JPH05239005A - N-(2-aminoethyl)benzamides and their new intermediate - Google Patents

Abstract

PURPOSE:To obtain a new N-(2-aminoethyl)benzamide expectable as a therapeutic agent for improving diseases of mental function resulting from intracerebral organic disorder, such as cerebrovascular disorder or geriatric dementia. CONSTITUTION:A compound of formula 6 [Y1 to Y3 are OH, OBn, and Y1 and Y2 are H with the proviso that when Y1=H, Y2=Y3 and when Y2=H, Y1=Y3; Bn is benzyl; R6 is NH2 N(CH3)2, N (C2H5)2, pyrrolidino, piperidino or morpholino] such as 2-[2-(diethylamino)ethyl]-2,5-dihydroxybenzamide. The compound (compound of formula 1 to formula 2) is produced by treating a compound of formula 5 (one of R1 and R2 is H and the other is OH; R3 is CH3 or C2H5) with a base, reacting the resultant substance with a benzyl halide to give a new substance of formula 4 (one of R4 and R5 is H and the other is OBn), hydrolyzing this compound under an alkali condition to give a new substance of formula 3, reacting this compound with SOCl2 in the presence of a tertiary amine, then with an ethylenediamine and optionally further hydrogenating.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to pharmaceuticals, especially cerebrovascular disorders,
N- (2-aminoethyl) benzamides represented by the following formula (A), which are expected as therapeutic agents for improving mental function symptoms caused by organic disorders in the brain such as senile dementia, and synthetic intermediates of the compounds And dibenzyloxybenzoic acids represented by the following formula (B), which are useful as

More specifically, the present invention provides the following formula (A):

[Chemical 3] (In the formula, Y ₁ and Y ₂ represent a hydrogen atom, a hydroxyl group or a benzyloxy group, and Y ₃ represents a hydroxyl group or a benzyloxy group. When Y ₁ is a hydrogen atom, Y ₂ and Y ₃ are the same group. When Y ₂ is a hydrogen atom, Y ₁ and Y ₃ represent the same group, and R ₆ represents amino, dimethylamino, diethylamino, pyrrolidino, piperidino and morpholino groups. N- (2-aminoethyl) benzamides represented and the following formula (B) useful as a synthetic intermediate for the compound

[Chemical 4] (In the formula, R ₄ and R ₅ represent a hydrogen atom or a benzyloxy group, but do not represent the same group at the same time.
₇ represents a hydrogen atom, a methyl group or an ethyl group, and Bn represents a benzyl group.). Furthermore, a novel process for producing the compound of formula (A) and formula (B) is also provided.

[0003]

2. Description of the Related Art As a therapeutic agent for improving psychiatric function symptoms caused by organic disorders in the brain such as cerebrovascular disorder and senile dementia, which contains an amine derivative having an aromatic ring as an active ingredient, for example, N is used.
-[2- (diethylamino) ethyl] -2-methoxy-
5-Methanesulfonylbenzamide and a hydrochloric acid adduct of the compound (hereinafter referred to as tiapride), N-methyl-4- [2- (phenylmethyl) phenoxy] -1-butanamine and a hydrochloric acid adduct of the compound (hereinafter, Known as biphemerans), and some proposals have been made (JP-A-64-2284).
No. 7, JP-B-59-31492, JP-B-59-35
386, Japanese Patent Publication No. 60-6349, Japanese Patent Publication No. 2-33
689).

[0004]

However, with the aging of society, measures against senile dementia have become an urgent problem.
In order to cope with this, it is strongly desired to develop an improved therapeutic drug for cerebral functional symptoms together with conventional biphemerans or tiapride.

[0005]

[Means for Solving the Problems] In order to solve the above-mentioned problems, the inventors of the present invention have conducted extensive studies. As a result, amelioration and treatment of psychiatric function symptoms via novel compounds of the above formula (B) including the compounds of the following formulas (4) and (3) that can be easily synthesized from the compounds of the following formula (5) It has been discovered that the novel formula (A) including the compounds of formula (2) and formula (1), which can be expected as a drug, can be provided. Therefore, an object of the present invention is to provide a compound of formula (A), which can be expected as a remedy for improving psychological symptoms. Further, it is to provide a new production method capable of obtaining the compound in good yield and high purity.

According to the present invention, the compound of the following formula (2) and the following formula (1) included in the formula (A) and the formula (B).
The compounds of the following formulas (4) and (3) included in the formula (4) are synthesized by reacting the alkyldihydroxybenzoates of the formula (5) with benzyl halide (BnX). Step of forming oxybenzoates [hereinafter referred to as step (a)]: Step of hydrolyzing the compound of the formula (4) to form dibenzyloxybenzoic acids of the following formula (3) [hereinafter, (b ) Step]: a step of treating the compound of the formula (3) with thionyl chloride and then reacting with ethylenediamine to form N- (2-aminoethyl) dibenzyloxybenzamides of the following formula (2). [Hereinafter, referred to as step (c)]: A step of reducing the compound of the formula (2) to form N-2- (aminoethyl) dihydroxybenzamides of the formula (1) described below. [Hereinafter, (d) referred to as Step] it consists. Furthermore, the present invention provides the steps (b) and (c).
As an alternative method for synthesizing the compound of formula (2) that does not go through a step, a step of directly reacting a compound of formula (4) with ethylenediamine to form a compound of formula (2) [hereinafter referred to as step (e)] It also includes.

The compound of the following formula (4) and the following formula (3) included in the formula (B) of the present invention and the compound of the following formula (2) and the following formula (1) included in the formula (A) are used. The respective steps to be synthesized can be represented by the following reaction formulas.

[0008]

[Chemical 5] (In the formula, R ₁ and R ₂ represent a hydrogen atom or a hydroxyl group, but they do not represent the same group at the same time. Further, R ₃ represents a methyl group or an ethyl group, and X represents a halogen atom. R ₄ , R ₅ and R ₆ represent the same groups as described above).

The manufacturing method of each step will be described in detail below with reference to the above reaction step diagrams. Step (a) In the reaction for synthesizing the compound of formula (4) included in the compound of formula (B) from the compound of formula (5), the compound of formula (5) is treated with a base in an organic solvent. Then, it can be easily carried out by reacting with a benzyl halide in the presence of a phase transfer catalyst. The compound of formula (5) as a starting material is commercially available or can be easily produced by subjecting the corresponding dihydroxybenzoic acid to an esterification reaction with a lower alcohol such as methanol or ethanol in the presence of an acid.

The reaction time and reaction temperature of the above reaction are
It can be appropriately selected, for example, from about 0 ° C to about 50 ° C.
It may be performed in the temperature range of about 5 to about 20 hours. As the halogen of benzyl halide used in this reaction,
For example, fluorine, chlorine, bromine, etc. can be mentioned,
The amount of these benzyl halides used is preferably in the range of, for example, about 2 to about 5 mol, relative to 1 mol of the compound of the formula (5).

Examples of the base include sodium hydride,
Examples thereof include sodium methoxide, sodium ethoxide, sodium amide, and potassium carbonate. There is no particular limitation on the amount used, and for example, about 2 to about 5 moles relative to 1 mole of the compound of formula (5). The range is appropriate. Further, as the phase transfer catalyst, for example, tetra-normal butyl ammonium iodide, tetra-normal butyl ammonium bromide, tetramethyl ammonium iodide, tetramethyl ammonium bromide and the like,
The amount used is, for example, 1 mol of the compound of the formula (5),
For example, a range of about 0.001 to about 0.01 mol can be mentioned. Further, the organic solvent used may be a solvent inert to the reaction, such as tetrahydrofuran,
Examples thereof include diethyl ether and dimethylformamide. The amount of these solvents used may be appropriately selected,
For example, an amount of about 10 to about 50 times by weight the amount of the compound of the formula (5) is preferable. After completion of the reaction, the product is washed, extracted, and purified by a conventional method such as column chromatography according to a conventional method to obtain a good yield of the novel alkyldibenzyloxybenzoates represented by the above formula (4). It can be obtained with high rate and high purity. Specific examples of the compound of formula (4) thus obtained include methyl 2,5-dibenzyloxybenzoate and ethyl
2,5-dibenzyloxybenzoate, methyl 2,
3-dibenzyloxybenzoate, ethyl 2,3-
An example is dibenzyloxybenzoate.

Step (b) The reaction of synthesizing the compound of formula (3) included in the compound of formula (B) from the compound of formula (4) obtained as described above is It can be easily carried out by hydrolysis under alkaline conditions.

The above hydrolysis may be carried out according to a usual method. For example, the compound of formula (4) dissolved in an organic solvent such as methanol or ethanol is treated with sodium hydroxide,
It may be brought into contact with an aqueous alkaline solution such as potassium hydroxide. The amount of alkali used can be, for example, a range of equimolar or more, for example, about 1 to about 2 mol per 1 mol of the compound of the formula (4). Although the reaction time varies depending on the reaction temperature, it can be carried out, for example, in the temperature range of about 20 ° C. to about 60 ° C. for about 1 to about 10 hours. After completion of the reaction, the novel dibenzyloxybenzoic acid represented by the above formula (3) of the present invention can be obtained in good yield by using a purification means such as washing, extraction and column chromatography of the product. .. Specific examples of the compound of formula (3) thus obtained include 2,3-dibenzyloxybenzoic acid and 2,5-dibenzyloxybenzoic acid.

(C) Step The compound of the formula (3) is reacted with thionyl chloride in the presence of a tertiary amine in an organic solvent to form an acid chlorinated compound of the compound of the formula (3), and then the chlorinated compound is treated with an organic compound. A novel N- (2-aminoethyl) dibenzyl represented by the above formula (2) included in the compound of formula (A) by amidation reaction with ethylenediamines in the presence of a tertiary amine in a solvent. Oxybenzamides can be synthesized.

The reaction time of the chlorination reaction of the compound of formula (3) varies depending on the reaction temperature, but is, for example, about 0 ° C to about 30 ° C.
It can be carried out in the temperature range of about 1 to about 5 hours. Examples of the tertiary amine used in the above reaction include triethylamine and diisopropylethylamine.
The amount of these amines used is preferably, for example, about 1 to about 5 mol per 1 mol of the compound of the formula (3). The amount of thionyl chloride used can be, for example, an equimolar amount or more, for example, about 1 to about 5 times the molar amount of the compound of the above formula (3). Furthermore, examples of the organic solvent include halogen-based organic solvents such as methylene chloride and chloroform, and the amount of the solvent used may be appropriately selected. For example, about 5 to about 5 relative to the compound of the formula (3). About 50 times by weight can be mentioned. After completion of the reaction, the chlorinated product of the compound of the formula (3) may be isolated by a method such as extraction of the product according to a conventional method, but normally, the chlorinated product is reacted with ethylenediamines without isolation. Can be amidated.

The reaction time and the reaction temperature of the amidation reaction are, for example, about 1 to about 20 in the temperature range of about 0 ° C to about 30 ° C.
It can be done in about an hour. This reaction can be carried out in accordance with the above-mentioned chlorination reaction of the compound of the formula (3). For example, the type of the tertiary amine and the organic solvent used in the reaction and the amounts thereof used are The same types and usage ranges as illustrated can be shown. The types of ethylenediamines include, for example, ethylenediamine, N, N-dimethylethylenediamine, N, N-diethylethylenediamine, 1- (2-aminoethyl) pyrrolidine, 1- (2-aminoethyl) piperidine, 4-
(2-Aminoethyl) morpholine and the like can be mentioned, and the use amount thereof can be, for example, about 1 to about 5 times mol per 1 mol of the compound of the formula (3). After completion of the reaction, the N- (2-aminoethyl) dibenzyloxybenzamide represented by the above-mentioned novel formula (2) of the present invention is used by using a purification means such as washing, extraction and column chromatography of the product. You can synthesize the kind. Specific examples of the compound of formula (2) thus obtained include:
N- (2-aminoethyl) 2,3-dibenzyloxybenzamide, N- (2-aminoethyl) 2,5-dibenzyloxybenzamide, N- [2- (dimethylamino) ethyl] 2,3-di Benzyloxybenzamide,
N- [2- (dimethylamino) ethyl] 2,5-dibenzyloxybenzamide, N- [2- (diethylamino) ethyl] 2,3-dibenzyloxybenzamide,
N- [2- (diethylamino) ethyl] 2,5-dibenzyloxybenzamide, N- (2-pyrrolidinoethyl) 2,3-dibenzyloxybenzamide, N- (2
-Pyrrolidinoethyl) 2,5-dibenzyloxybenzamide, N- (2-piperidinoethyl) 2,3-dibenzyloxybenzamide, N- (2-piperidinoethyl) 2,5-dibenzyloxybenzamide, N- (2
-Morpholinoethyl) 2,3-dibenzyloxybenzamide, N- (2-morpholinoethyl) 2,5-dibenzyloxybenzamide and the like can be mentioned.

Step (d) To synthesize the N- (2-aminoethyl) dihydroxybenzamides of the above formula (1) included in the compound of the formula (A) from the compound of the above formula (2), the following formula ( It can be carried out by carrying out a hydrogenation reaction of the compound of 2) in an organic solvent in the presence of a hydrogenation catalyst.

The hydrogenation reaction is usually carried out under pressure,
Since the reaction proceeds sufficiently even under atmospheric pressure conditions,
It can be carried out without using a pressure device such as an autoclave. This reaction can be carried out, for example, at a reaction temperature of about 10 ° C. to about 50 ° C. and a reaction time of about 1 to about 20 hours. Examples of the type of hydrogenation catalyst include palladium-carbon, Raney nickel, rhodium-carbon, etc., and the amount thereof used is, for example, about 0.1 to about 0.1 with respect to the compound of the formula (2). 1.
A range of about 0 parts by weight can be more preferably shown.
The amount of hydrogen gas used may be, for example, about 2 mol or more, preferably about 2 to about 10 mol, based on the compound of formula (2).

Further, examples of the organic solvent used in this reaction include methanol, ethanol, etc., and these solvents are about 5 to 5 with respect to the compound of the formula (2).
The amount used is preferably about 50 times by weight. After the reaction, the product is separated and purified by a conventional method to obtain the N- (2-aminoethyl) dihydroxybenzamide represented by the formula (1) in a good yield. Specific examples of the compound of the formula (1) which can be synthesized in this manner include N-
(2-Aminoethyl) 2,3-dihydroxybenzamide, N- (2-aminoethyl) 2,5-dihydroxybenzamide, N- [2- (dimethylamino) ethyl]
2,3-Dihydroxybenzamide, N- [2- (dimethylamino) ethyl] 2,5-dihydroxybenzamide, N- [2- (diethylamino) ethyl] 2,3-dihydroxybenzamide, N- [2- (diethylamino) Ethyl] 2,5-dihydroxybenzamide, N-
(2-pyrrolidinoethyl) 2,3-dihydroxybenzamide, N- (2-pyrrolidinoethyl) 2,5-dihydroxybenzamide, N- (2-piperidinoethyl)
2,3-Dihydroxybenzamide, N- (2-piperidinoethyl) 2,5-dihydroxybenzamide, N-
(2-morpholinoethyl) 2,3-dihydroxybenzamide, N- (2-morpholinoethyl) 2,5-dihydroxybenzamide and the like can be mentioned.

(E) As an alternative method for synthesizing the compound of process formula (2), the above (b)
By heating the compound of the formula (4) and ethylenediamine without heating through the step and the step (c),
The compound of formula (2) can be directly synthesized.

The reaction temperature of the heating reaction is preferably a temperature above the boiling point of methanol or ethanol produced in the reaction, and for example, a temperature range of about 120 ° C. to about 150 ° C. can be exemplified. Although the reaction time varies depending on the reaction temperature, about 1 to about 5 hours is sufficient within the above temperature range. With respect to the types of ethylenediamines used in this reaction and the amounts thereof used, for example, the types and use ranges exemplified in the above-mentioned [step (c)] can be used. After completion of the reaction, the product is washed, extracted, and
The compound of formula (2) can be obtained in good yield by using a purification means such as column chromatography.

The method for synthesizing the compounds of formula (A) and formula (B) of the present invention will be described in detail below with reference to examples.

[0023]

Example 1 Methyl 2,5-dibenzyloxybenzoate
Synthesis of [Compound of (4)] [Step (a)]. Sodium hydride (60%) 4.4 g (0.11 mol)
And 110 ml of dry tetrahydrofuran are charged and stirred. A solution of 8.4 g (0.05 mol) of methyl 2,5-dihydroxybenzoate [compound of formula (5)] and 110 ml of dry dimethylformamide was added dropwise at 10 to 20 ° C over 1 hour, and then hydrogen gas was further generated. Stir for 1 hour until stops. To the reaction solution, 50 mg of a phase transfer catalyst, tetranormal butylammonium iodide, was added, and then 20.5 g (0.12 mol) of benzyl bromide was added dropwise at room temperature for 30 minutes, and the mixture was further reacted overnight with stirring. The reaction solution is added to 300 ml of water and extracted with ether. The extract was washed with water, dried over magnesium sulfate and concentrated. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2).
Purification with 0: 1 to 3: 1) gave 16.4 g of pure methyl 2,5-dibenzyloxybenzoate (yield: 94%). The IR data is as follows. IR (cm ^-1 ): 1731 (-CO-), 1502 (aromatic ring), 1027 (CO)

[0024]

Examples 2 to 4 According to the method of Example 1, various compounds of the formula (5) were used in place of the methyl 2,5-dihydroxybenzoate of Example 1 to prepare corresponding compounds of the formula (4). Synthesized. The IR data of these compounds are as follows. No Compound name IR data 2 Methyl 2,3-dibenzyloxy benzoate 1740 (-CO-), 1480 (aromatic ring), 1030 (CO) 3 Ethyl 2,3-dibenzyloxy benzoate 1742 (-CO-), 1477 (Aromatic ring), 1025 (CO) 4 Ethyl 2,5-Dibenzyloxy benzoate 1730 (-CO-), 1505 (Aromatic ring), 1722 (CO)

[0025]

Example 5 2,5-Dibenzyloxybenzoic Acid [Compound of (3)]
[Step (b)]. To a solution of methyl 2,5-dibenzyloxybenzoate [compound of formula (4)] 16.2 g (46.6 mmol) and methanol 80 ml was added 20% aqueous sodium hydroxide solution 18.5 g (93,2 mmol), 50-60
Heat to ℃ and stir for 3 hours. After cooling, the reaction mixture becomes 2
The mixture was made weakly acidic with normal hydrochloric acid, extracted with methylene chloride, washed with water, dried over magnesium sulfate, and concentrated to obtain 15.2 g of crude 2,5-dibenzyloxybenzoic acid (yield: 97).
%). The IR data is as follows. IR (cm ^-1 ): 3450 (-COOH), 1694 (-CO-), 1479 (aromatic ring), 1085
(CO)

[0026]

Example 6 N- [2- (diethylamino) ethyl] 2,5-diben
Synthesis of Ziroxybenzamide [Compound of (2)]
[Step (c)]. 2,5-Dibenzyloxybenzoic acid [compound of (3)]
15.0 g (44.9 mmol), dry triethylamine 9.1 g (89.8 mmol) and dry methylene chloride 4
Charge 00 ml and thionyl chloride 8.
0 g (67.4 mmol) is added in 10 minutes. Then, the temperature is gradually brought to room temperature and the reaction is carried out with stirring for 3 hours. After the reaction, the solvent and excess thionyl chloride are distilled off under reduced pressure. 400 ml of dry tetrahydrofuran and 11.3 g (112 mmol) of dry triethylamine were added to the residue, and
N, N-diethylethylenediamine 7,8 g (67.4
(Mmol) under cooling for 5 minutes, and the mixture is reacted with stirring at room temperature overnight. The reaction solution was added to 300 ml of an aqueous solution of soda ash, extracted with ether, washed with water, dried over magnesium sulfate and concentrated, and the obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to obtain a highly pure product. N- [2- (diethylamino) ethyl] 2,5-dibenzyloxybenzamide 15.1 g
Was obtained (yield: 78%). The IR data is as follows. IR (cm ^-1 ): 3292 (-NH), 1632 (-CO-N), 1514 (aromatic ring), 1218 (-
NEt ₂ ), 1002 (CO)

[0027]

Examples 7 to 17 In accordance with the method of Example 6, 2,3-
Or 2,5-dibenzyloxybenzoic acid and various ethyl ethers
Reaction of diamines with the corresponding compound of formula (2)
Was synthesized. The IR data of these compounds are as follows
Is.No Compound name 7N- (2-aminoethyl) 2,3-geenyloxy benzamide IR (cm^-1): 3350 (-NH), 1630 (-CO-N), 1512 (aromatic ring), 1250 (-NH₂), 1004 (C-O) 8N- (2-aminoethyl) 2,5-benzyl oxy benzamide IR (cm^-1): 3355 (-NH), 1633 (-CO-N), 1510 (aromatic ring), 1225 (-NH₂), 1007 (C-O) 9N- [2- (Dimethylamino) ethyl] 2,3-dibenzyloxybenzene amine IR (cm^-1): 3290 (-NH), 1630 (-CO-N), 1504 (aromatic ring), 1215 (-NMe₂), 1005 (C-O) 10N- [2- (diethylamino) ethyl] 2,3-dibenzyloxybenzene amine IR (cm^-1): 3292 (-NH), 1630 (-CO-N), 1506 (aromatic ring), 1211 (-NEt₂), 1006 (C-O) 11N- [2- (Dimethylamino) ethyl] 2,5-dibenzyloxybenzene amine IR (cm^-1): 3298 (-NH), 1629 (-CO-N), 1512 (aromatic ring), 1215 (-NMe₂), 1002 (C-O) 12N- (2-Prolysinoethyl) 2,3-Benzyloxybenzene Amide IR (cm^-1): 3290 (-NH), 1634 (-CO-N), 1508 (aromatic ring), 1180 (tertiary amine), 1015 (C-O) 13N- (2-Prolysinoethyl) 2,5-Benzyloxy Benzene Amide IR (cm^-1): 3303 (-NH), 1630 (-CO-N), 1520 (aromatic ring), 1185 (tertiary amine), 1020 (C-O) 14N- (2-Phenylidinoethyl) 2,3-Benzyloxybenzene Amide IR (cm^-1): 3296 (-NH), 1635 (-CO-N), 1507 (aromatic ring), 1182 (tertiary amine), 1018 (C-O) 15N- (2-Phenylaminoethyl) 2,5-Benzyloxybenzene Amide IR (cm^-1): 3310 (-NH), 1630 (-CO-N), 1522 (aromatic ring), 1182 (tertiary amine), 1022 (C-O) 16N- (2-morpholinoethyl) 2,3-benzene oxybenzamide IR (cm^-1): 3300 (-NH), 1635 (-CO-N), 1510 (aromatic ring), 1175 (tertiary amine), 1030 (C-O) 17N- (2-morpholinoethyl) 2,5-beginyloxybenzene amine  IR (cm^-1): 3320 (-NH), 1635 (-CO-N), 1525 (aromatic ring), 1180 (tertiary amine), 1020 (C-O)

[0028]

Example 18 N- [2- (diethylamino) ethyl] 2,5-dihydride
Synthesis of Roxybenzamide [compound of (1)] [(d)
Process]. 6.1 g of N- [2- (diethylamino) ethyl] 2,5-dibenzyloxybenzamide [compound of (2)]
(14.1 mmol), 61 ml of methanol and 5%
3 g of palladium-carbon (Pd-C) is charged, and hydrogenation reaction is carried out at room temperature for 6 hours with hydrogen gas under normal pressure.
After the catalyst was filtered off, it was concentrated and dried under reduced pressure to give N- [2-
3.0 g of (diethylamino) ethyl] 2,5-dihydroxybenzamide was obtained (yield: 84%). IR data and NMR data are as follows. IR (cm ^-1 ): 2980 (-NH), 2550 (-OH), 1653 (-CO-N), 1562 (aromatic ring), 1278 (tertiary amine) ¹ H-NMR: δ (90MHz.DMSO- d ₆ ) ppm: 0.98 (t; 6H), 2.30 ■ 2.70
(m; 6H), 3.20 ■ 3.50 (m; 2H), 6.76 (s; 1H), 6.81
(d; 1H), 7.24 (d; 1H), 8.45 ■ 8.80 (m; 1H)

[0029]

[Examples 19 to 29] Implemented according to the method of Example 18.
N- [2- (diethylamino) ethyl] 2.5 of Example 18
-Various formulas instead of dibenzyloxybenzamide
Using the compound of (2), the corresponding compound of formula (1) was combined.
I made it. IR and NMR data for these compounds
Is as follows.No Compound name 19N- (2-aminoethyl) 2,3-dihydroxybenzoamide IR (cm^-1): 3230 (-NH), 2690 (-OH), 1650 (-CO-N), 1555 (aromatic ring), 1260 (-NH₂) ¹ H-NMR: δ (90MHz.DMSO-d₆) ppm: 1.13 (s; 2H), 2.80 ■ 3.15 (m; 2H), 3.40 ■ 3.70 (m; 2H), 6.70 ■ 7.50 (m; 3H), 8.95 (br.t; 1H) 20N- (2-aminoethyl) 2,5-dihydroxybenzoamide IR (cm^-1): 2990 (-NH), 2570 (-OH), 1650 (-CO-N), 1555 (aromatic ring), 1260 (-NH₂) ¹ H-NMR: δ (90MHz.DMSO-d₆) ppm: 1.05 (s; 2H), 2.55 ■ 2.85 (m; 2H), 3.30 ■ 3.55 (m; 2H), 6.60 ■ 6.90 (m; 2H), 7.15 (d; 1H), 8.70 ■ 8.90 (m; 1H) 21N- [2- (Dimethylamino) ethyl] 2,3-dihydroxybenzoamide IR (cm^-1): 3260 (-NH), 2670 (-OH), 1645 (-CO-N), 1540 (aromatic ring), 1250 (tertiary amine)¹H-NMR: δ (90MHz.DMSO-d₆) ppm: 2.30 (s; 6H), 3.10 ■ 3.40 (m; 2H), 3.60 ■ 3.90 (m; 2H), 9.05 (br.t; 1H) 22N- [2- (Dimethylamino) ethyl] 2,5-dihydroxybenzoylamine IR (cm^-1): 2990 (-NH), 2620 (-OH), 1640 (-CO-N), 1560 (aromatic ring), 1275 (tertiary amine)¹H-NMR: δ (90MHz.DMSO-d₆) ppm: 2.45 (s; 6H), 2.40 ■ 2.80 (m; 2H), 3.30 ■ 3.55 (m; 2H), 6.70 (s; 1H), 6.83 (d; 1H), 7.23 (d; 1H), 8.30 ■ 8.60 (m; 1H) 23N- [2- (diethylamino) ethyl] 2,3-dihydroxybenzoamide IR (cm^-1): 3260 (-NH), 2666 (-OH), 1644 (-CO-N), 1545 (aromatic ring), 1270 (tertiary amine)¹H-NMR: δ (90MHz.DMSO-d₆) ppm: 1.27 (t; 6H), 2.90 ■ 3.50 (m; 6H), 3.50 ■ 3.90 (m; 2H), 6.69 (t; 1H), 7.01 (d; 1H), 7.46 (d; 1H), 9.31 (br.t; 1H) 24N- (2-Progyrinoethyl) 2,3-dihydroxybenzoamide IR (cm^-1): 3280 (-NH), 2690 (-OH), 1650 (-CO-N), 1550 (aromatic ring), 1190 (tertiary amine)¹H-NMR: δ (90MHz.DMSO-d₆) ppm: 1.90 ■ 2.30 (m; 4H), 2.90 ■ 3.90 (m; 8H), 6.80 (t; 1H), 7.15 (d; 1H), 7.55 (d; 1H), 9.10 ■ 9.35 (m; 1H) twenty five N- (2-progyrinoethyl) 2,5-dihydroxybenzoamide IR (cm^-1): 3010 (-NH), 2600 (-OH), 1648 (-CO-N), 1560 (aromatic ring), 1192 (tertiary amine)¹H-NMR: δ (90MHz.DMSO-d₆) ppm: 1.50 ■ 1.85 (m; 4H), 2.90 ■ 2.95 (m; 6H), 3.45 ■ 3.65 (m; 2H), 6.72 (s; 1H), 6.85 (d; 1H), 7.33 (d; 1H), 8.85 ■ 9.05 (m; 1H) 26N- (2-Phenylaminoethyl) 2,3-dihydroxybenzoamide IR (cm^-1): 3270 (-NH), 2685 (-OH), 1648 (-CO-N), 1550 (aromatic ring), 1185 (tertiary amine)¹H-NMR: δ (90MHz.DMSO-d₆) ppm: 1.90 ■ 2.20 (m; 6H), 2.80 ■ 3.80 (m; 8H), 6.78 (t; 1H), 7.10 (d; 1H), 7.53 (d; 1H), 8.95 ■ 9.15 (m; 1H) 27N- (2-Phenylamino) 2,5-dihydroxybenzoamide IR (cm^-1): 3005 (-NH), 2610 (-OH), 1653 (-CO-N), 1555 (aromatic ring), 1188 (tertiary amine)¹H-NMR: δ (90MHz.DMSO-d₆) ppm: 1.35 ■ 1.65 (m; 6H), 2.50 ■ 2.95 (m; 6H), 3.45 ■ 3.65 (m; 2H), 6.68 (s; 1H), 6.80 (d; 1H), 7.36 (d; 1H), 8.50 ■ 8.75 (m; 1H) 28N- (2-morpholinoethyl) 2,3-dihydroxybenzoamide IR (cm^-1): 3260 (-NH), 2665 (-OH), 1645 (-CO-N), 1548 (aromatic ring), 1195 (tertiary amine)¹H-NMR: δ (90MHz.DMSO-d₆) ppm: 2.90 ■ 3.20 (m; 4H), 3.20 ■ 3.40 (m; 2H), 3.50 ■ 3.90 (m; 2H), 3.90 ■ 4.30 (m; 4H), 6.68 (t; 1H), 7.03 ( d; 1H), 7.55 (d; 1H), 8.80 ■ 9.05 (m; 1H) 29N- (2-morpholinoethyl) 2,5-dihydroxybenzoamide IR (cm^-1): 3060 (-NH), 2620 (-OH), 1650 (-CO-N), 1550 (aromatic ring), 1202 (tertiary amine)¹H-NMR: δ (90MHz.DMSO-d₆) ppm: 2.50 ■ 2.70 (m; 2H), 2.80 ■ 3.00 (m; 4H), 3.25 ■ 3.50 (m; 2H), 3.60 ■ 3.90 (m; 4H), 6.71 (s; 1H), 6.83 ( d; 1H), 7.35 (d; 1H), 8.35 8.60 (m; 1H)

[0030]

Example 30 N- [2- (diethylamino) ethyl] 2,5-diben
Synthesis of Ziroxybenzamide [Compound of (2)]
[Step (e)]. Methyl 2,5-dibenzyloxybenzoate 3.4
Charge 8 g (10 mmol) and N, N-diethylethylenediamine 5.8 g (50 mmol) to obtain 130-
Heat to 140 ° C. While distilling off the generated methanol to the outside of the system, the reaction is carried out with stirring for 5 hours. After cooling, add to 30 g of water and extract with ether. The extract was washed with water, dried over magnesium sulfate and concentrated, and the obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to obtain highly pure N- [2- (diethylamino) ethyl] 2. 3.16 g of 5-dibenzyloxybenzamide was obtained (yield: 73%).

[0031]

INDUSTRIAL APPLICABILITY According to the present invention, a novel compound of the above formula (B) containing the compound of the above formula (4) and the compound of the above formula (3), which can be produced by using the compound of the formula (5), which is easily available, as a starting material. ) And a novel N- (2-aminoethyl) benzamide represented by the above formula (A), which includes the compound of the above formula (2) and the compound of the above formula (1). Can be provided. The compounds of the formulas (A) and (B) are expected as therapeutic agents for improving psychiatric function symptoms caused by organic disorders in the brain such as cerebrovascular disorders and senile dementia.

[Chemical 6]

[Chemical 7]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical indication location C07D 295/12 Z (72) Inventor Yoshinori Katayama 39-9 Umegaoka, Midori-ku, Yokohama-shi, Kanagawa Japan Kogyo Co., Ltd. Umegaoka No. 1 Apartment No. 105 (72) Inventor Hiroshi Tamura 335 Hasegawa Kaori, Nakahara-ku, Kawasaki-shi, Kanagawa Kawasaki Research Institute Co., Ltd. (72) Inventor Keiichi Takagi Kaori Hasegawa 335, Kayajuku, Nakahara-ku, Kawasaki, Kanagawa

Claims (2)

[Specification] [Claims] 1. The following formula (A): (In the formula, Y ₁ and Y ₂ represent a hydrogen atom, a hydroxyl group or a benzyloxy group, and Y ₃ represents a hydroxyl group or a benzyloxy group. When Y ₁ is a hydrogen atom, Y ₂ and Y ₃ are the same group. When Y ₂ is a hydrogen atom, Y ₁ and Y ₃ represent the same group, and R ₆ represents amino, dimethylamino, diethylamino, pyrrolidino, piperidino and morpholino groups. N- (2-aminoethyl) benzamides represented. 2. The following formula (B): (In the formula, R ₄ and R ₅ represent a hydrogen atom or a benzyloxy group, but do not represent the same group at the same time.
₇ is a hydrogen atom, a methyl group or an ethyl group, and Bn is a benzyl group.).