JP2931190B2 - 2,3-dihydrobenzofuran derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel 2,3-dihydrobenzofuran derivative or a salt thereof, a method for producing them, and a pharmaceutical composition containing them.

[0002]

BACKGROUND OF THE INVENTION During the last few years, the neurotransmitter serotonin (5-hydroxytryptamine (5-HT)) has been associated with appetite, memory, thermoregulation, sleep, sexual behavior, anxiety, depression, stress and other physiology. It has been found to be related to the phenomenon (Glennon, RA, J. Me.
d. Chem. , 30, 1 (1987))).

[0003] Of the receptors on which serotonin acts, 5
A compound acting on an HT1A receptor is an anxiolytic,
It is known that it is useful as an antidepressant, an anorexia ameliorating agent, a blood pressure lowering agent, an antiemetic (including an anti-motion sickness agent, an anti-sickness agent, an anti-vertigo agent, a drug-induced emesis inhibitor, etc.). Many reports have already been made on these compounds (Japanese clinical study, vol. 47, extra number 1989, No. 1241-
1248; P. Feignev, W.C. F. Bo
yer, Psychopathology, 22, 21
(1989); R. Saxena, C.A. M. Vil
lalon, Tips, 11, 95 (1990);
Matsuki et al. , Jpa. J. Phar
macol, Suppl. , 58, 313 (1992).
etc).

[0004]

However, it has been desired to broadly search for and find a compound having the above-mentioned excellent pharmacological action and to provide the compound.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, synthesized various compounds, and examined their pharmacological actions. The inventors have found that a 2,3-dihydrobenzofuran derivative has a high affinity for 5-HT1A receptor on which serotonin acts and an excellent pharmacological action, thereby completing the present invention.

That is, the present invention provides the following formula (1)

[0007]

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Wherein R 1 is a hydrogen atom or a lower alkyl group; n is an integer from 2 to 6; A is CO or S
R2 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group or a cyano group which may be substituted by a halogen atom; * represents an asymmetric carbon; A) a 2,3-dihydrobenzofuran derivative or a salt thereof, and a method for producing the same.

Another object of the present invention is to provide a therapeutic agent for a serotonin nervous system-related disease, comprising a 2,3-dihydrobenzofuran derivative represented by the above formula (1) or a salt thereof as an active ingredient. is there. In the present invention, a lower alkyl group refers to an alkyl group which may be branched from C1 to C4, and specifically, methyl, ethyl,
Represents a group such as propyl, butyl, isopropyl, isobutyl, sec-butyl and tert-butyl.

[0010] In the present invention, the lower alkoxy group means an alkoxy group which may be branched from C1 to C4, and specifically, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, isobutoxy, Represents a group such as butoxy and tert-butoxy. The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

The lower alkyl group which may be substituted with a halogen atom means the above-mentioned lower alkyl group and a group in which some or all of the hydrogen atoms in the lower alkyl group are substituted with halogen atoms. When there are a plurality of atoms, they may be the same or different halogen atoms, and their positions are not particularly limited.
Specific examples include a trifluoromethyl group, a difluoromethyl group, a methyl group, an ethyl group, a tert-butyl group, and the like.

The 2,3-dihydrobenzofuran derivative of the present invention or a salt thereof can be prepared by the following reaction route. That is, equation (2)

[0013]

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(Wherein * and n have the same meanings as described above, and R11 represents an amino-protecting group or a lower alkyl group);

[0015]

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(Wherein, R2 and A have the same meanings as described above, and X represents a leaving group).

[0017]

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(Wherein R11, R2, A, * and n have the same meanings as described above).
When 11 is a protecting group for an amino group, the protecting group may be eliminated to produce a 2,3-dihydrobenzofuran derivative represented by the formula (1) of the present invention. If necessary, when a compound in which R1 in the formula (1) is a lower alkyl group is obtained from a compound in which R1 in the formula (1) is a hydrogen atom, a lower alkyl group is introduced with an alkylating reagent described later. Steps may be added.

The protecting group for the amino group in R11 is such that the amino group having R11 is protected from side reaction during the reaction with the compound of the formula (3), and if necessary, the desired product Any group can be used as long as it is a group that can be easily removed under conditions that do not cause an unnecessary reaction. These groups may be referred to a conventionally known document (Green)
Written by Protective Groups in Organic Synthesis
in organic synthesis) 1981
Year Chapter 7, Green, Wut
s), Protective Groups in Organic Synthesis (Protectivegroups)
in organic synthesis), 2nd edition, 1991, Chapter 7, etc.). Specific examples of the protecting group include, for example, a t-butoxycarbonyl group (Boc
Group), benzyloxycarbonyl group (Cbz group), 9-
Examples include a fluorenyloxycarbonyl group (Fmoc group), an ethoxycarbonyl group, a methoxycarbonyl group, an acetyl group, and a benzyl group.

The preparation of the compound of formula (2) is as described below. On the other hand, the leaving group X in the compound of the formula (3)
In the reaction of the compound of the formula (2) with the compound of the formula (3) to give a compound of the formula (4), the compound is a group which is eliminated from the compound of the formula (3) before and after the reaction, A chlorine atom, a bromine atom or the like, a highly reactive leaving group such as a group constituting a symmetric acid anhydride, or an OH group in some cases, may be an OH group. It is usually preferred to use them in combination.

The compound of the formula (3) is a known compound such as benzoyl chloride, benzoyl bromide, benzenesulfonyl chloride, benzoic anhydride, o-methylbenzoyl chloride, p-butylbenzoyl chloride, o-methoxybenzoyl. Chloride,
m-methoxybenzoyl chloride, p-methoxybenzoyl chloride, o-chlorobenzoyl chloride, o-bromobenzoyl chloride, o-fluorobenzoyl chloride, o-trifluoromethylbenzoyl chloride, p
-Trifluoromethylbenzoyl chloride, o-nitrobenzoyl chloride, m-cyanobenzoyl chloride,
Examples include p-methoxybenzenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, and the like.For example, they are commercially available from Tokyo Chemical Industry Co., Ltd. It is simple.

The reaction between the compound of the formula (2) and the compound of the formula (3) can be carried out by using a conventionally known amidation technique. Typically, the compound of the formula (2) and the compound of the formula (3) may be reacted in an inert medium. Examples of the inert medium include chloroform, methylene chloride, diethyl ether, tetrahydrofuran and the like. No. The compound of formula (3) is usually added to the compound of formula (2) in an amount of 0.1
10 to 10 equivalents, particularly preferably 1 to 2 equivalents, may be used.
The inert medium may be selected in an appropriate amount, but is determined by the formula (2)
5 to 100-fold doses of the compound are exemplified. The reaction is
Typically, it can be performed at around room temperature. The end of the reaction can be known from the disappearance of the raw materials, but is usually completed in 1 hour to 3 days.

In the reaction of the compound of the formula (2) with the compound of the formula (3), it is more preferred that a base is present, and the base may also serve as the inert medium. As the base, triethylamine, pyridine,
Examples thereof include organic bases such as 4-methylmorpholine, and inorganic bases such as potassium carbonate, sodium carbonate, and sodium hydrogen carbonate. The amount of the base to be used is usually preferably equivalent to the acid derivative of the formula (3) or a small excess of about 1.5 equivalents.

When X of the compound of the formula (3) is OH, it is preferable to use an acid activator in the reaction with the compound of the formula (2).
In addition to isobutyl chloroformate, ethyl chloroformate, methyl chloroformate, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, N-hydroxysuccinimide, N-hydroxybenzotriazole and the like can be mentioned. .

For example, when chloroformates such as isobutyl chloroformate, ethyl chloroformate and methyl chloroformate are used as the acid activator, activation of benzoic acid, p-methoxybenzoic acid and the like is performed. A compound of formula (3), which is a required acid, and isobutyl chloroformate, ethyl chloroformate,
The compound of formula (3) can be activated by reacting it with a chloroformate such as methyl chloroformate in an inert medium, usually in the presence of a base. Examples of the base include organic bases such as triethylamine, pyridine and 4-methylmorpholine, and inorganic bases such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate. The base may also serve as an inert medium.
The acid activating agent used in the reaction is reacted with 1 to 5 equivalents, particularly preferably 1 to 1.5 equivalents, of the compound of the formula (3). The amount of the base used in the reaction is 1 to 2 equivalents, particularly preferably 1 to 1.5 equivalents, of the above-mentioned acid activator. As described above, the inert medium can be used as long as it is an inert medium in the reaction. The amount of the inert medium may be appropriately selected, and a dose of 5 to 100 times the acid used in the reaction is exemplified. The reaction can be typically performed at around room temperature, but is particularly preferably performed at a low temperature of about -25 ° C to about 5 ° C. The completion of the reaction can be known by disappearance of the raw materials, but is usually completed in 15 minutes to 2 hours. The acid derivative activated by the acid activator may or may not be taken out of the reaction system, but can usually be used as it is in the reaction with the compound of the formula (2) without being taken out.

Thus, the compound of the formula (4) is obtained, and when R11 of the compound of the formula (4) is a protecting group for an amino group, further elimination is required. The compound of formula (4) may or may not be purified from the reaction product, but is preferably purified by a known purification method such as column chromatography using a carrier such as silica gel.
The elimination of the protecting group depends on the group selected as the protecting group,
A known appropriate method may be selected. For example, when the protecting group is a t-butoxycarbonyl group (Boc group) or the like, the protecting group is deprotected by contact with an acid such as hydrochloric acid, sulfuric acid, or trifluoroacetic acid. You. The amount of acid used is usually 1
The dose may be equal to or more than the equivalent, but preferably, a dose of 1 to 100 equivalents is exemplified. At this time, the acid can be used after being diluted with a solvent. Examples of the solvent to be diluted include chloroform, methylene chloride, diethyl ether, tetrahydrofuran, methanol, water, and the like. The reaction can typically be carried out at a temperature from -25C to 40C, particularly preferably around 0C. The end of the reaction can be known from the disappearance of the raw materials, or can be stopped when a large amount of the target substance is formed, but is usually completed in 1 hour to 24 hours.

When the protecting group is a benzyloxycarbonyl group (Cbz group), a benzyl group, or the like, the protective group is deprotected by contact with hydrogen gas in the presence of a catalyst such as palladium black, palladium-activated carbon, or platinum oxide. Is done.
At this time, examples of the solvent to be used include diethyl ether, tetrahydrofuran, methanol, ethyl acetate, dimethylformamide, water and the like. The reaction can be carried out typically under cooling to heating conditions, particularly preferably at around room temperature. The end of the reaction can be known by the disappearance of the raw materials, or can be stopped when a large amount of the target product is formed.
Ends in days.

When the protecting group is a benzyloxycarbonyl group (Cbz group) or the like, the protecting group is removed with an acetic acid solution of hydrobromic acid or a trifluoroacetic acid solution, aluminum chloride, boron tribromide or the like. Protected. The amount of the acid used is usually 1 equivalent or more, preferably,
A dose of 1-100 equivalents is exemplified. At this time, the acid can be used after being diluted with a solvent. As a solvent to be diluted, chloroform, methylene chloride, diethyl ether,
Tetrahydrofuran and the like can be mentioned as examples. Further, it is preferable that anisole, thioanisole and the like coexist as a scavenger for benzyl cation generated during the reaction in the reaction solution. The amount of the scavenger to be used is usually 1 equivalent or more, but preferably a dose of 1 to 100 equivalents is exemplified. The reaction is typically carried out under cooling to heating conditions, particularly preferably at 0 ° C.
It can be carried out at a temperature from about ° C to about room temperature. The end of the reaction can be known by the disappearance of the raw materials, or can be stopped when a large amount of the target product is formed.
Ends in days.

When the protecting group is a 9-fluorenyloxycarbonyl group (Fmoc group), an ethoxycarbonyl group, a methoxycarbonyl group, an acetyl group or the like, an organic base such as morpholine or the like; Deprotected by inorganic base. Thus, a compound of the formula (1) wherein R1 is a hydrogen atom is obtained. Further, when a compound in which R1 is a lower alkyl group is obtained from this compound, the compound in which R1 in Formula (1) is a hydrogen atom is introduced into a lower alkyl group by an alkylating reagent described later to obtain a compound represented by Formula (1). R
Compounds in which 1 is a lower alkyl group can also be formed.

On the other hand, the compound of the formula (2) is prepared, for example, by the following method. That is, equation (5)

[0031]

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(Wherein R11 and n have the same meanings as described above) can be prepared by reduction. That is, a catalytic amount for the compound of the formula (5),
Typically, 1% to 20% by weight, particularly preferably 5% to 10% by weight, of palladium-activated carbon of the compound of formula (5) is used and hydrogen gas is added. Palladium-
As the activated carbon, commercially available palladium-activated carbon can be used. Typically, 5% palladium-activated carbon or 10% palladium-activated carbon is used. As another method, reduction can be performed using lithium aluminum hydride, sodium borohydride, or the like. The reduction reaction may be generally performed in an inert medium, and any inert medium may be used as long as it is inert to the reaction. For example, dimethylformamide, dimethylacetamide, diethyl ether, tetrahydrofuran, methanol, ethanol, water, etc. Can be used. The amount of the inert medium may be appropriately selected.
A 00-fold dose is exemplified. The reaction may be usually carried out under cooling or heating conditions, and particularly preferably at around room temperature. The reaction time can be determined by the disappearance of the starting material.
Ends by days. In R11 of the compound of the formula (5), depending on the kind of the protecting group for the amino group, the elimination reaction occurs during the above-mentioned reduction. Therefore, a protecting group that does not cause the elimination reaction is selected or the protecting group is introduced again. do it.

Further, the compound of the formula (5) is, for example, a compound of the formula (6)

[0034]

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(Wherein, R11 and n have the same meanings as described above, and X1 represents a leaving group). The leaving group X1 means a group which is substituted with an azide group with an azide reagent, for example, a halogen atom such as a chlorine atom or a bromine atom or a methanesulfonyloxy group, a p-toluenesulfonyloxy group Is exemplified.

Examples of the azide reagent include sodium azide and lithium azide. The azide reagent may be used in an amount of 1 to 10 equivalents, particularly preferably 1 to 3 equivalents, based on the compound of the formula (6). The reaction may be carried out usually in an inert medium, and the inert medium may be any as long as it is inert to the reaction. Examples thereof include dimethylformamide, dimethylacetamide, diethyl ether, tetrahydrofuran, chloroform, and methylene chloride. However, dimethylformamide gives good results. The amount of the inert medium may be appropriately selected, and the amount of the inert medium is represented by the formula (6).
5 to 100-fold doses of the compound are exemplified. The reaction is
Usually, it may be carried out under cooling conditions or heating conditions, particularly preferably under heating conditions. The reaction time can be determined by the disappearance of the starting material.
Completed by hours to 24 hours.

When X1 in the formula (6) is a methanesulfonyloxy group, a p-toluenesulfonyloxy group or the like,
For example, equation (7)

[0038]

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(Wherein R11 and n are the same as described above), and p-toluenesulfonyl chloride,
It is obtained by reacting with a sulfonylating reagent such as p-toluenesulfonic anhydride and methanesulfonyl chloride. These sulfonylation reagents may be used in an amount of 1 to 10 equivalents, particularly preferably 1 to 1.5 equivalents, based on the compound of the formula (7). In the reaction,
A base is preferably present, and examples of the base include organic bases such as triethylamine, pyridine and 4-methylmorpholine, and inorganic bases such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate. The amount of the base to be used is preferably equivalent to the sulfonylating reagent or a small excess amount up to 1.5 equivalents. The reaction may be usually performed in an inert medium, and any inert medium can be used as long as it is inert to the reaction. That is, chloroform, methylene chloride, diethyl ether,
Tetrahydrofuran and the like can be mentioned as examples. The amount of the inert medium may be selected as appropriate,
A 5 to 100-fold dose of the compound of the formula (7) is exemplified.
The reaction can be carried out usually at -25 ° C to 40 ° C, particularly preferably at around room temperature. The end of the reaction can be known by disappearance of the raw materials, but is usually completed in 1 hour to 24 hours.

When X1 in the formula (6) is a halogen atom such as a chlorine atom or a bromine atom, the compound of the formula (7) and the halogen-containing compound are converted into a phosphine compound such as triphenylphosphine and diethylazodiamine. It is obtained by reacting in the presence of an azo compound such as carboxylate. Examples of the halogen-containing compound include carbon tetrachloride and carbon tetrabromide. The amount of the halogen-containing compound may be 1 equivalent or more based on the compound of the formula (7), but may be usually 10 equivalents or more. A phosphine compound such as triphenylphosphine and an azo compound such as diethylazodicarboxylate are represented by the formula (7)
1 to 10 equivalents, particularly preferably 1
It is sufficient to use up to 3 equivalents. The reaction may be usually performed in an inert medium, for example, dimethylformamide, dimethylacetamide, diethyl ether, tetrahydrofuran and the like. It is also preferable to use a halogen-containing compound instead of the inert medium. The amount of the inert medium may be appropriately selected, and a dose 5 to 100 times that of the compound of the formula (7) is exemplified. The reaction may be usually carried out under cooling or heating conditions, and particularly preferably at around room temperature. The completion of the reaction can be known from the disappearance of the raw materials, but the reaction is usually completed within 30 minutes to 1 day.

The compound of the formula (7) can be obtained by using a conventionally known method. For example, when R11 in the formula (7) is a lower alkyl group, the formula (8)

[0042]

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(Wherein, n has the same meaning as described above), and the compound represented by the formula It is obtained by introducing an alkyl group. These alkylating reagents are used in an amount of 1 to 10 equivalents, particularly preferably 1 to 10 equivalents, based on the compound of the formula (8).
Three equivalents may be used. In the reaction, it is preferable to allow a base to be present. Examples of the base include organic bases such as triethylamine, pyridine and 4-methylmorpholine, and inorganic bases such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate. The reaction is usually
It may be performed in an inert medium, for example, chloroform,
Examples include methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile, and the like. The amount of the inert medium may be selected as appropriate,
A 5 to 100-fold dose of the compound of the formula (8) is exemplified.
The reaction can be typically performed at -25 ° C to 40 ° C, particularly preferably around room temperature. The end of the reaction can be known from the disappearance of the raw materials, but is usually completed in 1 hour to 3 days.

When R11 in the formula (7) is a lower alkyl group, as another method for obtaining a compound of the formula (7), for example, the aforementioned compound may be prepared by adding an aqueous solution of formaldehyde, an alcohol solution of formaldehyde, acetaldehyde or the like. React with an aldehyde reagent, sodium borohydride,
It is obtained by reductive alkylation with a reducing agent such as sodium cyanoborohydride. The amount of the aldehyde reagent used for the reaction is based on the compound of the formula (8)
1 to 10 equivalents, particularly preferably 1 to 3 equivalents, may be used. The amount of the reducing agent used in the reaction may be 1 to 10 equivalents, particularly preferably 1 to 3 equivalents, based on the compound of the formula (8). The reaction is usually performed in an inert medium, and examples thereof include diethyl ether, tetrahydrofuran, methanol, and ethanol. The amount of the inert medium may be appropriately selected, and a dose 5 to 100 times that of the compound of the formula (8) is exemplified. The reaction can be typically performed at -25 ° C to 40 ° C, particularly preferably around room temperature. The end of the reaction can be known from the disappearance of the raw materials, but usually from 1 hour to 3 hours.
Complete in days.

When R11 in the formula (7) is a protecting group for an amino group, the compound of the formula (8) is converted to di-t-butyl dicarbonate (Boc2O), benzyloxycarbonyl chloride (Cbz-Cl), It is obtained by reacting with a protecting reagent such as 9-fluorenylmethyl chloroformate (Fmoc-Cl). These protective reagents may be used in an amount of 1 to 10 equivalents, particularly preferably 1 to 3 equivalents, based on the compound of the formula (8). In the reaction, it is preferable to allow a base to be present. As the base, an organic base such as triethylamine, pyridine and 4-methylmorpholine or an inorganic base such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate is reacted. Will be implemented. The reaction may be usually performed in an inert medium, and examples thereof include chloroform, methylene chloride, diethyl ether, and tetrahydrofuran. The amount of the inert medium may be appropriately selected, but the amount of the compound of the formula (8) may be 5 to 100.
Double doses are exemplified. The reaction is typically at −25 ° C.
To 40 ° C., particularly preferably around room temperature. The end of the reaction can be known by disappearance of the raw materials, but is usually completed in 1 hour to 24 hours.

The compound of the formula (8) can be obtained by a conventionally known method. For example, equation (9)

[0047]

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(In the formula, X1 has the same meaning as described above.)
A compound consisting of 2-aminoethanol, 3-amino-1-propanol, 4-amino-1-butanol,
Reaction with an amino alcohol such as -amino-1-pentanol and 6-amino-1-hexanol gives the compound of formula (8). The amino alcohol used for the reaction may be usually at least 1 equivalent to the compound of the formula (9),
Particularly preferably, 3 to 5 equivalents may be used. The reaction may usually be performed in an inert medium. In the reaction, it is preferable to allow a base to be present.
Organic bases such as triethylamine, pyridine, 4-methylmorpholine or potassium carbonate, sodium carbonate,
The reaction is carried out in the presence of an inorganic base such as sodium bicarbonate. The base may also serve as an inert medium. The amino alcohol described above may be used instead of a base or an inert medium.

Examples of the inert medium include dimethylformamide, dimethylacetamide, diethyl ether, tetrahydrofuran, methanol, ethanol, acetonitrile and the like. The amount of the inert medium may be appropriately selected.
A zero-fold dose is exemplified. The reaction may be typically performed under cooling to heating conditions, particularly preferably under heating conditions. The completion of the reaction can be known by disappearance of the raw materials, but is usually completed in 3 hours to 2 days.

A method for obtaining such a compound of the formula (9) is described in Pharmaceutical Journal 88 (5), 503-512 (196).
8) or JP-A-3-188077. According to these methods, the compound of formula (9)
It can be synthesized from commercially available 2-allylphenol.

As another method for obtaining the compound of the formula (2), for example, there is the following method. That is, equation (10)

[0052]

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(Wherein *, n, and R11 have the same meanings as described above). The compound is reacted with a hydrazine reagent to remove a phthalimide group. That is, 1 to 10 equivalents to the compound of the formula (10),
Particularly preferably, 1 to 3 equivalents of anhydrous hydrazine, 100
% Hydrazine, 80% hydrazine water and the like. The reaction may be usually performed in an inert medium, and any inert medium may be used as long as it is inert to the reaction. For example, diethyl ether, tetrahydrofuran, methanol, ethanol, water, or the like can be used. The amount of the inert medium may be appropriately selected, and a dose 5 to 100 times that of the compound of the formula (10) is exemplified. The reaction may be usually carried out under cooling or heating conditions, and particularly preferably at around room temperature.
The reaction time can be determined by the disappearance of the raw materials, and the reaction is usually completed within 30 minutes to 3 days.

The compound of the formula (10) is, for example, a compound of the formula (1)
1)

[0055]

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(Wherein R11 has the same meaning as described above.)
And N- (2-bromoethyl) phthalimide, N- (3-bromopropyl) phthalimide, N
It is obtained by reacting with an imide reagent such as-(4-bromobutyl) phthalimide. The imide reagent used for the reaction can be obtained by using a conventionally known technique. For example, it is commercially available from Tokyo Chemical Industry Co., Ltd., Aldrich Co., etc., and is easy to use. The imide reagent used in the reaction may be usually used in an amount of at least 1 equivalent, particularly preferably 1 to 5 equivalents, based on the compound of the formula (11). The reaction is usually performed in an inert medium, and examples of the inert medium include dimethylformamide, dimethylacetamide, diethyl ether, tetrahydrofuran, methanol, ethanol, and acetonitrile. The amount of the inert medium may be appropriately selected, and a dose 5 to 100 times that of the compound of the formula (11) is exemplified. The reaction may be typically performed under cooling to heating conditions, particularly preferably under heating conditions. The completion of the reaction can be known by disappearance of the raw materials, but is usually completed in 3 hours to 2 days. In the reaction, it is preferable to allow a base to be present. As the base, an organic base such as triethylamine, pyridine and 4-methylmorpholine or an inorganic base such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate is reacted. Will be implemented. The base may also serve as an inert medium.

The compound of the formula (11) is, for example, a compound represented by the above formula (9) and benzylamine, 4-methoxybenzylamine, 3,4-dimethoxybenzylamine, diphenylmethylamine, triphenylmethyl It is obtained by reacting with an amine such as an amine. The amine used for the reaction can be obtained by a conventionally known method. For example, it is commercially available from Tokyo Chemical Industry Co., Ltd., Aldrich Co., etc., and is easy to use. The amine used for the reaction is usually 1 to the compound of the formula (9).
It is sufficient if it is at least equivalent, and it is particularly preferable to use 1 to 5 equivalent. The reaction is usually performed in an inert medium, and examples of the inert medium include dimethylformamide, dimethylacetamide, diethyl ether, tetrahydrofuran, methanol, ethanol, and acetonitrile. The amount of the inert medium may be appropriately selected, and a dose 5 to 100 times that of the compound of the formula (9) is exemplified. The reaction may be typically performed under cooling to heating conditions, particularly preferably under heating conditions. The completion of the reaction can be known by disappearance of the raw materials, but is usually completed in 3 hours to 2 days. In the reaction, it is preferable to allow a base to be present. As the base, an organic base such as triethylamine, pyridine and 4-methylmorpholine or an inorganic base such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate is reacted. Will be implemented. The base may also serve as an inert medium. The above amines may be used instead of a base or an inert medium.

As described above, the compound of the formula (2) can be derived.

Formula (1) of the present invention obtained by the above reaction
The compound of formula (1) may or may not be purified from the reaction product, but is preferably purified by a known purification method such as column chromatography using a carrier such as silica gel. The compound of the formula (1) of the present invention can be formed into an acid addition salt. Such salts include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid,
Propionic acid, p-toluenesulfonic acid, maleic acid,
Acid addition salts with organic acids such as tartaric acid, citric acid, glycolic acid, gluconic acid, succinic acid, malic acid and the like can be mentioned. Further, depending on the type of R2 in the formula (1), it can be formed into a salt such as a sodium salt or a potassium salt.

In order to obtain these salts from the compound of the formula (1), they can be produced by a known method for obtaining a salt from a free base. For example, one equivalent or more of a hydrochloric acid / methanol solution is added to the compound of the formula (1) of the present invention to precipitate a hydrochloride, and this may be recovered. When the salt is difficult to precipitate, a medium such as diethyl ether may be added to the salt for precipitation.

The compound of the formula (1) has an asymmetric carbon and exists as a racemate or an optically active compound. The compound of the formula (1) is intended to include these racemic forms or optically active forms. Certain optically active isomers can be purified, as is known in the art, by chromatography on a chiral stationary phase, resolution via separation by chiral salt formation followed by selective crystallization, or enzymatic use of stereoselective esterases. It can be separated and recovered by a technique such as hydrolysis. It can also be derived from optically active starting materials.

The thus obtained novel 2,3-
The dihydrobenzofuran derivative or a salt thereof is 5-HT
It acts on the 1A receptor and thus can be used as a therapeutic agent for serotonin nervous system-related diseases. In the present invention, the serotonin nervous system-related disease means a disease of the nervous system in which serotonin is involved, and specifically, anxiety, depression, eating disorders, hypertension, vomiting (motion sickness, space sickness, dizziness, drug-induced Vomiting and the like). As shown in the examples, preferred examples of the formula (1) are as follows. n is preferably 4. R1 is preferably a hydrogen atom, or a methyl group or an ethyl group. It is also preferred that n is 4 and A is a carbonyl group. n is 4 and R2 is a combination of a hydrogen atom or a fluorine atom or n is 4;
And R2 is a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group, a cyano group, which may be substituted with a halogen,
A chlorine atom or a bromine atom, and the bonding position of R2 is 3
Are preferred. Also, n is 4,
And it is preferable that R2 is a methyl group or a methoxy group. Further, the compounds listed in the examples are preferable,
In particular, (-)-2- {N- (4-benzoylamino)
Butyl diaminomethyl-2,3-dihydrobenzofuran or a salt thereof.

To prepare such a therapeutic agent for serotonin nervous system-related diseases, a compound of the formula (1) or a salt thereof is combined with a pharmaceutically acceptable pharmaceutical carrier, and the compound is orally or parenterally administered by a known method. It may be formulated for administration. Examples of the dosage form for the formulation include injections, drops, tablets, pills, powders, granules, capsules, and the like. Various acceptable pharmaceutical carriers can be used.

For example, in preparing oral preparations such as tablets, granules and capsules, starch, lactose, sucrose, mannitol, carboxymethyl cellulose, corn starch,
Excipients such as inorganic salts, disintegrants such as methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol, sodium lauryl sulfate, soy lecithin, sucrose fatty acid ester,
Surfactants such as polysorbate 80, talc, wax,
Lubricants such as hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate,
Flowability enhancers and flavoring agents can be used. The drug of the present invention can also be used as an emulsion, syrup, and elixir.

For preparing parenteral preparations, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, propylene glycol, polyethylene glycol and the like can be generally used as diluents. If necessary, a bactericide, a preservative, a stabilizer, an isotonic agent, a soothing agent and the like may be added. The therapeutic agent for serotonin nerve transfusion-related disease of the present invention,
The compound can be administered orally or parenterally. Examples of parenteral administration include intramuscular injection, intravenous injection, and the like, and transdermal, nasal, and vaginal administration.

The dose of the therapeutic agent for serotonergic neuropathy-related diseases of the present invention varies depending on the administration route, age, body weight, symptoms and the like of the recipient. 0.001-100mg / kg
It should be about the degree.

[0067]

Next, the results of examining the pharmacological effects of the compounds of the present invention will be described. 1. Affinity for Serotonin 1A Receptor-Experimental Method-(A) Preparation of Rat Hippocampal Membrane Fraction After decapitation of an SD male rat (7-week-old, Charles River), the brain was immediately removed, and 50 mM Tris was added thereto under ice-cooling. -A hydrochloric acid buffer (pH 7.4) was added for suspension and homogenization. The homogenate is centrifuged (4800
0 × g, 15 minutes) and the precipitate was resuspended in the above buffer. This suspension was kept at 30 ° C. for 20 minutes to degrade endogenous serotonin, and then centrifuged (48000).
× g, 15 minutes), and the sediment was used as a hippocampal membrane fraction. (B) Method for measuring 3H-8-hydroxy-2-dipropylaminotetralin (3H-8-OH-DPAT) binding ability Rat hippocampus membrane fraction prepared above (about 0.1 to 0.2 m)
g protein) and 3H-8-OH-DPAT (New England Newclair, NEN) (final concentration 0.5n)
M) and pargyline (manufactured by Sigma) (final concentration: 0.01 mM) were reacted at 30 ° C. for 30 minutes, and the reaction was stopped by suction filtration with a Whatman GF / C filter to stop the reaction. The adsorbed radioactivity was measured with a liquid scintillation counter, and the obtained measured value was defined as the total binding amount (TB). Non-specific binding amount (NB) was determined by adding serotonin (final concentration 0.01 mM) to the above composition and reacting in the same manner.
And Instead of serotonin, an appropriate concentration of a sample of each compound was added and reacted to obtain a measured value (DTB).

(C) Calculation of Ki Value The binding inhibition rate of a sample at a certain concentration was calculated by the following formula.

The binding inhibition rate at an appropriate concentration (from high concentration to low concentration) was determined for each specimen, and the logarithmic value of the concentration was plotted on the horizontal axis, and the binding inhibition rate was plotted on the vertical axis, and the curve was calculated by the nonlinear least squares method. Was subtracted, and the IC50 value (concentration of 50% binding) of each sample was determined. The Ki value was calculated by the following formula.

[0070]

[L]; radioligand concentration used in the experiment (0.2 n
M) Kd; concentration indicating the affinity of the radioligand for the receptor (0.7174 nM) IC50; concentration of the drug that inhibits the binding between the receptor and the radioligand by 50% What was done was used. -Experimental results-

[0072]

[Table 1]

2. Animal experiments (evaluation of antiemetic effect)-Experimental method-Sunks were used as experimental animals. Sunks are small animals of the shrew family and are known to cause motion sickness and vomiting (Bioscience, 42, 538 (199)
0)). Sunks, when subjected to simple acceleration stimuli, exhibit symptoms equivalent to motion sickness in humans (motion sickness) and eventually cause vomiting. It is also known that administration of drugs such as cisplatin causes vomiting.

The test compound was intraperitoneally administered to Sunks, and 30 minutes later, an acceleration stimulus having an amplitude of 4 cm and a frequency of 1 Hz was applied to observe the occurrence of vomiting. -Experimental results-

[0075]

[Table 2]

Accordingly, it is also useful as an anti-sickness agent, an anti-vertigo agent, an agent for suppressing drug-induced emesis, and the like.

[0077] 3. Affinity for Adrenaline α1 Receptor -Experimental Method- (A) Preparation of Membrane Preparation of Rat Adrenaline α1 Receptor After decapitation of a male SD rat (7 weeks old, Charles River), the brain was quickly removed, and ice was taken out. The cerebral cortex was separated at 50 mM under cooling. The extracted cerebral cortex was frozen at -80 ° C for one day or more. The frozen tissue was thawed slowly under ice-cooling, and then a 50 mM Tris / hydrochloric acid buffer (pH 7.0) was used.
4) was added, suspended and homogenized. This homogenate was centrifuged (48000 × g, 15 minutes), the precipitate was washed twice with the above buffer, and the obtained precipitate was resuspended in the above buffer to obtain a membrane preparation of adrenergic α1 receptor. did.

(B) Method for Measuring 3H-Prazosin Binding Ability The membrane preparation of rat adrenergic α1 receptor prepared above, 3H-prazosin (NEN, New England Nuclea, NEN) (final concentration 0.2 nM) and 2 ml of ascorbic acid (final concentration 0.005%)
The reaction was performed at 5 ° C. for 30 minutes. The reaction solution was converted to Whatman GF /
After filtration with suction through a C filter, the filter paper was washed three times with 4 ml of 50 mM Tris / hydrochloric acid buffer (pH 7.4), transferred to a vial, and added with a scintillator to measure radioactivity.
The obtained measurement value was defined as the total binding amount (TB). The same composition was further added with prazosin (final concentration: 100 nM) and reacted in the same manner. The measured value was defined as the non-specific binding amount (NB). Instead of prazosin, an appropriate concentration of each compound was added and reacted to obtain a measured value (DTB).

(C) Calculation of Ki Value The binding inhibition rate of a sample at a certain concentration was calculated by the following formula.

The binding inhibition rate at an appropriate concentration (from high concentration to low concentration) was determined for each sample, and the logarithmic value of the concentration was plotted on the horizontal axis, and the binding inhibition rate was plotted on the vertical axis, and the curve was calculated by the nonlinear least squares method. Was subtracted, and the IC ₅₀ value (concentration of 50% binding) of each sample was determined. The Ki value was calculated by the following formula.

[L]; concentration of radioligand used in the experiment (0.2 n
M) Kd; concentration representing the affinity of radioligand for receptor (0.133 nM) IC ₅₀ ; concentration of drug that inhibits the binding of receptor and radioligand by 50% Was used. -Experimental results-

[0082]

[Table 3]

4. Antidepressant action (rat forced swimming) When a rat is put into an aquarium, it struggles desperately to escape from it (forced swimming). However, it has been known that administration of an antidepressant enhances swimming action to escape, and conversely shortens immobility. In addition, the forced swimming of rats is the most reliable screening method in the development of antidepressants because the reduction in immobility time due to the forced swimming with the drug and the clinical antidepressant effect are well correlated. Male Wistar rats were used for the experiment, and the compound of the present invention (hydrochloride) of Examples 1, 17, and 18 was orally administered. After 30 minutes, the rats were placed in an aquarium and observed for 6 minutes. The time was measured.

As shown in Table 4 below, Examples 1 and 1
7, 18 compounds of the present invention (hydrochloride) (30, 60 mg /
kg) markedly shortened the immobility time of the rat and showed an antidepressant effect.

[0085]

[Table 4]

5. Toxicity test The compound of formula (1) has low toxicity. (For example, the compound of Example 1 is 100 mg / kg in mice
i. p. No deaths occurred on administration. )

[0087]

As described above, the formula (1) of the present invention is obtained.
Has high affinity for the serotonin 1A receptor, and is an anxiolytic, antidepressant, anorexia, an antihypertensive, an antiemetic (an anti-motion sickness agent, an anti-sickness agent,
(Including an anti-vertigo agent, a drug-induced emesis suppressant, etc.) and the like, and is useful as a therapeutic agent for serotonin nervous system-related diseases.

It has been confirmed that the compound of the formula (1) of the present invention has a high affinity for the serotonin 1A receptor, but has a low affinity for the adrenergic α1 receptor and exhibits a selective action. Was.

[0089]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail by reference examples and examples, but the present invention is not limited thereto. Table 5 below shows the substituents of the compounds of Reference Examples and Examples, and shows the results of nuclear magnetic resonance spectrum and mass spectrometry thereof in Tables 6 to 18. Reference Example 1 Synthesis of 2- (N- (4-aminobutyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan Step A Synthesis of 2-acetoxyallylbenzene 2- 1.3 ml (10 mmol) of allylphenol was dissolved in 6.5 ml of pyridine, cooled to 0 ° C., and 24 mg (0.2 mmol) of dimethylaminopyridine and 1.9 ml (20 mmol) of acetyl chloride were added. After stirring the reaction solution at 0 ° C. for 2 hours, 50 ml of chloroform was added thereto, and 50 ml of saturated aqueous sodium hydrogen carbonate and 50 ml of water were added.
After washing with 50 ml of a saturated saline solution, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was distilled under reduced pressure (78-80 ° C / 4 mmHg),
1.64 g of the title compound were obtained as a colorless oil. 93% yield

Step B Synthesis of 3- (2-acetoxyphenyl) -1,2-dibromopropane 2-acetoxyallylbenzene 5 prepared in Step A
Dissolve 80 mg (3.0 mmol) in 5 ml of carbon tetrachloride, cool to 0 ° C., and add 0.16 ml (3.0 mmol) of bromine.
l) was added dropwise. After stirring the reaction solution at 0 ° C. for 2 hours, chloroform (20 ml) was added, and the mixture was washed with sodium hydrogen sulfite (20 ml), water (20 ml), and saturated saline (20 ml).
The chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to obtain 0.93 g of the title compound as a colorless oil. This compound was used for the next reaction without further purification. 92% yield

Step C Synthesis of 2-bromomethyl-2,3-dihydrobenzofuran 340 mg of 3- (2-acetoxyphenyl) -1,2-dibromopropane prepared in Step B (1.0 m
mol) was dissolved in 3 ml of ethanol, cooled to 0 ° C., and 1.2 ml (1.2 mmol) of 1N sodium ethoxide in ethanol was added dropwise. Reaction solution
After stirring at 2 ° C. for 2 hours, chloroform (20 ml) was added.
It was dehydrated through PS filter paper and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (Merck, Ar
t. 9385, 10 g) and eluted with a mixed solvent of hexane: ethyl acetate = 30: 1 to give 140 mg of the title compound.
Was obtained as a colorless oil. 66% yield

Step D Synthesis of 2- (N- (4-hydroxybutyl)) aminomethyl-2,3-dihydrobenzo [b] furan 2-bromomethyl-prepared in the same manner as in Step C
430 mg of 2,3-dihydrobenzofuran (2.0 mm
ol) was dissolved in 4 ml of acetonitrile, and 4-amino-
0.92 ml (10.0 mmol) of 1-butanol and 550 mg (4.0 mmol) of potassium carbonate were added to give 8
After stirring at 0 ° C. for 8 hours, 20 ml of chloroform was added, and 20 ml of saturated aqueous sodium hydrogen carbonate and 20 ml of water were added.
After washing with 20 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (manufactured by Merck, Art. 9385, 10 g), and eluted with a mixed solvent of chloroform: methanol: concentrated aqueous ammonia = 10: 1: 0.1 to give 300 mg of the title compound in pale yellow color. Obtained as an oil. 67% yield

Step E Synthesis of 2- (N- (t-butoxycarbonyl) -N- (4-hydroxybutyl)) aminomethyl-2,3-dihydrobenzo [b] furan (N- (4-hydroxybutyl)) aminomethyl-2,3-dihydrobenzo [b] furan (220 mg, 1.0 mmol) in methylene chloride (2 m)
, cooled to 0 ° C, and triethylamine 0.1
5 ml (1.1 mmol) and 240 mg (1.1 mmol) of ditertiary butoxycarbonyl anhydride were added. After stirring the reaction solution at room temperature for 2 hours, chloroform 2 was added.
0 ml, and saturated aqueous sodium hydrogen carbonate solution 20 ml,
After washing with 20 ml of water and 20 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g) and eluted with chloroform to obtain 306 mg of the title compound as a colorless oil. 95% yield

Step F Synthesis of 2- (N- (t-butoxycarbonyl) -N- (4- (4-methylphenylsulfonyloxy) butyl)) aminomethyl-2,3-dihydrobenzo [b] furan Step E 322 mg of 2- (N- (t-butoxycarbonyl) -N- (4-hydroxybutyl)) aminomethyl-2,3-dihydrobenzo [b] furan prepared in
(1.00 mmol) in 4 ml of methylene chloride,
After cooling to 0 ° C., 0.56 ml of triethylamine (4.
0 mmol), tosyl chloride 300 mg (1.58
mmol). After the reaction solution was stirred at room temperature for 24 hours, 50 ml of chloroform was added, and the mixture was washed with 50 ml of water and 50 ml of a saturated saline solution. The residue was subjected to silica gel column chromatography (Arc, A
rt. 9385, 10 g) and eluted with hexane: ethyl acetate = 5: 1 to give 459 mg of the title compound as a colorless oil. 96% yield

Step G 2- (N- (4-azidobutyl)
-N- (t-butoxycarbonyl)) aminomethyl-
Synthesis of 2,3-dihydrobenzo [b] furan 2- (N- (t-butoxycarbonyl) -N- (4- (4-methylphenylsulfonyloxy) butyl)) aminomethyl-prepared in Step F 184 mg (0.39 mmol) of 2,3-dihydrobenzo [b] furan was dissolved in 1 ml of N, N-dimethylformamide, and 100 mg (1.54 mmol) of sodium azide was added.
After the reaction solution was stirred at 40 ° C. for 4 hours, chloroform 20 was added.
After washing with 20 ml of water and 20 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10).
g) and eluted with hexane: ethyl acetate = 20: 1 to give 120 mg of the title compound as a colorless oil.
89% yield

Step H 2- (N- (4-aminobutyl)
-N- (t-butoxycarbonyl)) aminomethyl-
Synthesis of 2,3-dihydrobenzo [b] furan 2- (N- (4-azidobutyl) prepared in step G
-N- (t-butoxycarbonyl)) aminomethyl-
117 mg of 2,3-dihydrobenzo [b] furan (0.
34 mmol) was dissolved in 2 ml of methanol, and 15 mg of 10% palladium activated carbon was added. After stirring the reaction solution under a hydrogen atmosphere at room temperature for 24 hours, the reaction solution was filtered through celite, washed with a small amount of methanol, and the filtrate was concentrated under reduced pressure to obtain 108 mg of the title compound as a colorless transparent oil. This compound was used for the reaction of the compounds described in Examples 1 to 16 and 27 and 28 below without further purification. 100% yield

Reference Example 2 Synthesis of 2- (N- (2-aminoethyl) -N-benzyl) aminomethyl-2,3-dihydrobenzo [b] furan Step A 2- (N-benzyl) aminomethyl-2 , 3-
Synthesis of dihydrobenzo [b] furan 2-bromomethyl-, prepared in step C of Example 1
1.07 g of 2,3-dihydrobenzofuran (5.00 m
mol) was dissolved in 11 ml of acetonitrile, 1.64 ml (15.0 mmol) of benzylamine and 2.07 g (15.0 mmol) of potassium carbonate were added, and the mixture was stirred at 80 ° C. for 8 hours, and 100 ml of chloroform was added.
After washing with 100 ml of water and 100 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 50 g) and eluted with chloroform to obtain 873 mg of the title compound as a yellow oil. 73% yield

Step B 2- (N-benzyl-N- (2-
Synthesis of phthalimidoethyl)) aminomethyl-2,3-dihydrobenzo [b] furan 2.39 g of 2- (N-benzyl) aminomethyl-2,3-dihydrobenzo [b] furan prepared in Step A (1
0.0mmol) in 24 ml of acetonitrile,
5.08 g of N- (2-bromoethyl) phthalimide (2
0.0 mmol) and 2.76 g (20.0 g) of potassium carbonate.
mmol), and the mixture was stirred at 80 ° C. for 8 hours. Then, 100 ml of chloroform was added, and the mixture was washed with 100 ml of water and 100 ml of saturated saline, and then the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (Merck, Ar
t. 9385, 50 g) and eluted with a mixed solvent of hexane: ethyl acetate = 20: 1 to give the title compound (3.08 g).
Was obtained as a yellow oil. 75% yield

Step C 2- (N- (2-aminoethyl)
Synthesis of -N-benzyl) aminomethyl-2,3-dihydrobenzo [b] furan 2- (N-benzyl-N- (2-
Phthalimidoethyl)) 2.06 g (5.00 mmol) of aminomethyl-2,3-dihydrobenzo [b] furan
Methylene chloride: ethanol = 9: 1 mixed solvent 20m
Dissolved in 100% water at 0 ° C 0.29m
After adding 1 (6.00 mmol) and stirring at room temperature for 3 days, chloroform (50 ml) was added, washed with water (50 ml) and saturated saline (50 ml), and the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Arc, A
rt. 9385, 50 g) and eluted with a mixed solvent of chloroform: methanol: concentrated aqueous ammonia = 30: 1: 0.1 to obtain 1.19 g of the title compound as a yellow oil. 84% yield

Reference Example 3 Synthesis of 2- (N- (3-aminopropyl) -N-benzyl) aminomethyl-2,3-dihydrobenzo [b] furan Step A 2- (N-benzyl-N- (3 -Phthalimidopropyl)) Synthesis of aminomethyl-2,3-dihydrobenzo [b] furan 2- (N-benzyl) prepared in Step A of Reference Example 2
Aminomethyl-2,3-dihydrobenzo [b] furan 8
64 mg (3.60 mmol) in 9 ml of acetonitrile
And 1.94 g (7.20 mmol) of N- (3-bromopropyl) phthalimide and potassium carbonate 1.1
1 g (8.00 mmol) was added, and the mixture was stirred at 80 ° C. for 8 hours.
After washing with 20 ml of a saturated saline solution, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (manufactured by Merck, Art. 9385, 20 g) and eluted with a mixed solvent of hexane: ethyl acetate = 10: 1 to obtain 1.47 g of the title compound as a yellow oil. 98% yield

Step B Synthesis of 2- (N- (3-aminopropyl) -N-benzyl) aminomethyl-2,3-dihydrobenzo [b] furan Prepared in Step A, 2- (N-benzyl- N- (3-
Phthalimidopropyl)) aminomethyl-2,3-dihydrobenzo [b] furan 1.28 g (3.00 mmol)
1) methylene chloride: ethanol = 9: 1 mixed solvent 2
Dissolve in 0 ml, and add 100% water hydrazine 0.1% at 0 ° C.
After adding 7 ml (3.60 mmol) and stirring at room temperature for 2 days, 50 ml of chloroform was added and 50 ml of water was added.
After washing with 50 ml of a saturated saline solution, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 20 g) and eluted with a mixed solvent of chloroform: methanol: concentrated aqueous ammonia = 30: 1: 0.1 to give 678 mg of the title compound as a yellow oil. Obtained as a product. 76% yield

Example 1 Synthesis of 2- (N- (4-benzoylaminobutyl)) aminomethyl-2,3-dihydrobenzo [b] furan Step A 2- (N- (4-benzoylaminobutyl)-
N- (t-butoxycarbonyl)) aminomethyl-2,
Synthesis of 3-dihydrobenzo [b] furan 2- (N- (4-aminobutyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b prepared according to Reference Example 1. ] Fran 128mg
(0.40 mmol) was dissolved in 1.3 ml of methylene chloride, cooled to 0 ° C., and 0.08 ml of triethylamine was dissolved.
(0.6 mmol), 0.06 ml of benzoyl chloride
(0.5 mmol) was added. The reaction solution was gradually raised from 0 ° C., and stirred at room temperature for 24 hours.
And then add 20 ml of saturated aqueous sodium hydrogen carbonate and 20 ml of water.
After washing with 20 ml of a saturated saline solution, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g) and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to obtain 151 mg of the title compound as a colorless oil. 89% yield

Step B Synthesis of 2- (N- (4-benzoylaminobutyl)) aminomethyl-2,3-dihydrobenzo [b] furan 2- (N- (4-benzoyl) prepared in Step A above (Aminobutyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan 15
1 mg (0.36 mmol) was cooled to 0 ° C, 1.5 ml of trifluoroacetic acid was added, and the mixture was stirred at 0 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was cooled again to 0 ° C., 12 ml of diethyl ether was added, and the mixture was stirred for 2 hours. The precipitated solid was collected by filtration, washed with a small amount of diethyl ether,
It was dissolved in 20 ml of chloroform. The solution was saturated sodium bicarbonate solution (20 ml), water (20 ml), and saturated saline solution (20 m).
After washing with l, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to obtain 89 mg of the title compound as a pale yellow oil. 76% yield

Example 2 Synthesis of 2- (N- (4-benzenesulfonamidobutyl)) aminomethyl-2,3-dihydrobenzo [b] furan Step A 2- (N- (4-benzenesulfonamidobutyl) Synthesis of -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan 2- (N- (4-aminobutyl) -N- (t- Butoxycarbonyl)) 128 mg of aminomethyl-2,3-dihydrobenzo [b] furan
(0.40 mmol) was dissolved in 1.3 ml of methylene chloride, cooled to 0 ° C., and 0.08 ml of triethylamine was dissolved.
(0.6 mmol), benzenesulfonyl chloride 0.
06 ml (0.5 mmol) were added. After the reaction solution was stirred at 0 ° C. for 1 hour, chloroform (20 ml) was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml), and saturated saline (20 ml). did. The residue is subjected to silica gel column chromatography (Merck, Ar
t. 9385, 10 g) and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to obtain 167 mg of the title compound as a pale yellow oil. 91% yield

Step B Synthesis of 2- (N- (4-benzenesulfonamidobutyl)) aminomethyl-2,3-dihydrobenzo [b] furan The 2- (N- (4- 156 mg (0.34 mmol) of benzenesulfonamidobutyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan were cooled to 0 ° C.
1.6 ml of trifluoroacetic acid was added, and the mixture was stirred at 0 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was cooled again to 0 ° C., 12 ml of diethyl ether was added, and the mixture was stirred for 2 hours. The precipitated solid was collected by filtration, washed with a small amount of diethyl ether, and then dissolved in 20 ml of chloroform. The solution was washed with 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water and 20 ml of saturated saline, and the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to obtain 109 mg of the title compound as a pale yellow oil. 89% yield

Example 3 Synthesis of 2,3-dihydro-2- (N- (4- (2-methylbenzoylamino) butyl)) aminomethylbenzo [b] furan Step A 2,3-dihydro-2- ( Synthesis of N- (4- (2-methylbenzoylamino) butyl) -N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan 2- (N- (4-amino) prepared according to Reference Example 1 Butyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan 160 mg
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol) and 0.08 ml (0.6 mmol) of o-toluoyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) were added. After stirring the reaction solution at 0 ° C. for 2 hours, chloroform 20 ml
And then add 20 ml of saturated aqueous sodium hydrogen carbonate and 20 ml of water.
After washing with 20 ml of a saturated saline solution, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g), and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to obtain 192 mg of the title compound as a colorless oil. 88% yield

Step B 2,3-dihydro-2- (N-
Synthesis of (4- (2-methylbenzoylamino) butyl)) aminomethylbenzo [b] furan 2,3-dihydro-2- (N
-(4- (2-methylbenzoylamino) butyl) -N
190 mg (0.43 mmol) of-(t-butoxycarbonyl)) aminomethylbenzo [b] furan was cooled to 0 ° C, 1.9 ml of trifluoroacetic acid was added, and
Stirred for hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution was washed with 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water and 20 ml of saturated saline, and the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to obtain 141 mg of the title compound as a pale yellow oil. 97% yield

Example 4 Synthesis of 2,3-dihydro-2- (N- (4- (3-methylbenzoylamino) butyl)) aminomethylbenzo [b] furan Step A 2,3-dihydro-2- ( Synthesis of N- (4- (3-methylbenzoylamino) butyl) -N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan 2- (N- (4-amino) prepared according to Reference Example 1 Butyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan 160 mg
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol) and 0.08 ml (0.6 mmol) of m-toluoyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) were added. After stirring the reaction solution at 0 ° C. for 2 hours, chloroform 20 ml
And then add 20 ml of saturated aqueous sodium hydrogen carbonate and 20 ml of water.
After washing with 20 ml of a saturated saline solution, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g), and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to obtain 174 mg of the title compound as a pale yellow oil. 79% yield

Step B 2,3-dihydro-2- (N-
Synthesis of (4- (3-methylbenzoylamino) butyl)) aminomethylbenzo [b] furan 2,3-dihydro-2- (N
-(4- (3-methylbenzoylamino) butyl) -N
170 mg (0.39 mmol) of-(t-butoxycarbonyl)) aminomethylbenzo [b] furan was cooled to 0 ° C, 1.7 ml of trifluoroacetic acid was added, and the mixture was stirred at 0 ° C for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution is saturated sodium bicarbonate aqueous solution 20 ml, water 20 ml, saturated saline solution 20 ml
After washing with, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to obtain 134 mg of the title compound as a pale yellow oil. 100% yield

Example 5 Synthesis of 2,3-dihydro-2- (N- (4- (4-methylbenzoylamino) butyl)) aminomethylbenzo [b] furan Step A 2,3-dihydro-2- ( Synthesis of N- (4- (4-methylbenzoylamino) butyl) -N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan 2- (N- (4-amino) prepared according to Reference Example 1 Butyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan 160 mg
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol) and 0.08 ml (0.6 mmol) of p-toluoyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) were added. After the reaction solution was stirred at 0 ° C. for 1.5 hours, chloroform 20 was added.
After washing with 20 ml of saturated aqueous sodium bicarbonate, 20 ml of water and 20 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g), and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to obtain 192 mg of the title compound as a pale yellow oil. Yield 8
7%

Step B 2,3-dihydro-2- (N-
Synthesis of (4- (4-methylbenzoylamino) butyl)) aminomethylbenzo [b] furan 2,3-dihydro-2- (N
-(4- (4-methylbenzoylamino) butyl) -N
190 mg (0.43 mmol) of-(t-butoxycarbonyl)) aminomethylbenzo [b] furan was cooled to 0 ° C, 1.9 ml of trifluoroacetic acid was added, and the mixture was stirred at 0 ° C for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution is saturated sodium bicarbonate aqueous solution 20 ml, water 20 ml, saturated saline solution 20 ml
After washing with, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to obtain 154 mg of the title compound as a pale yellow oil. 100% yield

Example 6 2,3-dihydro-2- (N- (4- (2-methoxybenzoylamino) butyl)) aminomethylbenzo [b]
Synthesis of Furan Step A Synthesis of 2,3-dihydro-2- (N- (4- (2-methoxybenzoylamino) butyl) -N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan Reference Example 1 160 mg of 2- (N- (4-aminobutyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan prepared by
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol) and 0.09 ml (0.6 mmol) of o-anisoyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) were added. After stirring the reaction solution at 0 ° C. for 2 hours, chloroform 20 ml
And then add 20 ml of saturated aqueous sodium hydrogen carbonate and 20 ml of water.
After washing with 20 ml of a saturated saline solution, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g) and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to obtain 215 mg of the title compound as a pale yellow oil. 94% yield

Step B 2,3-dihydro-2- (N-
Synthesis of (4- (2-methoxybenzoylamino) butyl)) aminomethylbenzo [b] furan 2,3-dihydro-2- (N
-(4- (2-methoxybenzoylamino) butyl)-
200 mg (0.44 mmol) of N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan was cooled to 0 ° C., 2.0 ml of trifluoroacetic acid was added, and the mixture was stirred at 0 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution is saturated sodium bicarbonate aqueous solution 20 ml, water 20 ml, saturated saline solution 20 ml
After washing with, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to obtain 164 mg of the title compound as a pale yellow oil. 100% yield

Example 7 2,3-dihydro-2- (N- (4- (3-methoxybenzoylamino) butyl)) aminomethylbenzo [b]
Synthesis of Furan Step A Synthesis of 2,3-dihydro-2- (N- (4- (3-methoxybenzoylamino) butyl) -N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan Reference Example 1 160 mg of 2- (N- (4-aminobutyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan prepared by
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol) and 0.08 ml (0.6 mmol) of m-anisoyl chloride (manufactured by Aldrich) were added. After the reaction solution was stirred at 0 ° C. for 1.5 hours, chloroform (20 ml) was added, and saturated aqueous sodium hydrogen carbonate (20 ml) was added.
After washing with 1, 20 ml of water and 20 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g) and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to obtain 196 mg of the title compound as a pale yellow oil. 86% yield

Step B 2,3-dihydro-2- (N-
Synthesis of (4- (3-methoxybenzoylamino) butyl)) aminomethylbenzo [b] furan 2,3-dihydro-2- (N
-(4- (3-methoxybenzoylamino) butyl)-
190 mg (0.42 mmol) of N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan was cooled to 0 ° C., 1.9 ml of trifluoroacetic acid was added, and the mixture was stirred at 0 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution is saturated sodium bicarbonate aqueous solution 20 ml, water 20 ml, saturated saline solution 20 ml
After washing with, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to obtain 153 mg of the title compound as a pale yellow oil. 100% yield

Example 8 2,3-dihydro-2- (N- (4- (4-methoxybenzoylamino) butyl)) aminomethylbenzo [b]
Synthesis of Furan Step A Synthesis of 2,3-dihydro-2- (N- (4- (4-methoxybenzoylamino) butyl) -N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan Reference Example 1 160 mg of 2- (N- (4-aminobutyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan prepared by
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol) and 102 mg (0.6 mmol) of p-anisoyl chloride (manufactured by Aldrich) were added.
After the reaction solution was stirred at 0 ° C. for 2 hours, chloroform 20m
l, add 20 ml of saturated aqueous sodium bicarbonate,
After washing with 0 ml and 20 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g), and eluted with a mixed solvent of hexane: ethyl acetate = 1: 1 to obtain 203 mg of the title compound as a pale yellow oil. 89% yield

Step B 2,3-Dihydro-2- (N-
Synthesis of (4- (4-methoxybenzoylamino) butyl)) aminomethylbenzo [b] furan 2,3-dihydro-2- (N
-(4- (4-methoxybenzoylamino) butyl)-
190 mg (0.42 mmol) of N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan was cooled to 0 ° C., 1.9 ml of trifluoroacetic acid was added, and the mixture was stirred at 0 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution is saturated sodium bicarbonate aqueous solution 20 ml, water 20 ml, saturated saline solution 20 ml
After washing with, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to obtain 148 mg of the title compound as a pale yellow oil. 100% yield

Example 9 2,3-dihydro-2- (N- (4- (2-fluorobenzoylamino) butyl)) aminomethylbenzo [b]
Synthesis of Furan Step A Synthesis of 2,3-dihydro-2- (N- (4- (2-fluorobenzoylamino) butyl) -N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan Reference Example 1 160 mg of 2- (N- (4-aminobutyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan prepared by
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol) and 0.07 ml (0.6 mmol) of o-fluorobenzoyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) were added. After the reaction solution was stirred at 0 ° C. for 1.5 hours, 20 ml of chloroform was added thereto, and 20 ml of a saturated aqueous sodium hydrogen carbonate solution was added.
After washing with 20 ml of water, 20 ml of water and 20 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper,
After concentration under reduced pressure, 210 mg of the title compound was obtained as a pale yellow oil. 95% yield

Step B 2,3-dihydro-2- (N-
Synthesis of (4- (2-fluorobenzoylamino) butyl)) aminomethylbenzo [b] furan 2,3-dihydro-2- (N
-(4- (2-fluorobenzoylamino) butyl)-
200 mg (0.45 mmol) of N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan was cooled to 0 ° C, 2.0 ml of trifluoroacetic acid was added, and the mixture was cooled at 0 ° C.
Stirred for hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution was washed with 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water and 20 ml of saturated saline, and the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to obtain 150 mg of the title compound as a pale yellow oil. 97% yield

Example 10 2,3-Dihydro-2- (N- (4- (3-fluorobenzoylamino) butyl)) aminomethylbenzo [b]
Synthesis of Furan Step A Synthesis of 2,3-dihydro-2- (N- (4- (3-fluorobenzoylamino) butyl) -N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan Reference Example 1 160 mg of 2- (N- (4-aminobutyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan prepared by
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol) and 0.07 ml (0.6 mmol) of m-fluorobenzoyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) were added. After the reaction solution was stirred at 0 ° C. for 2 hours, chloroform (20 ml) was added, and saturated aqueous sodium hydrogen carbonate (20 ml) was added.
After washing with 1, 20 ml of water and 20 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g) and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to obtain 209 mg of the title compound as a pale yellow oil. 94% yield

Step B 2,3-dihydro-2- (N-
Synthesis of (4- (3-fluorobenzoylamino) butyl)) aminomethylbenzo [b] furan 2,3-dihydro-2- (N
-(4- (3-fluorobenzoylamino) butyl)-
190 mg (0.43 mmol) of N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan was cooled to 0 ° C., 1.9 ml of trifluoroacetic acid was added, and
Stirred for hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution was washed with 20 ml of saturated aqueous sodium hydrogencarbonate, 20 ml of water and 20 ml of saturated saline, and the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to obtain 153 mg of the title compound as a pale yellow oil. 100% yield

Example 11 2,3-Dihydro-2- (N- (4- (4-fluorobenzoylamino) butyl)) aminomethylbenzo [b]
Synthesis of Furan Step A Synthesis of 2,3-dihydro-2- (N- (4- (4-fluorobenzoylamino) butyl) -N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan Reference Example 1 160 mg of 2- (N- (4-aminobutyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan prepared by
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol) and 0.07 ml (0.6 mmol) of p-fluorobenzoyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) were added. After the reaction solution was stirred at 0 ° C. for 2 hours, chloroform (20 ml) was added, and saturated aqueous sodium hydrogen carbonate (20 ml) was added.
After washing with 1, 20 ml of water and 20 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g) and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to obtain 187 mg of the title compound as a pale yellow oil. 84% yield

Step B 2,3-dihydro-2- (N-
Synthesis of (4- (4-fluorobenzoylamino) butyl)) aminomethylbenzo [b] furan 2,3-dihydro-2- (N
-(4- (4-fluorobenzoylamino) butyl)-
180 mg (0.41 mmol) of N- (t-butoxycarbonyl) aminomethylbenzo [b] furan was cooled to 0 ° C., 1.8 ml of trifluoroacetic acid was added, and
Stirred for hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution was washed with saturated aqueous sodium bicarbonate (20 ml), water (20 ml) and saturated saline (20 ml), and the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to obtain the title compound (136 mg) as a pale yellow oil. 97% yield

Example 12 Synthesis of 2,3-dihydro-2- (N- (4- (2-trifluoromethylbenzoylamino) butyl)) aminomethylbenzo [b] furan Step A 2,3-dihydro-2 -(N- (4- (2-trifluoromethylbenzoylamino) butyl) -N-
Synthesis of (t-butoxycarbonyl)) aminomethylbenzo [b] furan 2- (N- (4-aminobutyl) -N- (t-butoxycarbonyl)) aminomethyl-2, prepared according to Reference Example 1. 160 mg of 3-dihydrobenzo [b] furan
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol), 0.09 ml of o-trifluoromethylbenzoyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) (0.6 mm)
ol). After stirring the reaction solution at 0 ° C. for 2 hours, 20 ml of chloroform was added, and the mixture was washed with 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water and 20 ml of saturated saline, and the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. did. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10).
g) and eluted with a mixed solvent of hexane: ethyl acetate = 1: 1 to give 213 mg of the title compound as a pale yellow oil. 87% yield

Step B 2,3-dihydro-2- (N-
Synthesis of (4- (2-trifluoromethylbenzoylamino) butyl)) aminomethylbenzo [b] furan 2,3-dihydro-2- (N
-(4- (2-trifluoromethylbenzoylamino)
Butyl) -N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan 210 mg (0.43 mmol
1) was cooled to 0 ° C, 2.0 ml of trifluoroacetic acid was added, and the mixture was stirred at 0 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution was added with 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water, and saturated saline 2
After washing with 0 ml, the chloroform layer was washed with Whatman 1PS.
Dehydrate through filter paper and concentrate under reduced pressure to give the title compound 166.
mg was obtained as a pale yellow oil. 99% yield

Example 13 Synthesis of 2,3-dihydro-2- (N- (4- (3-trifluoromethylbenzoylamino) butyl)) aminomethylbenzo [b] furan Step A 2,3-dihydro-2 -(N- (4- (3-trifluoromethylbenzoylamino) butyl) -N-
Synthesis of (t-butoxycarbonyl)) aminomethylbenzo [b] furan 2- (N- (4-aminobutyl) -N- (t-butoxycarbonyl)) aminomethyl-2, prepared according to Reference Example 1. 160 mg of 3-dihydrobenzo [b] furan
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol), 0.09 ml of m-trifluoromethylbenzoyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) (0.6 mm)
ol). After stirring the reaction solution at 0 ° C. for 2 hours, 20 ml of chloroform was added, and the mixture was washed with 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water and 20 ml of saturated saline, and the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. did. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10).
g) and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to give 205 mg of the title compound as a pale yellow oil. 83% yield

Step B 2,3-Dihydro-2- (N-
Synthesis of (4- (3-trifluoromethylbenzoylamino) butyl)) aminomethylbenzo [b] furan 2,3-dihydro-2- (N
-(4- (3-trifluoromethylbenzoylamino)
Butyl) -N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan 198 mg (0.40 mmol
1) was cooled to 0 ° C, 2.0 ml of trifluoroacetic acid was added, and the mixture was stirred at 0 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution was added with 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water, and saturated saline 2
After washing with 0 ml, the chloroform layer was washed with Whatman 1PS.
Dehydrate through filter paper and concentrate under reduced pressure to give the title compound 158
mg was obtained as a pale yellow oil. 100% yield

Example 14 Synthesis of 2,3-dihydro-2- (N- (4- (4-trifluoromethylbenzoylamino) butyl)) aminomethylbenzo [b] furan Step A 2,3-dihydro-2 -(N- (4- (4-trifluoromethylbenzoylamino) butyl) -N-
Synthesis of (t-butoxycarbonyl)) aminomethylbenzo [b] furan 2- (N- (4-aminobutyl) -N- (t-butoxycarbonyl)) aminomethyl-2, prepared according to Reference Example 1. 160 mg of 3-dihydrobenzo [b] furan
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol), 0.09 ml (0.6 mm) of p-trifluoromethylbenzoyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.)
ol). After stirring the reaction solution at 0 ° C. for 2 hours, 20 ml of chloroform was added, and the mixture was washed with 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water and 20 ml of saturated saline, and the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. did. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10).
g) and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to give 205 mg of the title compound as a pale yellow oil. 83% yield

Step B 2,3-dihydro-2- (N-
Synthesis of (4- (4-trifluoromethylbenzoylamino) butyl)) aminomethylbenzo [b] furan 2,3-dihydro-2- (N
-(4- (4-trifluoromethylbenzoylamino)
Butyl) -N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan 200 mg (0.41 mmol
1) was cooled to 0 ° C, 2.0 ml of trifluoroacetic acid was added, and the mixture was stirred at 0 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution was added with 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water, and saturated saline 2
After washing with 0 ml, the chloroform layer was washed with Whatman 1PS.
Dehydrate through filter paper and concentrate under reduced pressure to give the title compound 154
mg was obtained as a pale yellow solid. 96% yield

Example 15 Synthesis of 2,3-dihydro-2- (N- (4- (3-nitrobenzoylamino) butyl)) aminomethylbenzo [b] furan Step A 2,3-dihydro-2- ( Synthesis of N- (4- (3-nitrobenzoylamino) butyl) -N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan 2- (N- (4-amino) prepared according to Reference Example 1 Butyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan 160 mg
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol) and 111 mg (0.6 mmol) of m-nitrobenzoyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) were added. After stirring the reaction solution at 0 ° C. for 2 hours, chloroform 2 was added.
0 ml, and saturated aqueous sodium hydrogen carbonate solution 20 ml,
After washing with 20 ml of water and 20 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g) and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to obtain 200 mg of the title compound as a pale yellow oil. Yield 8
5%

Step B 2,3-Dihydro-2- (N-
Synthesis of (4- (3-nitrobenzoylamino) butyl)) aminomethylbenzo [b] furan 2,3-dihydro-2- (N
-(4- (3-nitrobenzoylamino) butyl) -N
200 mg (0.43 mmol) of-(t-butoxycarbonyl)) aminomethylbenzo [b] furan was cooled to 0 ° C, 2.0 ml of trifluoroacetic acid was added, and the mixture was cooled at 0 ° C.
Stirred for hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution was washed with 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water and 20 ml of saturated saline, and the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to obtain 141 mg of the title compound as a brown solid. 90% yield

Example 16 Synthesis of 2,3-dihydro-2- (N- (4- (3-cyanobenzoylamino) butyl)) aminomethylbenzo [b] furan Step A 2,3-dihydro-2- ( Synthesis of N- (4- (3-cyanobenzoylamino) butyl) -N- (t-butoxycarbonyl)) aminomethylbenzo [b] furan 2- (N- (4-amino) prepared according to Reference Example 1 Butyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan 160 mg
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol) and 99 mg (0.6 mmol) of m-cyanobenzoyl chloride (manufactured by Aldrich) were added. After the reaction solution was stirred at 0 ° C. for 2 hours, chloroform (20 ml) was added, and saturated aqueous sodium hydrogen carbonate (20 ml) was added.
After washing with 1, 20 ml of water and 20 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g) and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to obtain 199 mg of the title compound as a pale yellow oil. 88% yield

Step B 2,3-dihydro-2- (N-
Synthesis of (4- (3-cyanobenzoylamino) butyl)) aminomethylbenzo [b] furan 2,3-dihydro-2- (N
-(4- (3-cyanobenzoylamino) butyl) -N
190 mg (0.42 mmol) of-(t-butoxycarbonyl)) aminomethylbenzo [b] furan was cooled to 0 ° C, 2.0 ml of trifluoroacetic acid was added, and the mixture was cooled at 0 ° C.
Stirred for hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution was washed with 20 ml of saturated aqueous sodium hydrogencarbonate, 20 ml of water and 20 ml of saturated saline, and the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to obtain 153 mg of the title compound as a pale yellow oil. 100% yield

Example 17 Synthesis of (+)-2,3-dihydro-2- (N- (4- (benzoylamino) butyl)) aminomethylbenzo [b] furan.hydrochloride Obtained in Example 1. , 2- (N- (4- (benzoylamino) butyl)) aminomethylbenzo [b] furan 4
4.2 g (136 mmol) was dissolved in 910 ml of methanol, and (R)-(-)-N- (3,5-dinitrobenzoyl) -α-phenylglycine (Tokyo Kasei) 4
7.1 g (136 mmol) were added. After leaving the reaction solution at room temperature for 6 hours, the precipitated crystals were collected by filtration and dried under reduced pressure. The crystals were recrystallized twice from methanol. 22.2 g of the obtained crystals were dissolved in 70 ml of a 0.5 N aqueous solution of sodium hydroxide, and extracted twice with 100 ml of chloroform. The chloroform layer was washed with 100 ml of water and 100 ml of saturated saline, dehydrated through Whatman 1PS filter paper, and concentrated under reduced pressure. The residue was dissolved in 2.7N methanolic hydrochloric acid solution, concentrated under reduced pressure, and the precipitated crystals were filtered and dried under reduced pressure to obtain 10.9 g of the title compound as white crystals. Optical purity: 98.0% ee (Chiral cell OD, manufactured by Osaka Soda Co., Ltd., column size: 0.46 × 25 cm, elution solvent: hexane: ethanol = 90: 10 (containing 0.1% triethylamine), elution rate: 0.6 ml / Min, detection wavelength
270 nm) [α] D 58.4 (c = 0.5, methanol)

Example 18 Synthesis of (−)-2,3-dihydro-2- (N = (4- (benzoylamino) butyl) aminomethyl) benzo [b] furan hydrochloride The crystallization of Example 17 All mother liquors used for recrystallization were collected, concentrated under reduced pressure, dissolved in 120 ml of 1.0 N aqueous sodium hydroxide solution, and extracted twice with 100 ml of chloroform. The chloroform layer was washed with 100 ml of water and 100 ml of saturated saline, dehydrated through Whatman 1PS filter paper, and concentrated under reduced pressure. The obtained pale yellow oil was dissolved in methanol (1.041), and (S)-(+)-N-
35.6 g (103 mmo) of (3,5-dinitrobenzoyl) -α-phenylglycine (manufactured by Aldrich)
l) was added. After leaving the reaction solution at room temperature for 5 hours, the precipitated crystals were collected by filtration and dried under reduced pressure. The crystals were recrystallized once with methanol. 22.5 g of the obtained crystals were dissolved in 70 ml of a 0.5 N aqueous sodium hydroxide solution and extracted twice with 100 ml of chloroform. The chloroform layer was washed with 100 ml of water and 100 ml of saturated saline, dehydrated through Whatman 1PS filter paper, and concentrated under reduced pressure. The residue was dissolved in 2.0N methanolic hydrochloric acid solution, concentrated under reduced pressure, and the precipitated crystals were filtered and dried under reduced pressure to obtain 11.2 g of the title compound as white crystals. Optical purity: 98.0% ee (Chiral cell OD, manufactured by Osaka Soda Co., Ltd., column size: 0.46 × 25 cm, elution solvent: hexane: ethanol = 90: 10 (containing 0.1% triethylamine), elution rate: 0.6 ml / Min, detection wavelength;
270 nm) [α] D-61.6 (c = 0.5, methanol)

Example 19 Synthesis of 2- (N- (2-benzoylaminoethyl)) aminomethyl-2,3-dihydrobenzo [b] furan Step A 2- (N- (2-benzoylaminoethyl)-
Synthesis of N-benzyl) aminomethyl-2,3-dihydrobenzo [b] furan 2- (N- (2-aminoethyl) -N-benzyl) aminomethyl-2,3- prepared according to Reference Example 2. 141 mg (0.50 mmol) of dihydrobenzo [b] furan
Is dissolved in 2.0 ml of methylene chloride, cooled to 0 ° C.,
0.14 ml (1.00 mmol) of triethylamine,
Benzoyl chloride 0.07 ml (0.6 mmol) was added. After the reaction solution was stirred at 0 ° C. for 2 hours, chloroform (20 ml) was added, and saturated aqueous sodium hydrogen carbonate (20 ml) was added.
After washing with 1, 20 ml of water and 20 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g), and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to obtain 190 mg of the title compound as a pale yellow oil. 98% yield

Step B Synthesis of 2- (N- (2-benzoylaminoethyl)) aminomethyl-2,3-dihydrobenzo [b] furan 2- (N- (2-benzoylaminoethyl) prepared by Step A Ethyl) -N-benzyl) aminomethyl-2,3
-179 mg of dihydrobenzo [b] furan (0.46 m
mol) was dissolved in 2.0 ml of methylene chloride, cooled to 0 ° C., and 0.82 ml (1.38 mmol) of a toluene solution of carbobenzoxychloride (manufactured by Tokyo Chemical Industry Co., Ltd.) was added. After the reaction solution was stirred at 40 ° C. for 6 hours, 20 ml of chloroform was added, and 20 ml of saturated aqueous sodium hydrogen carbonate was added.
After washing with 1, 20 ml of water and 20 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g) and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to give 2- (N- (2-benzoylaminoethyl) -N −
183 mg of carbobenzoxy) aminomethyl-2,3-dihydrobenzo [b] furan were obtained.

Of these, 180 mg (0.42 mmol)
Was dissolved in 0.5 ml of acetic acid, 0.05 ml of anisole was added, the mixture was cooled to 0 ° C., and a 30% aqueous solution of hydrobromic acid in 0.1 ml of acetic acid was added.
92 ml were added. After stirring the reaction at room temperature for 1 hour,
After adding 20 ml of ether, the deposited precipitate was collected by filtration, dissolved in 20 ml of chloroform, washed with 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water and 20 ml of saturated saline, and the chloroform layer was dehydrated through Whatman 1PS filter paper, and dried under reduced pressure. Concentration gave 129 mg of the title compound as a colorless oil. 95% yield

Example 20 Synthesis of 2- (N- (2- (3-methylbenzoylamino) ethyl)) aminomethyl-2,3-dihydrobenzo [b] furan Step A 2- (N-benzyl-N-furan) (2- (3-methylbenzoylamino) ethyl)) aminomethyl-2,3-
Synthesis of dihydrobenzo [b] furan 141 mg (0.50 mmol) of 2- (N- (2-aminoethyl) -N-benzyl) aminomethyl-2,3-dihydrobenzo [b] furan prepared according to Reference Example 2. )
Is dissolved in 2.0 ml of methylene chloride, cooled to 0 ° C.,
0.14 ml (1.00 mmol) of triethylamine,
0.079 ml of m-toluoyl chloride (0.60 mm
ol). After stirring the reaction solution at 0 ° C. for 2 hours, 20 ml of chloroform was added, and the mixture was washed with 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water and 20 ml of saturated saline, and the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. did. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10).
g) and eluted with a mixed solvent of hexane: ethyl acetate = 10: 1 to give 195 mg of the title compound as a pale yellow oil. 97% yield

Step B: Synthesis of 2- (N- (2- (3-methylbenzoylamino) ethyl)) aminomethyl-2,3-dihydrobenzo [b] furan Prepared by Step A, 2- (N- (2- (3-methylbenzoylamino) ethyl) -N-benzyl) aminomethyl-2,3-dihydrobenzo [b] furan 195m
g (0.49 mmol) was dissolved in 2.0 ml of methylene chloride, cooled to 0 ° C, and 0.87 ml of a toluene solution of carbobenzoxycyclolide (manufactured by Tokyo Chemical Industry Co., Ltd.) (1.46 m
mol) was added. After the reaction solution was stirred at 40 ° C. for 6 hours, 20 ml of chloroform was added, and the mixture was washed with 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water and 20 ml of saturated saline, and the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. did. The residue was subjected to silica gel column chromatography (Merck, Art. 9385,
10 g), and eluted with a mixed solvent of hexane: ethyl acetate = 5: 1 to give 2- (N- (2- (3-methylbenzoylamino) ethyl) -N-carbobenzoxy) aminomethyl-2, 194 mg of 3-dihydrobenzo [b] furan
I got

The obtained compound (200 mg, 0.45 mm
ol) in 0.8 ml of acetic acid and 0.08 of anisole
The mixture was cooled to 0 ° C., and 1.48 ml of a 30% hydrobromic acid in acetic acid solution was added. After stirring the reaction solution at room temperature for 1 hour, 20 ml of ether was added, and the deposited precipitate was collected by filtration, dissolved in 20 ml of chloroform, washed with 20 ml of a saturated aqueous solution of sodium hydrogencarbonate, 20 ml of water and 20 ml of a saturated saline solution, and then chloroform layer was added. Was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385,
10g), chloroform: methanol = 10: 1
This was eluted with a mixed solvent of to give 122 mg of the title compound as a pale yellow oil. 78% yield

Example 21 2- (N- (2- (4-fluorobenzoyl) aminoethyl)) aminomethyl-2,3-dihydrobenzo [b]
Synthesis of furan Step A 2- (N-benzyl-N- (2- (4-fluorobenzoylamino) ethyl)) aminomethyl-2,3
Synthesis of -dihydrobenzo [b] furan 141 mg of 2- (N- (2-aminoethyl) -N-benzyl) aminomethyl-2,3-dihydrobenzo [b] furan prepared in Reference Example 2 (0.1 mg). 50 mmol)
Is dissolved in 2.0 ml of methylene chloride, cooled to 0 ° C.,
0.14 ml (1.00 mmol) of triethylamine,
0.071 ml of 4-fluorobenzoyl chloride (0.
60 mmol) was added. After the reaction solution was stirred at 0 ° C. for 2 hours, 20 ml of chloroform was added thereto, and 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water, and 20 ml of saturated saline were added.
After washing with, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 938).
Hexane: ethyl acetate = 10: 1
And 189 mg of the title compound were obtained as a pale yellow oil. 93% yield

Step B 2- (N- (2- (4-fluorobenzoylamino) ethyl)) aminomethyl-2,3-
Synthesis of dihydrobenzo [b] furan 2- (N- (2- (4-fluorobenzoylamino) ethyl) -N-benzyl) aminomethyl-2,3-dihydrobenzo [b] furan prepared by step A 180
mg (0.45 mmol) was dissolved in 2.0 ml of methylene chloride, cooled to 0 ° C., and 0.80 ml (1.35) of a toluene solution of carbobenzoxyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.).
mmol). After the reaction solution was stirred at 40 ° C. for 6 hours, 20 ml of chloroform was added, and the mixture was washed with 20 ml of a saturated aqueous solution of sodium hydrogen carbonate, 20 ml of water and 20 ml of a saturated saline solution. did. The residue was subjected to silica gel column chromatography (Merck, Art. 9385,
10 g) and eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to give 2- (N- (2- (4-fluorobenzoylamino) ethyl) -N-carbobenzoxy) aminomethyl-2, 179 m of 3-dihydrobenzo [b] furan
g was obtained.

The obtained compound (179 mg, 0.40 mm
ol) was dissolved in 0.72 ml of acetic acid, and anisole 0.0
8 ml was added, the mixture was cooled to 0 ° C., and 1.33 ml of a 30% hydrobromic acid in acetic acid solution was added. After the reaction solution was stirred at room temperature for 1 hour, ether (20 ml) was added, and the deposited precipitate was collected by filtration, dissolved in chloroform (20 ml), saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml), and saturated saline (20 ml).
After washing with, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 938).
5,10 g) and eluted with a mixed solvent of chloroform: methanol: concentrated aqueous ammonia = 30: 1: 0.1 to obtain 121 mg of the title compound as a colorless oil. Yield 8
5%

Example 22 Synthesis of 2- (N- (3-benzoylaminopropyl)) aminomethyl-2,3-dihydrobenzo [b] furan Step A 2- (N- (3-benzoylaminopropyl)
Synthesis of -N-benzyl) aminomethyl-2,3-dihydrobenzo [b] furan 2- (N- (3-aminopropyl) -N-benzyl) aminomethyl-2,3 prepared according to Reference Example 3. 445 mg of dihydrobenzo [b] furan (1.50 mmol
l) was dissolved in 5.0 ml of methylene chloride, cooled to 0 ° C., and 0.42 ml (3.00 mmol) of triethylamine was dissolved.
l), 0.21 ml of benzoyl chloride (1.8 mmol)
l) was added. After the reaction solution was stirred at 0 ° C. for 2 hours, chloroform (20 ml) was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml), and saturated saline (20 ml).
The chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (Merck, Art. 9385, 10 g).
The residue was eluted with a mixed solvent of hexane: ethyl acetate = 2: 1 to obtain 555 mg of the title compound as a pale yellow oil. 92% yield

Step B Synthesis of 2- (N- (3-benzoylaminopropyl)) aminomethyl-2,3-dihydrobenzo [b] furan 2- (N- (3-benzoylamino) prepared by Step A Propyl) -N-benzyl) aminomethyl-2,
180 mg of 3-dihydrobenzo [b] furan (0.45
was dissolved in 2.0 ml of methylene chloride and cooled to 0 ° C., and 0.80 ml (1.34 mmol) of a toluene solution of carbobenzoxychloride (manufactured by Tokyo Chemical Industry Co., Ltd.) was added. After the reaction solution was stirred at 40 ° C. for 4 hours, chloroform (20 ml) was added, and saturated aqueous sodium hydrogen carbonate was added to the reaction mixture.
After washing with 20 ml of water, 20 ml of water and 20 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper,
It was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g) and eluted with chloroform to give 2- (N- (3-benzoylaminopropyl) -N-carbobenzoxy) aminomethyl-2, 203 mg of 3-dihydrobenzo [b] furan
I got

Of these, 152 mg (0.34 mmol)
Was dissolved in 0.5 ml of acetic acid, 0.05 ml of anisole was added, the mixture was cooled to 0 ° C., and a 30% aqueous solution of hydrobromic acid in acetic acid was added.
75 ml was added. After stirring the reaction at room temperature for 1 hour,
After adding 20 ml of ether, the deposited precipitate was collected by filtration, dissolved in 20 ml of chloroform, washed with 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water and 20 ml of saturated saline, and the chloroform layer was dehydrated through Whatman 1PS filter paper, and dried under reduced pressure. Concentrated. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10).
g) and eluted with a mixed solvent of chloroform: methanol = 30: 1 to obtain 105 mg of the title compound as a pale yellow oil. 99% yield

Example 23 Synthesis of 2- (N- (3- (4-fluorobenzoylamino) propyl)) aminomethyl-2,3-dihydrobenzo [b] furan Step A 2- (N-benzyl-N- (3- (4-fluorobenzoylamino) propyl)) aminomethyl-2,
Synthesis of 3-dihydrobenzo [b] furan 227 mg of 2- (N- (3-aminopropyl) -N-benzyl) aminomethyl-2,3-dihydrobenzo [b] furan prepared in Reference Example 3 (0 .76mmo
l) was dissolved in 2.0 ml of methylene chloride, cooled to 0 ° C., and 0.23 ml of triethylamine (1.62 mmol) was added.
l), 0.12 ml of 4-fluorobenzoyl chloride
(0.97 mmol) was added. After the reaction solution was stirred at 0 ° C. for 2 hours, chloroform (20 ml) was added, and saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml), and saturated saline (2) were added.
After washing with 0 ml, the chloroform layer was washed with Whatman 1PS.
It was dehydrated through filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9).
385, 10 g) and hexane: ethyl acetate = 2:
Elution with the mixed solvent of 1 gave 321 mg of the title compound as a pale yellow oil. 100% yield

Step B 2- (N- (3- (4-fluorobenzoylamino) propyl)) aminomethyl-2,3
Synthesis of -dihydrobenzo [b] furan 2- (N- (3- (4-fluorobenzoylamino) propyl) -N-benzyl) aminomethyl-2,3-dihydrobenzo [b] prepared by step A Franc 20
0 mg (0.48 mmol) of methylene chloride 2.0 ml
And cooled to 0 ° C, and 0.85 ml of a toluene solution of carbobenzoxychloride (manufactured by Tokyo Chemical Industry Co., Ltd.) (1.4
3 mmol) was added. After the reaction solution was stirred at 40 ° C. for 2.5 hours, 20 ml of chloroform was added, and 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water, and 20 ml of saturated saline were added.
After washing with chloroform, the chloroform layer was dehydrated through Whatman 1PS filter paper. (50 mmol) and concentrated.
The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g), and eluted with a mixed solvent of hexane: ethyl acetate = 1: 1 to give 2- (N- (3
-(4-fluorobenzoylamino) propyl) -N-
194 mg of (carbobenzoxy) aminomethyl-2,3-dihydrobenzo [b] furan were obtained.

The obtained compound (192 mg, 0.42 mm
ol) in 0.5 ml of acetic acid and 0.05
The mixture was cooled to 0 ° C, and 0.92 ml of a 30% hydrobromic acid in acetic acid solution was added. After stirring the reaction solution at room temperature for 1 hour, 20 ml of ether was added, and the deposited precipitate was collected by filtration, dissolved in 20 ml of chloroform, washed with 20 ml of a saturated aqueous solution of sodium hydrogencarbonate, 20 ml of water and 20 ml of a saturated saline solution, and then chloroform layer was added. Was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385,
10g), chloroform: methanol = 30: 1
To give 121 mg of the title compound as a pale yellow oil. 77% yield

Example 24 Synthesis of 2- (N- (4-benzoylaminobutyl) -N-methyl) aminomethyl-2,3-dihydrobenzo [b] furan (4-Benzoylaminobutyl)) 160 mg (0.50 mmol) of aminomethyl-2,3-dihydrobenzo [b] furan are dissolved in 1.6 ml of methanol, cooled to 0 ° C, and 0.40 ml of a 37% aqueous formaldehyde solution (5%). .0 mmol)
Was added. Sodium cyanoborohydride 31mg
(0.50 mmol), stirred at 0 ° C. for 2 hours, added with 20 ml of chloroform, washed with 20 ml of water and 20 ml of saturated saline, dehydrated the chloroform layer through Whatman 1PS filter paper, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Arc, A
rt. 9385, 10 g) and eluted with a mixed solvent of chloroform: methanol = 50: 1 to give the title compound 13
9 mg was obtained as a colorless oil. 82% yield

Example 25 Synthesis of 2- (N- (4-benzoylaminobutyl) -N-ethyl) aminomethyl-2,3-dihydrobenzo [b] furan (4-Benzoylaminobutyl)) 160 mg (0.50 mmol) of aminomethyl-2,3-dihydrobenzo [b] furan are dissolved in 1.6 ml of acetonitrile, and 0.04 of ethyl iodide is dissolved.
8 ml (0.60 mmol) and 138 mg of potassium carbonate
(1.00 mmol), stirred at 60 ° C. for 24 hours, then added with 20 ml of chloroform, washed with 20 ml of water and 20 ml of saturated saline, dehydrated the chloroform layer through Whatman 1PS filter paper, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck,
Art. 9385, 10 g) and eluted with a mixed solvent of chloroform: methanol = 50: 1 to give the title compound 1
45 mg were obtained as a pale yellow oil. 82% yield

Example 26 Synthesis of 2- (N- (3-benzoylaminopropyl) -N-methyl) aminomethyl-2,3-dihydrobenzo [b] furan Dissolve 164 mg (0.53 mmol) of (3-benzoylaminopropyl)) aminomethyl-2,3-dihydrobenzo [b] furan in 1.6 ml of methanol, cool to 0 ° C.
0.40 ml (5.0 mmo
l) was added. Sodium cyanoborohydride 35mg
(0.56 mmol), stirred at 0 ° C. for 2 hours, added with 20 ml of chloroform, washed with 20 ml of water and 20 ml of saturated saline, dehydrated the chloroform layer through Whatman 1PS filter paper, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Arc, A
rt. 9385, 10 g) and eluted with a mixed solvent of chloroform: methanol = 30: 1 to give the title compound 12
8 mg were obtained as a colorless oil. 72% yield

Example 27 Synthesis of 2,3-dihydro-2- (N- (4- (4-fluorobenzenesulfonylamino) butyl)) aminomethylbenzo [b] furan Step A 2- (N- (t- Butoxycarbonyl) -N-
Synthesis of (4- (4-fluorobenzenesulfonylamino) butyl)) aminomethyl-2,3-dihydrobenzo [b] furan 2- (N- (4-aminobutyl) -N prepared according to Reference Example 1 -(T-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan 160 mg
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol), 117 mg (0.60 mmol) of p-fluorobenzenesulfonyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.)
l) was added. After the reaction solution was stirred at 0 ° C. for 2 hours, chloroform (20 ml) was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml), and saturated saline (20 ml).
The chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (Merck, Art. 9385, 10 g).
And eluted with a mixed solvent of hexane: ethyl acetate = 5: 1 to obtain 203 mg of the title compound as a pale yellow oil. 85% yield

Step B 2,3-dihydro-2- (N-
Synthesis of (4- (4-fluorobenzenesulfonylamino) butyl)) aminomethylbenzo [b] furan 2- (N- (t-butoxycarbonyl) -N- (4- (4 -Fluorobenzenesulfonylamino) butyl)) aminomethyl-2,3-dihydrobenzo [b] furan 194 mg (0.40 mmol)
Was cooled to 0 ° C., and 2.0 ml of trifluoroacetic acid was added.
Stirred at 0 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution was saturated sodium bicarbonate solution (20 ml), water (20 ml), and saturated saline solution (20 m).
After washing with l, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to give 148 mg of the title compound.
Was obtained as a pale yellow oil. 97% yield

Example 28 Synthesis of 2,3-dihydro-2- (N- (4- (3-nitrobenzenesulfonylamino) butyl)) aminomethylbenzo [b] furan Step A 2- (N- (t-butoxy) Carbonyl) -N-
Synthesis of (4- (3-nitrobenzenesulfonylamino) butyl)) aminomethyl-2,3-dihydrobenzo [b] furan 2- (N- (4-aminobutyl) -N- prepared according to Reference Example 1. (T-butoxycarbonyl)) aminomethyl-2,3-dihydrobenzo [b] furan 160 mg
(0.50 mmol) was dissolved in 1.6 ml of methylene chloride, cooled to 0 ° C., and 0.14 ml of triethylamine was dissolved.
(1.0 mmol), 133 mg (0.60 mmol) of m-nitrobenzenesulfonyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.)
l) was added. After the reaction solution was stirred at 0 ° C. for 2 hours, chloroform (20 ml) was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml), and saturated saline (20 ml).
The chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (Merck, Art. 9385, 10 g).
And eluted with a mixed solvent of hexane: ethyl acetate = 3: 1 to obtain 180 mg of the title compound as a pale yellow oil. 71% yield

Step B 2,3-Dihydro-2- (N-
Synthesis of (4- (3-nitrobenzenesulfonylamino) butyl)) aminomethylbenzo [b] furan The 2- (N- (t-butoxycarbonyl) -N- (4- (3- Nitrobenzenesulfonylamino) butyl)) 180 mg (0.36 mmol) of aminomethyl-2,3-dihydrobenzo [b] furan were cooled to 0 ° C., and 2.0 ml of trifluoroacetic acid was added.
Stirred at C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution is saturated sodium bicarbonate aqueous solution 20 ml, water 20 ml, saturated saline solution 20 ml
After washing with, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to give 143 mg of the title compound as a pale yellow oil. 99% yield

Example 29 Synthesis of 2,3-dihydro-2- (N- (4- (2-hydroxybenzoylamino) butyl)) aminomethylbenzo [b] furan Step A 2- (N- (t-butoxy) Carbonyl) -N-
(4- (2-acetoxybenzoylamino) butyl))
Synthesis of aminomethyl-2,3-dihydrobenzo [b] furan 2- (N- (4-aminobutyl) -N- (t-butoxycarbonyl)) aminomethyl-2,3 prepared according to Reference Example 1. -640 mg of dihydrobenzo [b] furan
(2.00 mmol) in 7 ml of methylene chloride,
After cooling to 0 ° C., 0.42 ml of triethylamine (3.
0 mmol) and 497 mg (2.50 mmol) of 0-acetylsalicyloyl chloride (manufactured by Aldrich) were added. After the reaction solution was stirred at 0 ° C. for 2 hours, chloroform (20 ml) was added, and saturated aqueous sodium hydrogen carbonate (20 ml) was added.
After washing with 1, 20 ml of water and 20 ml of saturated saline, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 20 g), and eluted with chloroform to obtain 760 mg of the title compound as a pale yellow oil. 79% yield

Step B 2,3-Dihydro-2- (N-
(4- (2-hydroxybenzoylamino) butyl))
Synthesis of aminomethylbenzo [b] furan 2- (N- (t-butoxycarbonyl) -N- (4- (2-acetoxybenzoylamino) butyl)) aminomethyl-2,3 prepared in Step A above. -600 mg (1.24 mmol) of dihydrobenzo [b] furan was dissolved in 6 ml of methanol, cooled to 0 ° C, and 1.5 ml of a 1N methanol solution of sodium methoxide was added.
After the reaction solution was stirred at 0 ° C. for 2 hours, chloroform 20m
and then add 20 ml of saturated aqueous ammonium chloride and 20 ml of water.
After washing with 20 ml of a saturated saline solution, the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art. 9385, 10 g) and eluted with chloroform to obtain a pale yellow oil. Remove this oil
And cooled to 0 ° C, and 4.8 ml of trifluoroacetic acid was added.
For 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml). The solution was washed with 20 ml of saturated aqueous sodium hydrogen carbonate, 20 ml of water and 20 ml of saturated saline, and the chloroform layer was dehydrated through Whatman 1PS filter paper and concentrated under reduced pressure to obtain 332 mg of the title compound as a white foam. 79% yield

[0160]

[Table 5]

[0161]

[Table 6]

[0162]

[Table 7]

[0163]

[Table 8]

[0164]

[Table 9]

[0165]

[Table 10]

[0166]

[Table 11]

[0167]

[Table 12]

[0168]

[Table 13]

[0169]

[Table 14]

[0170]

[Table 15]

[0171]

[Table 16]

[0172]

[Table 17]

[0173]

[Table 18]

Continuation of the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07D 307/81 A61K 31/34 CA (STN) REGISTRY (STN)

Claims (15)

(57) [Claims] (1) Formula (1) Wherein R 1 is a hydrogen atom or a lower alkyl group; n is an integer from 2 to 6; A is CO or SO 2;
Represents a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group, a hydroxyl group, a nitro group or a cyano group; * represents an asymmetric carbon, respectively. A) 2,3-dihydrobenzofuran derivative or a salt thereof. 2. The derivative according to claim 1, wherein n is 4
A 2,3-dihydrobenzofuran derivative or a salt thereof, which comprises the compound represented by the formula: 3. A 2,3-dihydrobenzofuran derivative or a salt thereof, wherein the derivative of claim 1 is a compound wherein R1 is hydrogen. 4. The derivative according to claim 1, wherein R1 is a methyl or ethyl group.
A dihydrobenzofuran derivative or a salt thereof. 5. The derivative according to claim 1, wherein n is 4
And a compound wherein A is a carbonyl group, or a salt thereof. 6. The derivative according to claim 1, wherein n is 4
And a compound wherein R2 is a hydrogen atom or a fluorine atom, or a 2,3-dihydrobenzofuran derivative or a salt thereof. 7. The derivative according to claim 1, wherein n is 4
And R2 is a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group, a cyano group, a chlorine atom or a bromine atom which may be substituted with a halogen,
A 2,3-dihydrobenzofuran derivative or a salt thereof comprising a compound in which the bonding position of 2 is at the 3-position. 8. The derivative according to claim 1, wherein n is 4
And a compound wherein R2 is a methyl group or a methoxy group , or a salt thereof. 9. A (-)-2- {N- (4-benzoylamino) butyl} aminomethyl-2,3-dihydrobenzofuran or a salt thereof. 10. A compound selected from the following group or a salt thereof. 2- {N- (4-benzoylamino) butyl} aminomethyl-2,3-dihydrobenzofuran, 2- {N- (4-benzenesulfonamido) butyl} aminomethyl-2,3-dihydrobenzofuran, 2,3 -Dihydro-2- [N- {4- (3-methylbenzoylamino) butyl}] aminomethylbenzofuran, 2,3-dihydro-2- [N- {4- (3-methoxybenzoylamino) butyl}] amino Methylbenzofuran, 2,3-dihydro-2- [N- {4- (2-fluorobenzoylamino) butyl}] aminomethylbenzofuran, 2,3-dihydro-2- [N- {4- (3-fluorobenzoyl) Amino) butyl}] aminomethylbenzofuran, 2,3-dihydro-2- [N- {4- (4-fluorobenzoylamino) butyl}] ami Methylbenzofuran, (+) - 2- {N- (4- benzoylamino) butyl}
Aminomethyl-2,3-dihydrobenzofuran, 2- {N- (3-benzoylamino) propyl} aminomethyl-2,3-dihydrobenzofuran, 2- {N- (4-benzoylamino) butyl-N-methyl} Aminomethyl-2,3-dihydrobenzofuran and 2- {N- (4-benzoylamino) butyl-N-ethyl} aminomethyl-2,3-dihydrobenzofuran 11. A compound selected from the following group or a salt thereof. 2,3-dihydro-2- [N- {4- (2-methylbenzoylamino) butyl}] aminomethylbenzofuran, 2,3-dihydro-2- [N- {4- (4-methylbenzoylamino) butyl {] Aminomethylbenzofuran, 2,3-dihydro-2- [N- {4- (2-methoxybenzoylamino) butyl}] aminomethylbenzofuran, 2,3-dihydro-2- [N- {4- (4 -Methoxybenzoylamino) butyl}] aminomethylbenzofuran, 2,3-dihydro-2- [N- {4- (2-trifluoromethylbenzoylamino) butyl}] aminomethylbenzofuran, 2,3-dihydro-2- [N- {4- (3-trifluoromethylbenzoylamino) butyl}] aminomethylbenzofuran, 2,3-dihydro-2- [N- {4- 4-trifluoromethylbenzoylamino) butyl}] aminomethylbenzofuran, 2,3-dihydro-2- [N- {4- (3-nitrobenzoylamino) butyl}] aminomethylbenzofuran, 2,3-dihydro-2 -[N- {4- (3-cyanobenzoylamino) butyl}] aminomethylbenzofuran, 2- {4- (2-benzoylamino) ethyl} aminomethyl-2,3-dihydrobenzofuran, 2,3-dihydro- 2- [N- {2- (3-methylbenzoylamino) ethyl}] aminomethylbenzofuran, 2,3-dihydro-2- [N- {2- (4-fluorobenzoylamino) ethyl}] aminomethylbenzofuran, 2,3-dihydro-2- [N- {3- (4-fluorobenzoylamino) propyl}] aminomethylbenzo Orchid, 2- {N- (3-benzoylamino) propyl-N-methyl} aminomethyl-2,3-dihydrobenzofuran, 2,3-dihydro-2- [N- {4- (4-fluorobenzenesulfonylamino) ) Butyl}] aminomethylbenzofuran, 2,3-dihydro-2- [N- {4- (3-nitrobenzenesulfonylamino) butyl}] aminomethylbenzofuran and 2,3-dihydro-2- [N- {4- (2-hydroxybenzoylamino) butyl}] aminomethylbenzofuran 12. The formula (2) (Wherein * represents an asymmetric carbon; n represents an integer of 2 to 6;
R11 represents a protecting group for an amino group or a lower alkyl group. And a compound represented by the formula (3): (Wherein R2 represents a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group, a hydroxyl group, a nitro group or a cyano group;
Or X represents a leaving group. ) To give a compound of formula (4) (Wherein, R11, R2, A, * and n have the same meanings as described above), and when R11 is a protecting group for an amino group, the protecting group is removed. leave,
Formula (1) (Wherein R1, R2, A, * and n have the same meanings as described above), characterized in that they are a 2,3-dihydrobenzofuran derivative or a salt thereof, A method for producing the salt. 13. The method according to claim 12, wherein the compound is (-)-2- {N- (4-benzoylamino) butyl} aminomethyl-2,3-dihydrobenzofuran or a salt thereof. The manufacturing method as described. 14. The formula (1) Wherein R 1 is a hydrogen atom or a lower alkyl group; n is an integer from 2 to 6; A is CO or SO 2;
Represents a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group, a hydroxyl group, a nitro group or a cyano group; * represents an asymmetric carbon, respectively. )) For the administration of antiemetic drugs comprising a 2,3-dihydrobenzofuran derivative or a salt thereof as an active ingredient.
Or a pharmaceutical composition for antidepressant . 15. The antiemetic or antiemetic according to claim 14.
In a pharmaceutical composition for depression, 2,3-dihydrobe
When the nzofuran derivative or a salt thereof is (-)-2- {N-
(4-benzoylamino) butyl @ aminomethyl-2,
3. The compound according to claim 1, which is 3-dihydrobenzofuran or a salt thereof.
5. The pharmaceutical composition according to 4.