JPS6032629B2 - Novel benzylpyridine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (1) (wherein, means an alkyl group, halogenated alkyl group, alkenyl group, aryl group, substituted aryl group, aralkyl group, or substituted aralkyl group having 17 or less carbon atoms.

In addition, the substituent of the substituted aryl group and the substituted aralkyl group is Q-(p-
acylamino-○-substituted or unsubstituted pendyl)pyridine. The pendylpyridine derivative, which is the object compound of the present application, is a new compound, has antidepressant and anti-inflammatory effects, and is a substance expected to be used as a medicine.

The method for producing the target compound of the present invention will be explained below.

That is, q−( expressed by the general formula (b) (where × has the same rhombus as above)
p-amino-○-substituted or unsubstituted penzyl)pyridine in an appropriate solvent with an acylating agent represented by the general formula (m)RCOOH (wherein R has the same meaning as above) or a functionally equivalent thereof. Q-(p-acylamino-○-substituted or unsubstituted pendyl)pyridine represented by general formula (0) can be produced by acylation with an acylating agent.

In the production of the object compound of the present invention, the raw material compound Q-(p-amino-○-substituted or unsubstituted penzyl)pyridine is, for example, Q
-(p-nitro 0 mono-substituted or unsubstituted pendyl) obtained by reducing pyridine.

Regarding the production of this raw material compound, if x is hydrogen, nitro group, or amino group, please refer to J. ChemS ratio. 1952P. 5
83 and is well known, when x is a halogen, nitrile group, trifluoromethyl group, etc., Q-(pnitro-○ monolayer fusuma pendyl)pyridine itself is a new compound, so it is a target compound of the present invention. An example of a method for producing a raw material compound used in the practice is shown below. ■ Production method of starting compound (b) when ×=CI Q-(0-nitrobenzyl)pyridine (J. Chem.
Soc. Q-(0-aminobenzyl)pyridine obtained by reducing Q-(0-aminobenzyl)pyridine (synthesized by the method described in No. 1,949,2408) with a suitable reducing agent, such as iron-hydrochloric acid, is diazotized with nitrous acid to give a diazonium salt, and this is diazotized with nitrous acid. When hydrogen chloride is reacted with a copper catalyst, Q-(0-chlorobenzyl)bridiso is obtained.

When this material is nitrated with nitric acid-sulfuric acid in a conventional manner, Q-
(0-chloro-p-nitrobenzyl)pyridine is obtained. When this is reduced with a suitable reducing agent such as iron-hydrochloric acid or stannous chloride-hydrochloric acid, Q-(0-k.lu-p-aminobenzyl)pyridine is obtained. 'B} X=CN
Method for producing raw material compound (b) in the case of (2) The diazonium salt of (2) above is reacted with sodium cyanide in the presence of cuprous cyanide, and then nitration and reduction are performed in the same manner as in (2) above. Q-(0-cyan-p-aminobesodyl)pyridine is obtained.

'C' Method for producing starting compound (0) when X=CF3 React commercially available ○-trifluoromethylbromobenzene with magnesium to obtain Grignard reagent, and react with Q-picolinaldehyde (0-trifluoromethylbromobenzene). Q-(0-trifluoromethylbenzyl)pyridine is obtained by converting fluoromethylphenyl)pyridine into methylcarbinol, converting it into a chloride with thionyl chloride, and further reducing it with valent lead-acetic acid.

After nitrating this with nitric acid, it is reduced with a suitable reducing agent such as iron-hydrochloric acid, stannous chloride-hydrochloric acid, etc.
O-trifluoromethyl-p-aminobenzyl)pyridine is obtained. In the production of the object compound of the present invention, a compound represented by the general formula (m) RCOOH or a compound functionally equivalent thereto may be used as an acylating agent in the acylation reaction of the raw material compound represented by the general formula (0). used.

Functionally equivalent acylating agents include: General formula (V) (However, in the formula, R has the same meaning as above.

) or general formula (W)RCOY
(However, in the formula, R has the same meaning as above, and Y means a halogen or phenoxy group.) An acyl halide or active ester represented by the formula is used. General formula (m
) Examples of the acylating agent include the following carboxylic acids.

Namely, aliphatic carboxylic acids such as acetic acid, n-butyric acid, isobutyric acid, caproic acid, cabric acid, caprylic acid, myristic acid, and stearic acid; substituted aliphatic carboxylic acids such as monochloroacetic acid, nitroacetic acid, and -frombutyric acid; Acrylic acid. Unsaturated aliphatic carboxylic acids such as crotonic acid.

Aromatic carboxylic acids such as benzoic acid, phthalic acid, and naphthalene carboxylic acid. Substituted aromatic carboxylic acids such as p-nitrobenzoic acid and p-chlorobenzoic acid. Aralkylcarboxylic acids such as phenylacetic acid, phenylpropionic acid, and naphthylacetic acid. and substituted aralkylcarboxylic acids such as -nitrophenyl acetic acid, p-chlorophenylacetic acid, and p-chlorophenylpropionic acid. The acid anhydride represented by the general formula (V) and the acyl halide or active ester represented by the general formula (machi) include acid anhydrides and acid halides of the carboxylic acid represented by the above general formula (machi) or phenolic acid halides. Shester is a specific example.

The reaction solvent used in the production of the object compound of the present invention may be any solvent as long as it does not react with the raw material.

Preferred are ether solvents such as ethyl ether, tetrahydrofuran, dioxane, and ethylene glycol jetyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as chloroform, dichloroethane, and tetrachloroethane, and ethyl acetate. Herther solvents such as ligroin, petroleum ether”n-
Hydrocarbons such as hexane and cyclohexane can be used. Further, the carboxylic acid used as the acylating agent can be used as a reaction solvent if it is liquid during the reaction. The reaction for producing the target compound of the present invention is carried out under cooling or under heating.

When a carboxylic acid, acid anhydride or active ester is used as the acylating agent, the reaction is carried out at room temperature or under heating, preferably at a temperature of 60 oo to 10,000. When an acyl halide is used as an acylating agent, the reaction is carried out at a temperature ranging from cooling to room temperature, preferably at -5°C to 25:00. A reaction time of 2 to 2 hours, usually about 5 hours is sufficient. As the raw material compound, 1 mol or more of carboxylic acid, acid anhydride, acyl halide, or active ester may be used per 1 mol of Q-(p-amino-○-substituted or unsubstituted pendyl)pyridine. Isolation and purification of the target compound from the reaction product can be carried out by a general method in which the target compound crystallized from the reaction product is separated in a furnace and recrystallized using an appropriate solvent.

Solvents used for recrystallization include methanol, ethanol,
Good results can be obtained by using soluble organic solvents such as ether, dioxane, and ethyl acetate'tetrahydrofuran, or insoluble solvents such as hexane, petroleum benzene, isopropyl ether, and ligroin, either alone or in combination. Furthermore, the Q-(p-acylami/-○-substituted or unsubstituted penzyl)pyridine represented by the general formula (1), which is the object compound of the present application obtained in this way, can be mutually converted by converting the substituent X at the ○ position. be.

For example, Q1 (p-acylamino-○-aminobenzyl)
Pyridine (when x = amino group) is Q-(p-acylamino-0-nitrobenzyl)pyridine by an appropriate substitution method,
For example, it can be obtained by catalytic reduction of pd-carbon under pressure. Q-(p-acylamino-○-chlorobenzyl)pyridine (when X=CI) is prepared by diazotizing Q-(p-acylamino-○-aminobenzyl)pyridine with nitrous acid and then chlorinating it with cuprous chloride. If you do, you will get it. The object compound of the present invention, Q-(p-acylamino-0 monosubstituted or unsubstituted pendyl)pyridine, has antidepressant and anti-inflammatory effects, and is a useful substance as a medicine or veterinary medicine.

When the object compound of the present invention is used as a medicine or veterinary drug, it is preferable to use the compound in the form of a salt.

Suitable salts include, for example, hydrochloride, hydrobromide, sulfate, phosphate, acetate, nocturnate, succinate, malate, tartrate, citrate, and the like. The salt is formed according to conventional methods, such as a neutralization method or a double decomposition method. Next, we discuss the antidepressant action and acute toxicity of the compound represented by general formula (1) and the known antidepressant (lmipram).
The results of comparison with those of im) are shown by animal experiments.

1 Antidepressant effect The method of GIMkman et al.
15, 169 (1969)).

Using DD male mice weighing 20 ± 2 days, 60 minutes after oral administration of the test compound, Reserplne5 o/k was administered.
9. Intraperitoneal administration was performed. Furthermore, 60 minutes later,
The anti-depressant effect was determined by observing symptoms such as heaviness under eye soap and decreased locomotor activity. The results are shown in Table 1. 1. Depressive effect 2. Acute toxicity in mice and rats (as LD rule)
A test compound was orally administered to a group of 5 male mice and rats weighing 20±1 TDD and observed for one week.

According to LD, the Wilcoxon method in Litchfield [for example, J. Phannacol & Expert.
Therap. 9699 (1949)]. The results are shown in Table 2. Table 2 Acute toxicity in mice and rats (LD5o basic oral) The method for producing the target compound of the present invention will be specifically explained below by giving Examples.

Example 1 3.7 liters of Q-(p-aminobenzyl)pyridine was dissolved in 20 liters of tetrahydrofuran, 2.4 liters of butyric anhydride was added, and the mixture was reacted at 60 qo for 4 hours.

After the reaction, the reaction solution was concentrated and dried to a solid state, and then 50 ml of water was added to the remaining bamboo, and an aqueous solution containing sodium hydroxide was added for 1.2 min.
When 0' is added, Q-(p-n-butylaminobenzyl)pyridine crystallizes. The crystals are separated in a furnace and recrystallized with ethanol to obtain 4.2 crystals of Q-(p-butyrylaminobenzyl)pyridine. Yield 82.6%, melting point 8
4-870. Elemental analysis C Day N C, 6th, Calculated value as 8N20 75.56 7.13 11.02 (%) Actual value 75.39 7.21 11.24 (%
) Example 2Q-(p-amino-○-nitrobenzyl)
Dissolve 1.1 parts of pyridine in 10 parts of dioxane, add 0.5 parts of acetic anhydride, and react at 60-7000 for 4 hours.

After the reaction, the reaction solution was concentrated and dried, and 30% of water was added to the residue to obtain Q-(p-acetylamino-○nitrobenzyl).
Pyridine crystallizes. The crystals are separated in a furnace and recrystallized from ethanol to obtain Q-(p-acetylamino-nitrobenzyl)pyridine.

Yield 73.2%, melting point 159-16 P○ elemental analysis C, 4 days, calculated value as 3N303 61. Period 4.8315.4 (%) Actual value 62.225.1115.27 (
%) Example 3 1.8 units of Q-(p-amino-○-trifluoromethylbenzyl)pyridine was added to a mixture of 15 units of butyric acid and 1.2 units of butyric anhydride, and 7
Allow time to react.

After the reaction, the reaction solution was concentrated, 20 parts of water and 40 parts of chloroform were added to the remaining solution, and the pH was adjusted to 12 with ION caustic soda water.
Adjust to. The chloroform layer is washed with water, dehydrated with molasses, concentrated, and n-hexane is added to crystallize Q-(p-n-butylamino--trifluoromethylbenzyl)pyridine.

When the crystals are chopped and recrystallized with cyclohexane, Q-(p
-n-butylamino-○-trifluoromethylbenzyl)
1.5 ml of pyridine is obtained. Yield 65.2%, melting point 7
4-76oo elemental analysis C day N F C, 7 days, calculated value as 7N20F3 63.35 5.32 8.69 17.68 (%
) Actual measurement value 63.51 5.48 8.36 1
7.58 (%) Example 4 2.5 ml of (p-amino-○-trifluoromethylbenzyl)pyridine is suspended in 50 ml of dichloroethane and cooled to 5 to 0°C.

To this, 1.06 g of n-butyryl chloride was slowly added dropwise. After completion of the dropwise addition, the reaction mixture was allowed to react at room temperature for 4 hours, and after the reaction, the reaction solution was concentrated to dryness. The residue is treated in the same manner as in Example 3 to obtain 2.7 g of Q-(p-n-butylamino-0-trifluoromethylbenzyl)pyridine. Yield 83.8%, melting point 74-7600. Elemental Analysis C Day N F C, 7th, Calculated value as 7N20F3 63.35 5.32 8.69 17. Spots (%) Actual value 63.14 5.48 8.45 17.7
4 (%) Example 5Q-(p-amino-○-cyanobenzyl)pyridine 2.09 ml was dissolved in 50 ml of tetrahydrofuran, and 1.56 ml of anhydrous acid was added to give 60-70 ml.
C for 4 hours.

After the reaction, the reaction solution is concentrated to dryness, 20 parts each of water and ethyl ether are added to the residue, and the pH is adjusted to 12 with one side of caustic soda. After washing the ether layer with water, it is dehydrated with ramie, and when hydrogen chloride gas is introduced, the hydrochloride of the target product is separated as an oil. After concentrating the ether, add 10 parts of ethanol for crystallization. The crystals are separated by a furnace to obtain 2.62 g of Q-(p-n-butylamino-cyanobenzyl)pyridine hydrochloride. Yield 83%, melting point 135-136q○. Elemental analysis C day N CI C, 7 days, calculated value as 7N30/HCI 64.66
5.74 13.31 11.23 (%) Actual measurement
Value 64.78 5.89 13.71 11.41 (
%) Example 6 2.29 parts of Q-(p-aminonitrobenzyl)pyridine are dissolved in 20 parts of butyric acid, 1.56 parts of butyric anhydride is added, and the mixture is reacted at 80 to 100 degrees for 4 hours.

After the reaction, the reaction solution is concentrated to dryness, 30 parts of water is added, and the pH is adjusted to 13 with an aqueous solution of caustic soda to precipitate crystals. This was separated into a furnace and Q-(p-n-butyrylamino○-
2.1 crystals of (nitrobenzyl)pyridine are obtained. Yield 72%, melting point 124oo. Elemental analysis C Day N C, 6th, Calculated value as 7N303 64.20 5.72 14.04 (%) Actual value 64.16 5.89 13.92 (%
) Examples 7 to 17 Compounds synthesized in the same manner as in the above Examples are shown in the following table as Examples 7 to 17.

In the following table, the general formulas of the compounds obtained in Examples 7 to 17 are expressed according to general formula (1).

Here, AH represents the acid used to prepare the acid salt of the target compound.

Yo: Examples 7, 8, 13, 14, and 15 are in Example 1, Examples 11 and 12 are in Example 2, and Example 9. Example 3. To,
Examples 16 and 17 are Example 4. I followed the instructions.

Claims (1)

[Claims] 1. A novel benzylpyridine derivative represented by the general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, X is hydrogen, nitro group, amino group, acylamino, halogen, cyano group, or trifluoromethyl group, and R means an alkyl group or an aryl group.)