol and 11 ml of 2N sodium hydroxide were added to the residue, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized by adding dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of hexane-ethyl acetate (95: 5) to give an oily 5,6,7,8-tetrahydro-1-methoxy- 1.61 g of 2-naphthol was obtained.

Physicochemical properties Mass spectrometric value (EI, m / z): 178 (M⁺) Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard
Quasi) δ: 1.7-1.9 (4H, m, C6-H ₂, C7-
H₂), 2.6-2.9 (4H, m, C5-H₂, C8-
H₂), 3.75 (3H, s, OCH₃), 5.65 (1
H, br s, OH), 6.75 (2H, s)

(3) 5,6,7,8-obtained in (2) above
Tetrahydro-1-methoxy-2-naphthol 1.54
g was dissolved in 8 ml of 1,2-dibromoethane, 8 ml of 3N sodium hydroxide aqueous solution and 150 mg of tetrabutylammonium hydrogen sulfate (TBAHS) were added, and 70
The mixture was stirred at 0 ° C for 3 hours. 0.5 g of sodium hydroxide
Was added and stirred for 3 hours, and then sodium hydroxide 0.5 was added.
g was added and the mixture was stirred for 2 hours. After cooling, the reaction mixture was extracted with dichloromethane and dried over anhydrous magnesium sulfate.
After distilling off the solvent, the residue was subjected to silica gel column chromatography and eluted with a mixed solvent of hexane-ethyl acetate (98: 2) to give colorless oily 2- (2-bromoethyl) -5,6,7. Thus, 1.96 g of 8-tetrahydro-1-methoxynaphthalene was obtained.

Physicochemical properties Mass spectrometric value (EI, m / z): 284 (M ⁺ ), 2
86 (M ⁺ +2) Nuclear magnetic resonance spectrum (CDCl _3, TMS internal standard) δ: 1.7-1.9 (4H, m , C6-H 2, C7-
_{H 2), 2.6-2.9 (4H,} m, C5-H 2, C8-
_{H 2), 3.65 (2H,} t, CH 2 Br), 3.84
(3H, s, OCH ₃ ), 4.28 (2H, t, OC H ₂
CH ₂ Br), 6.71 (1H, d), 6.74 (1
H, d)

Reference Example 8 (1) 2- (2-Bromoethyl) -5, obtained in Reference Example 7
0.60 g of 6,7,8-tetrahydro-1-methoxynaphthalene and 2.25 g of benzylamine were dissolved in 6 ml of acetonitrile and heated under reflux for 3 hours. The solvent was evaporated, ether was added to the residue, the insoluble material was filtered off, the filtrate was concentrated and subjected to silica gel column chromatography, and eluted with a mixed solvent of chloroform-methanol (99: 1) to give a colorless oil. N- [2- (5,6,7,8
-Tetrahydro-1-methoxy-2-naphthyloxy)
0.62 g of ethyl] benzylamine was obtained.

Physicochemical properties Mass spectrometric value (EI, m / z): 311 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.7-1.9 (4H, m, C6 ') -H ₂ , C
_{7'-H 2), 1.95 (} 1H, br s, NH),
2.6-2.9 (4H, m, C5'- H 2, C8'-
_{H 2), 3.04 (2H,} t, CH 2 C H 2 N), 3.8
_{0 (3H, s, OCH 3} ), 3.88 (2H, s, benzyl), 4.12 (2H, t, OCH 2), 6.71
(1H, d), 6.74 (1H, d)

(2) N- [2- (5, obtained in (1) above.
0.45 g of 6,7,8-tetrahydro-1-methoxy-2-naphthyloxy) ethyl] benzylamine was dissolved in 10 ml of methanol to obtain 10% palladium-carbon 0.3.
g, 88% formic acid 0.5 ml was added, and the mixture was stirred at room temperature for 6 hours. Palladium carbon was filtered off, the solvent was distilled off, diluted sodium hydroxide was added to the residue, and the mixture was extracted with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was evaporated, and colorless oily 2- (5,6,7,8-tetrahydro-1-methoxy-
0.31 g of 2-naphthyloxy) ethylamine was obtained.

Physicochemical properties Mass spectrometric value (EI, m / z): 221 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.56 (2H, br s, NH ₂ ), 1 .7-
1.9 (4H, m, C6'- H 2, C7'-H 2), 2.
6-2.8 (4H, m, C5'- H 2, C8'-H 2),
3.08 (2H, t, CH ₂ N), 3.82 (3H,
s, OCH ₃ ), 4.00 (2H, t, OC H ₂ CH
₂ N), 6.7-6.8 (2H, m)

Example 1 8- (2-Bromoethoxy) chroman (Compound of Reference Example 1) 400 mg, p-methoxyphenethylamine 470
Dissolve mg in 15 ml of dimethylformamide, 50 ℃
Heated for 20 hours. After the reaction, the solvent was distilled off, ether was added to the residue to remove the insoluble matter, the filtrate was concentrated and subjected to silica gel column chromatography, and eluted with a mixed solvent of chloroform-methanol (100: 3). , 420 mg of a colorless oily free base was obtained. By treating this with hydrogen chloride in ether, N- [2-
290 mg of (8-chromanyloxy) ethyl] -p-methoxyphenethylamine hydrochloride monohydrate was obtained.

Physicochemical properties Melting point 91-93 ° C. Elemental analysis value (as C ₂₀ H ₂₅ NO ₃ .HCl.H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 62.90 7.39 3.67 9.28 Experimental value 63.08 7.19 3.63 9.41 Mass spectrum (FAB, m / z): 328 (M ⁺ +1)
(Free base basis) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 1.88 (2H, m , C3'-H 2), 2.72
(2H, t, C4'-H 2), 3.00 (2H, m, N
_{CH 2 C H 2 Ar),} 3.20 (2H, m, NC H 2 CH 2
Ar), 3.36 (2H, t , OCH 2 C H 2 N), 3.
72 (3H, s, OCH ₃ ), 4.08 (2H, t, C
_{2'-H 2), 4.24 (} 2H, t, OC H 2 CH
₂ N), 6.6-6.8 (3H, m), 6.90 (2
H, d), 7.18 (2H, d), 9.36 (2H, b
r s) In the same manner as in Example 1, the compound of Example 2 was synthesized.

Example 2 N- [2- (8-chromanyloxy) ethyl] -4-methoxy-3- (methylthio) phenethylamine hydrochloride Raw material compound: 8- (2-bromoethoxy) chroman (from Reference Example 1) Compound) and 4-methoxy-3- (methylthio) phenethylamine (Compound of Reference Example 6)

Physicochemical properties Melting point 154-156 ° C. Elemental analysis value (as C ₂₁ H ₂₇ NO ₃ S.HCl) C (%) H (%) N (%) S (%) Cl (%) Theoretical value 61.52 6.88 3.42 7.82 8.65 Experimental value 60.88 6.67 3.38 7.77 8.72 Mass spectrometry value (FAB, m / z): 374 (M ⁺ +1)
(Free base standard) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.90 (2H, dt, C3′-H ₂ ), 2.3
8 (3H, s, SCH ₃ ), 2.73 (2H, t, C
4′-H ₂ ), 2.98 (2H, m, NCH ₂ CH ₂ A
r), 3.1-3.5 (4H, m), 3.79 (3H,
_{s, OCH 3), 4.10 (} 2H, t, C2'-H 2),
4.25 (2H, t, OC H 2 CH 2 N), 6.6-7.
1 (6H, m), 9.24 (2H, br s)

Example 3 390 mg of 8- (2-bromoethoxy) chroman (the compound of Reference Example 1) and 620 mg of tyramine were heated and refluxed in 5 ml of acetonitrile for 2 hours. After cooling, ether was added to the reaction solution to remove insoluble materials, and the filtrate was concentrated and subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform-methanol (97: 3) to give colorless crystals. 340 mg of free base were obtained. This is converted to a fumarate salt in methanol and recrystallized from a mixed solvent of ethanol-water to give 4- [2-[{2- (8-chromanyloxy) ethyl} amino] ethyl] phenol.
180 mg of hemifumarate was obtained.

Physicochemical properties Melting point 189-192 ° C. Elemental analysis value (as C ₁₉ H ₂₃ NO ₃ .0.5C ₄ H ₄ O ₄ ) C (%) H (%) N (%) Theoretical value 67.916 0.78 3.77 Experimental value 67.61 6.89 3.70 Mass spectrum value (FAB, m / z): 314 (M ⁺ +1)
(Free base basis) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 1.89 (2H, m , C3'-H 2), 2.72
(2H, t, C4'-H 2), 2.8-3.2 (6H,
m), 3.5-5.0 (brs), 4.04, 4.1
0 (4H, t × 2, C2'-H 2, OC H 2 CH 2 N),
6.50 (1H, s, CH = CH), 6.6-6.8
(3H, m), 6.74 (2H, d), 7.01 (2
H, d)

Example 4 8- (2-Bromoethoxy) chroman (Compound of Reference Example 1) 260 mg, p-methylphenethylamine 270 m
g was dissolved in 3 ml of acetonitrile, and potassium carbonate 14
0 mg was added, and the mixture was heated under reflux for 4 hours. After cooling, ether was added to the reaction solution, the resulting insoluble material was filtered off, the filtrate was concentrated and subjected to silica gel column chromatography, and eluted with a mixed solvent of chloroform-methanol (99: 1) to give a pale yellow oil. 181 mg of free base were obtained. Crude crystals were obtained by treating this with hydrogen chloride in ether and recrystallized from acetonitrile to give N- [2-
155 mg of (8-chromanyloxy) ethyl] -p-methylphenethylamine hydrochloride monohydrate was obtained.

Physicochemical properties Melting point 91-93 ° C. Elemental analysis value (as C ₂₀ H ₂₅ NO ₂ .HCl.H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 65.65 7.71 3.83 9.69 Experimental value 66.07 7.64 3.89 9.88 Mass spectrum (EI, m / z): 309 (M ⁺ ) (based on free base) Nuclear magnetic resonance spectrum (DMSO) -d _6, TMS internal standard) δ: 1.89 (2H, m , C3'-H 2), 2.28
(3H, s, ArCH ₃ ), 2.73 (2H, t, C
_{4'-H 2), 2.8-3.5 (} 6H, m), 4.10
(2H, t, C2'-H 2), 4.21 (2H, t, O
_{C H 2 CH 2 N),} 6.7-6.9 (3H, m), 7.1
5 (4H, s), 9.47 (2H, br s) By the same method as in Example 4, the compounds of the following Examples 5 to 8 were synthesized.

Example 5 N- [2-{(2,3-dihydro-7-benzofuranyl) oxy} ethyl] -p-methoxyphenethylamine hydrochloride 0.5 hydrate Raw material compound: 7- (2-bromoethoxy ) -2,3-Dihydrobenzofuran (Reference Example 2) and p-methoxyphenethylamine

Physicochemical properties Melting point 124-126 ° C. Elemental analysis value (as C ₁₉ H ₂₃ NO ₃ .HCl.0.5H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 63 0.59 7.02 3.90 9.88 experimental value 63.32 6.89 3.88 9.86 mass spectrometry value (EI, m / z): 314 (M ⁺ +1)
(Free base standard) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.8-3.5 (6H, m), 3.18 (2H,
_{t, C3'-H 2),} 3.74 (3H, s, OCH 3),
4.34 (2H, t, OC H ₂ CH ₂ N), 4.53 (2
_{H, t, C2'-H 2} ), 6.8-7.0 (3H,
m), 6.90 (2H, d), 7.18 (2H, d),
9.46 (2H, br s)

Example 6 N- [2-{(2,3-dihydro-2,2-dimethyl-
7-Benzofuranyl) oxy} ethyl] -p-methoxyphenethylamine hydrochloride 0.25 hydrate Raw material compound: 7- (2-bromoethoxy) -2,3-dihydro-2,2-dimethylbenzofuran (Reference Example 3)
And p-methoxyphenethylamine

Physicochemical properties Melting point 115-116 ° C. Elemental analysis value (as C ₂₁ H ₂₇ NO ₃ .HCl.0.25H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 65 .96 7.51 3.66 9.27 experimental value 66.17 7.72 3.66 9.30 mass spectrometry value (FAB, m / z): 342 (M ⁺ +1)
(Free base standard) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.40 (6H, s, CH ₃ × 2), 2.8-
3.3 (4H, m, NCH ₂ CH ₂ Ar), 3.00 (2
_{H, s, C3'-H 2} ), 3.36 (2H, t, OCH 2
C H ₂ N), 3.73 (3H, s, OCH ₃ ), 4.32
(2H, t, OC H ₂ CH ₂ N), 6.7-6.9 (3
H, m), 7.06 (2H, d), 7.31 (2H,
d), 9.42 (2H, br s)

Example 7 N- [2-{(2,3-dihydro-2,2-dimethyl-
7-Benzofuranyl) oxy} ethyl] -p-methylphenethylamine hydrochloride Raw material compound: 7- (2-bromoethoxy) -2,3-dihydro-2,2-dimethylbenzofuran (Reference Example 3)
And p-methylphenethylamine

Physicochemical properties Melting point 132-134 ° C. Elemental analysis value (as C ₂₁ H ₂₇ NO ₂ .HCl) C (%) H (%) N (%) Cl (%) Theoretical value 69.69 7.80 3 .87 9.80 experimental value 69.33 7.83 3.86 9.91 mass spectrometry value (FAB, m / z): 326 (M ⁺ +1)
(Free base standard) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.40 (6H, s, CH ₃ × 2), 2.29.
_{(3H, s, ArCH 3)} , 2.6-3.2 (4H,
m, NCH ₂ CH ₂ Ar), 3.00 (2H, s, C3 ′)
_{-H 2), 3.37 (2H,} t, OCH 2 C H 2 N),
4.30 (2H, t, OC H 2 CH 2 N), 6.6-6.
95 (3H, m), 7.14 (4H, s), 9.20
(2H, br s)

Example 8 N- [2- (8-Chromanyloxy) ethyl] -p-methoxy-α-methylphenethylamine hydrochloride 0.5
Hydrate Raw material compound: 8- (2-bromoethoxy) chroman (Reference Example 1) and p-methoxy-α-methylphenethylamine

Physicochemical properties Melting point 109-110 ° C. Elemental analysis value (as C ₂₁ H ₂₇ NO ₃ .HCl.0.5H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 65 .19 7.55 3.62 9.16 Experimental value 65.34 7.49 3.59 9.40 Mass spectrum value (FAB, m / z): 342 (M ⁺ +1)
(Free base standard) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.14 (3H, d, α-CH ₃ ), 1.91
(2H, m, C3'-H 2), 2.74 (2H, t, C
_{4'-H 2), 3.1-3.7 (} 5H, m, CH 2 NCH
CH ₂ Ar), 3.74 (3H, s, OCH ₃ ), 4.1
3 (2H, t, C2'- H 2), 4.29 (2H, t,
OC H ₂ CH ₂ N), 6.6-6.8 (3H, m), 6.
90 (2H, d), 7.19 (2H, d), 9.28
(2H, br s)

Example 9 (8-chromanyloxy) acetone (Compound of Reference Example 4) 350 mg, p-methoxyphenethylamine 260
mg was refluxed in methanol for 1 hour. To this was added 97 mg of sodium borohydride under ice cooling, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction solution, extracted with diluted hydrochloric acid,
The hydrochloric acid layer was neutralized and extracted with ether. The organic layer was concentrated, subjected to silica gel column chromatography, and eluted with a mixed solvent of chloroform-methanol (99: 1) to obtain 156 mg of a free base. Crude crystals were obtained by treating this with hydrogen chloride in ether and then recrystallized from acetonitrile to give N- [2- (8-chromanyloxy) -1-methylethyl] -p-methoxyphenethylamine hydrochloride. 115 mg was obtained.

Physicochemical properties Melting point 147-148 ° C. Elemental analysis value (as C ₂₁ H ₂₇ NO ₃ .HCl) C (%) H (%) N (%) Cl (%) Theoretical value 66.74 7.473 .71 9.38 experimental value 66.55 7.58 3.73 9.41 mass spectrum value (FAB, m / z): 342 (M ⁺ +1)
(Free base standard) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.36 (3H, d, NCHC H ₃ ), 1.89
(2H, m, C3'-H 2), 2.73 (2H, t, C
_{4'-H 2), 2.9-3.6 (} 5H, m, CHNCH 2
CH ₂ Ar), 3.74 (3H, s, OCH ₃ ), 4.0
6 (2H, d, OC H ₂ CHN), 4.13 (2H,
_{t, C2'-H 2),} 6.7-6.9 (3H, m),
6.90 (2H, d), 7.20 (2H, d), 9.1
8 (2H, br s)

Example 10 (1) 3- (p-methoxyphenyl) propionic acid 31
0 mg was dissolved in 3 ml of methylene chloride, 240 mg of oxalyl chloride and 1 drop of dimethylformamide were added, the mixture was stirred at room temperature for 1 hour, and the reaction solution was concentrated to give the corresponding acid chloride. Separately, 2- (8-chromanyloxy)
300 mg of ethylamine (the compound of Reference Example 5) and 190 mg of triethylamine were dissolved in 4 ml of methylene chloride, and the methylene chloride solution of the acid chloride prepared above (2
(ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with dilute hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give N- [2- (8-chromanyloxy) ethyl]-as a white solid. 560 mg of 3- (p-methoxyphenyl) propionamide was obtained.

Physicochemical properties Mass spectrometric value (FAB, m / z): 356 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.89 (2H, m, C3′-H _2). ), 2.46
(2H, m, COCH ₂ CH ₂ Ar), 2.79 (2H,
_{t, C4'-H 2),} 2.89 (2H, m, COCH 2 C
H ₂ Ar), 3.64 (2H, m, CH ₂ NH), 3.7
4 (3H, s, OCH ₃ ), 4.03, 4.22 (4
H, t × 2, OC H 2 CH 2 N, C2'-H 2), 6.1
9 (1H, br t, NHCO), 6.7-6.9 (3
H, m), 6.82 (2H, d), 7.11 (2H,
d)

(2) N- [2- (8-
Chromanyloxy) ethyl] -3- (p-methoxyphenyl) propionamide (550 mg) was added to borane-tetrahydrofuran complex (1M tetrahydrofuran solution) 4.6.
After adding ml, the mixture was stirred at room temperature for 2.5 days, 0.5 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 30 minutes. The solvent was distilled off, an aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with ether. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, evaporated to remove the solvent, and subjected to silica gel column chromatography. Elution with a mixed solvent of chloroform-methanol (99: 1) gave 280 mg of an oily free base. 260 mg of this was converted to fumarate and recrystallized from acetonitrile to give N- [2- (8-chromanyloxy) ethyl] -3.
258 mg of-(p-methoxyphenyl) propylamine hemifumarate was obtained.

Physicochemical properties Melting point 108-109 ° C. Elemental analysis value (as C ₂₁ H ₂₇ NO ₃ .0.5C ₄ H ₄ O ₄ ) C (%) H (%) N (%) Theoretical value 69.157 .32 3.51 Experimental value 69.05 7.28 3.48 Mass spectrum value (EI, m / z): 341 (M ⁺ ) (based on free base) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) ) Δ: 1.6-2.0 (4H, m, C3′-H ₂ , NH
_{CH 2 C H 2 CH 2 Ar} ), 2.5-2.9 (4H, m,
_{NHC H 2 CH 2 C H 2} Ar), 2.72 (2H, t, C
_{4'-H 2), 3.02 (} 2H, t, OCH 2 C H
₂ N), 3.71 (3H, s, OCH ₂ ), 4.06
4.12 (4H, t × 2, C2'-H 2, OC H 2 CH 2
N), 6.45 (1H, s, CH = CH), 6.6-
6.8 (3H, m), 6.86 (2H, d), 7.12
(2H, d)

Example 11 (1) In the same manner as in Example 10, N- [2- (8-chromanyl) was prepared from 4- (p-methoxyphenyl) butyric acid and 2- (8-chromanyloxy) ethylamine. Oxy)
Ethyl] -4- (p-methoxyphenyl) butyric acid amide was obtained.

Physicochemical properties Mass spectrometry value (EI, m / z): 369 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.8-2.3 (6H, m, C3 ′) -H2, CH
₂ CH ₂ Ar), 2.59 (2H, t, COCH ₂ ),
2.78 (2H, t, C4'- H 2), 3.60 (2
H, m, C H ₂ NH), 3.77 (3H, s, OC
H ₃ ), 4.07, 4.18 (4H, t × 2, OC H ₂ C
_{H 2 N, C2'-H 2} ), 6.23 (1H, br t, N
HCO), 6.6-6.9 (3H, m), 6.78 (2
H, d), 7.06 (2H, d)

(2) N- [2- (8-
Chromanyloxy) ethyl] -4- (p-methoxyphenyl) butyric acid amide was treated as in Example 10 and recrystallized from isopropanol to give N- [2- (8-chromanyloxy) ethyl] -4. -(P-Methoxyphenyl) butylamine hemifumarate was obtained.

Physicochemical properties Melting point 123-125 ° C. Elemental analysis value (as C ₂₂ H ₂₉ NO ₃ .0.5C ₄ H ₄ O ₄ ) C (%) H (%) N (%) Theoretical value 69.717 .56 3.39 Experimental value 69.27 7.44 3.31 Mass spectrum value (EI, m / z): 355 (M ⁺ ) (based on free base) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) ) δ: 1.54 (4H, m , C H 2 C H 2 CH 2 Ar),
1.88 (2H, m, C3'- H 2), 2.5-2.9
_{(6H, m, NC H 2} CH 2 CH 2 C H 2 Ar, C4'-H
_{2), 3.02 (2H, t} , OCH 2 C H 2 N), 3.7
_{1 (3H, s, OCH 3} ), 4.0-4.2 (4H,
m, C2′-H2, OC H ₂ CH ₂ N), 6.44 (1
H, s, CH = CH), 6.6-6.8 (3H, m),
6.85 (2H, d), 7.12 (2H, d)

Example 12 2- (2-Bromoethyl) -1-methoxy-5,6
7,8-Tetrahydronaphthalene (Compound of Reference Example 7)
0.40 g, p-methoxyphenethylamine 0.64
g and 5 ml of acetonitrile were mixed, and the mixture was heated under reflux for 3 hours. After cooling, ether was added and the precipitated crystals were filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform-methanol (99: 1) to give 0.44 g of a colorless oily free base. This was treated with hydrogen chloride in ethyl acetate, and the resulting crystals were collected by filtration and washed with ethyl acetate to give p-methoxy-N- [2- (1-methoxy-5,6,7,8-tetrahydro- 2-Naphthyloxy) ethyl] phenethylamine hydrochloride 0.5 hydrate 0.46 g was obtained.

Physicochemical properties Melting point 165-170 ° C. Elemental analysis value (as C ₂₂ H ₂₉ NO ₃ .HCl.0.5H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 65 .90 7.79 3.49 8.84 Experimental value 66.04 7.76 3.49 9.21 Mass spectrum (FAB, m / z): 356 (M ⁺ +1)
(Free base basis) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 1.6-1.9 (4H, m , C6'-H 2, C
_{7'-H 2), 2.5-2.8 (} 4H, m, C5'-
_{H 2, C8'-H 2)} , 2.9-3.4 (6H, m, CH
₂ NCH ₂ CH ₂ Ar), 3.70 (3H, s, OC
H ₃ ), 3.75 (3H, s, OCH ₃ ), 4.32 (2
_{H, t, OCH 2),} 6.7-7.3 (6H, m),
9.6 (2H, br s) In the same manner as in Example 12, the following compounds of Examples 13 and 14 were obtained.

Example 13 4-Methoxy-N- [2- (1-methoxy-5,6,6
7,8-Tetrahydro-2-naphthyloxy) ethyl]
-3- (methylthio) phenethylamine hydrochloride 0.2
Pentahydrate Raw material compound: 2- (2-bromoethyl) -1-methoxy-5,6,7,8-tetrahydronaphthalene (Reference Example 7)
Compound) and 4-methoxy-3- (methylthio) phenethylamine (compound of Reference Example 6)

Physicochemical properties Melting point 133 ° C. Elemental analysis value (as C ₂₂ H ₃₁ NO ₃ S.HCl.0.25H ₂ O) C (%) H (%) N (%) Cl (%) S (%) Theoretical value 62.43 7.40 3.17 8.01 7.25 Experimental value 62.41 7.13 3.11 8.17 7.41 Mass spectrometry value (FAB, m / z): 402 (M ⁺ +1)
(Free base standard) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.6-1.9 (4H, m, C6′-H ₂ , C
_{7'-H 2), 2.41 (} 3H, s, SCH 3), 2.5
-2.8 (4H, m, C5'- H 2, C8'-H 2),
_{3.1-3.6 (6H, m, CH 2} NCH 2 CH 2 A
r), 3.64 (3H, s, OCH ₃ ), 3.86 (3
H, s, OCH ₃ ), 4.42 (2H, br t, OC
H ₂ ), 6.7-7.1 (5H, m), 9.9 (2
H, br s)

Example 14 N- [2- (1-methoxy-5,6,7,8-tetrahydro-2-naphthyloxy) ethyl] -p-methylphenethylamine hydrochloride 0.5 hydrate Raw material compound: 2 -(2-Bromoethyl) -1-methoxy-5,6,7,8-tetrahydronaphthalene (Reference Example 7)
Compound) and p-methylphenethylamine

Physicochemical properties Melting point 170-173 ° C. Elemental analysis value (as C ₂₂ H ₂₉ NO ₂ .HCl.0.5H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 68 .64 8.12 3.64 9.21 experimental value 68.69 8.12 3.63 9.48 mass spectrometry value (FAB, m / z): 340 (M ⁺ +1)
(Free base standard) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.6-1.9 (4H, m, C6′-H ₂ , C
_{7'-H 2), 2.30 (} 3H, s, CH3), 2.5
-2.8 (4H, m, C5'- H 2, C8'-H 2),
_{3.1-3.6 (6H, m, CH 2} NCH 2 CH 2 A
r), 3.63 (3H, s, OCH ₃ ), 4.42 (2
H, t, OCH ₂ ), 6.74 (2H, s) 7.11
(4H, m), 9.8 (2H, br s)

Example 15 (1) 2- (1-Methoxy-5,6,7,8-tetrahydro-2-naphthyloxy) ethylamine (Compound of Reference Example 8) 280 mg, 4- (p-methoxyphenyl) butyric acid 245 mg was dissolved in 5 ml of dimethylformamide,
Under ice-cooling, 384 mg of diphenylphosphoric acid azide and then 140 mg of triethylamine were gradually added. 18 at room temperature
After stirring for 25 hours, the reaction mixture contains 25m each of ethyl acetate and toluene.
1 was added thereto, washed with diluted hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and saturated saline in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 4- (p-methoxyphenyl) as a colorless solid.
-N- [2- (1-methoxy-5,6,7,8-tetrahydro-2-naphthyloxy) ethyl] butanamide 4
80 mg was obtained.

Physicochemical properties Mass spectrometric value (FAB, m / z): 398 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.7-2.6 (10H, m), 2.6-2.9
(4H, m), 3.6-3.8 (2H, m, OCH ₂ C
H ₂ N), 3.77 (6H, s, OCH ₃ × 2), 4.0
_{-4.2 (2H, m, OCH 2} ), 6.1 (1H, br
s, NHCO), 6.6-7.2 (6H, m)

(2) 4- (p-methoxyphenyl) -N- [2- (1-methoxy-5,6,6 obtained in the above (1).
7,8-Tetrahydro-2-naphthyloxy) ethyl]
3.5 ml of borane-tetrahydrofuran (1 molar tetrahydrofuran solution) was added to 460 mg of butanamide, and the mixture was heated under reflux for 4 hours. After cooling to room temperature, 0.5 ml each of methanol and concentrated hydrochloric acid was added, and the mixture was further refluxed for 30 minutes. Aqueous sodium hydroxide solution was added to the reaction solution to make it alkaline, which was extracted with ether. The ether layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Crude crystals were obtained by treating this ether solution with hydrogen chloride, and recrystallized from acetonitrile-ether to give crude crystals.
4- (p-methoxyphenyl) -N- [2- (1-methoxy-5,6,7,8-tetrahydro-2-naphthyloxy) ethyl] butylamine hydrochloride 0.5 hydrate
380 mg was obtained.

Physicochemical properties Melting point 120-123 ° C. Elemental analysis value (as C ₂₄ H ₃₃ NO ₃ .HCl.0.5H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 67 .19 8.22 3.26 8.26 Experimental value 67.37 8.24 3.29 8.49 Mass spectrum (EI, m / z): 383 (M ⁺ ) (based on free base) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.5-2.2 (8H, m), 2.4-2.9
(6H, m), 2.9-3.5 (4H, m), 3.74
(3H, s, OCH ₃ ), 3.76 (3H, s, OC
_{H 3), 4.3-4.5 (2H,} m, OCH 2), 6.7
-7.2 (6H, m), 9.7 (2H, br s) Tables 3 to 7 below show the chemical structural formulas of the compounds obtained in the above Reference Examples and Examples.

[0104]

[Table 3]

[0105]

[Table 4]

[0106]

[Table 5]

[0107]

[Table 6]

[0108]

[Table 7]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical indication location A61K 31/34 AAM 7252-4C 31/35 AAH 7252-4C ACV 7252-4C C07D 307/79 311 / 64 6701-4C 313/08 6701-4C 313/20 6701-4C (72) Inventor Tokio Yamaguchi 6-16-3 Ryoke, Urawa-shi, Saitama City Core 402 (72) Inventor Fumikazu Wanibuchi 2 Kasuga, Tsukuba, Ibaraki Prefecture −35-2 Etoile Kasuga 303

Claims (4)

[Claims] 1. A novel aryloxyalkylamine derivative represented by the following general formula (I) or a salt thereof. [Chemical 1] (In the formula, A is the following general formula (II): R ¹ , R ² , R ⁵ and R ⁶ are the same or different, and a hydrogen atom or a lower alkyl group, and R ³ and R ⁴ are the same or different, a hydrogen atom, a lower alkyl group or a lower alkoxy group. A group, a lower alkylthio group or a hydroxy group (provided that R is
Except when both ³ and R ⁴ are hydrogen atoms. ), R
⁷ is a lower alkoxy group, n is an integer of 1 to 5, and m is an integer of 1 to 4, respectively. ) 2. N- [2- (8-chromanyloxy) ethyl] -p-methoxyphenethylamine or an acid addition salt thereof. 3. N- [2- (8-chromanyloxy) ethyl] -4- (p-methoxyphenyl) butylamine or an acid addition salt thereof. 4. p-Methoxy-N- [2- (1-methoxy-5,6,7,8-tetrahydro-2-naphthyloxy) ethyl] phenethylamine or an acid addition salt thereof.