JPS61115068A - 4-benzylpiperidinylpropoxyaniline derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R is H, lower alkyl, phenyl lower alkyl, lower alkanoyl, benzoyl, cinnamoyl, phenyl lower alkanoyl, or cyclohexylcarbonyl) and its acid addition salt. EXAMPLE:2-[3-(4-Benzyl-1-piperidinyl)propoxy]aniline. USE:Having antiarrhythmic action and locally anesthetic action, useful as a drug. PREPARATION:A nitrobenzene derivative shown by the formula II is reduced to give a compoud shown by the formula I where R is H. This compound is reacted with an organic acid derivative shown by the formula III (R1 is H, lower alkyl, phenyl, etc.; x is OH< halogen, or lower alkylcarbonyloxy) or its mineral acid salt as a deoxidizer in the presence of a base, to give a corresponding compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 4-benzylpiperidinylpropoxyaniline derivative having excellent antiarrhythmic and local anesthetic effects, and a pharmacologically acceptable acid addition salt thereof.

Structure of the invention, that is, the present invention is based on the general formula CI ) and its pharmacologically acceptable acid addition salts.

In the general formula (I) of the present invention, the lower alkyl group represented by R includes, for example, methyl, ethyl, propyl,
Examples of lower alkyl groups include benzyl, phenylethyl, phenylpropyl, phenylbutyl groups, etc., examples of lower alkanoyl groups include acetyl, propionyl, butyryl groups, and phenyl lower alkanoyl groups. Examples of the group include phenylacetyl, phenylpropionyl, and phenylbutyryl groups.

The compound represented by the general formula CI) of the present invention can be converted into a pharmacologically acceptable acid addition salt, or the base can be liberated from the generated acid addition salt, as desired.

Examples of the pharmacologically acceptable acid addition salts of the compound represented by the general formula (I) of the present invention include mineral acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. salt,
Alternatively, acetic acid, maleic acid, fumaric acid, citric acid,
Examples include organic acid salts such as oxalic acid and tartaric acid.

The novel 4-benzylpiperidinylpropoxyaniline derivative of the present invention represented by the general formula (I) can be produced by various methods.

That is, according to the first mode of the method for producing a compound according to the present invention, the compound represented by the general formula (I) can be produced by reducing the nitrobenzene derivative represented by the following formula (n). It can be produced by leading to an aniline derivative represented by the following formula (I-1) in which R is a hydrogen atom.

Examples of the reduction method used in the method of the present invention include reduction by catalytic hydrogenation, reduction by tin-hydrochloric acid, and the like.

According to the second mode of the method for producing a compound according to the present invention, the compound represented by the general formula (I) is prepared by the general formula C
In I), an aniline derivative represented by the above formula (I-1) in which R is a hydrogen atom, and the following general formula (III) R1-C-X (Ili) (wherein R is a hydrogen atom, a lower alkyl group, phenyl lower alkyl group, phenyl group, phenyl lower alkenyl group, or cyclohexyl group, and X represents a hydroxyl group, a halogen atom, or a lower alkylcarbonyloxy group) or its mineral acid salt; It can be produced by reacting in a solvent in the presence of a base as a deoxidizing agent.

Examples of the base used as a deoxidizing agent in the method of the present invention include potassium carbonate, pyridine, and triethylamine.

Any solvent may be used in this reaction as long as it does not inhibit the reaction, such as benzene,
Toluene, pyridine, lutidine.

dimethylformamide etc.

Further, the reaction is carried out at 0° to reflux temperature of the solvent, but preferably at room temperature.

According to the third mode of the method for producing a compound according to the present invention, the compound represented by the general formula CI) is prepared by the general formula C
The aniline derivative represented by I-1) and the general formula (I-1)
II) is reacted with the organic acid derivative or its mineral acid salt to form the following general formula ((in the formula, R represents the same meaning as above), and then reduced with a reducing agent in a solvent. It can be manufactured by

Examples of the reducing agent used in the method of the present invention include lithium aluminum hydride, and examples of the solvent include anhydrous ether and anhydrous tetrahydrofuran. It is done below.

According to the fourth mode of the method for producing a compound according to the present invention, the compound represented by the general formula CI) is prepared by the general formula (CI).
The aniline derivative represented by I-1) and the following general formula (I
V) It can be produced by reacting an aldehyde derivative represented by R1-CHO (TV) (in the formula, R represents the same meaning as above) in a solvent, and then reducing it with a reducing agent.

Examples of the solvent used in the method of the present invention include methanol, ethanol, isopropanol, and diglyme, and examples of the reduction method include reduction with sodium borohydride and reduction by catalytic hydrogenation. can be mentioned.

Further, the reaction is carried out at a temperature ranging from room temperature to the temperature at which the solvent is heated to reflux.

Effects of the Invention The 4N compound represented by the general formula (I) produced in this way
-Phenylnicotinamide derivatives and pharmacologically acceptable mono-acid addition salts thereof have excellent antiarrhythmic and local anesthetic effects and are extremely useful as pharmaceuticals.

Hereinafter, the present invention will be explained by examples.

Example 1 2-[3-(4-Benzyl-1-piperidinyl)propoxycoaniline a) 1-(3-bromopropoxy)-2-nitrobenzene 2-nitrophenol 13. θgt) IJium was hydroxylated in a mixture of 40.4 g of rimethylene bromide and 100 g of water under heating under reflux.8. After dropping a solution of 201 Og in water, the mixture was heated under reflux for 10 hours. Cool the reaction mixture and extract with ether. The ether layer is washed successively with a 10% aqueous sodium hydroxide solution and water, and then dehydrated. The solvent was distilled off and the residue was distilled to a boiling point of 164-187" (4wm
15.8 g of a yellow liquid of Hg) are obtained.

Mass spectrum m/e: 259.281 (M”)b
) 2-[3-(4-benzyl-1-piperidinyl)propoxycoaniline 1-(3-bromopropoxy)-2-nitrobenzene 2
A mixture of 8.6 g of potassium carbonate, 15.2 g of potassium carbonate, 23.0 g of 4-benzylpiperidine, and 1001 g of dimethylformamide was heated and stirred at 80° for 8 hours. Cool the mixture, add water to the reaction mixture, and extract with benzene. The benzene layer is dehydrated using a water washer, and the solvent is distilled off. The obtained residue is dissolved in methanol 2501, 0.20 g of platinum oxide is added, and catalytic reduction is carried out at room temperature and normal pressure. Filter off the catalyst and concentrate the filtrate. Add ethanolic hydrochloric acid to the residue. The precipitate was collected by filtration to obtain 22.8 g of light brown crystals (as hydrochloride).

Recrystallization from a mixture of ethanol and methanol gives colorless needles with a melting point of 199-202° (decomposition).

Elemental analysis value C21N28 N20・2HCI theoretical value
C, $3.47i H, 7,81; N, 7.05 Experimental value C, 83,29; H, F, 72i N, 7.
05 Example 2 N-[:2-[3-(4-benzyl-1-piperidinyl)propoxy]phenyl]acetamide φ oxalate 2-[3-(4-benzyl-1-piperidinyl)propoxycoaniline 1. A mixture of 82 g of acetic anhydride and 1.02 g of acetic anhydride is left at room temperature for 20 minutes. After the reaction, the mixture is made alkaline with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dehydrated. The solvent was distilled off, and 1.30 g of the resulting residue was converted into a shela salt by a conventional method. Recrystallized from methanol, melting point 206-207
Obtain colorless prismatic crystals.

Elemental analysis value C23H3ON202/C2H204 theoretical value C, G5.77; H, 7,08; N, 6.1
4 Experimental values C, 85, 59; H, 7, 15; N,
8.24 Example 3 2- [:3- (4-benzyl-1-piperidinyl)
Flopoxyco N-methylaniline fumarate A mixture of 1.83 g of 2-[3-(4-benzyl-1-piperidinyl)propoxy]aniline, 1.01 l of 90% formic acid, and 30 l of benzene is heated under reflux for 3 hours. . After the reaction, the solvent is distilled off, and ether is added to the resulting residue.

The precipitated crystals are collected by filtration and washed with a mixture of ether and ethyl acetate. The obtained crystals were suspended in anhydrous ether, and lithium aluminum hydride was added.3. Add OOg. The mixture is heated to reflux for 57 hours. After the reaction, water is added and extracted with ether. After the ether layer is dehydrated, the solvent is distilled off and hexane is added to the resulting residue. The precipitated crystals are collected by filtration and converted into fumarate by a conventional method. Recrystallization is performed from a mixture of chloroform and methanol to obtain pale blue prismatic crystals with a melting point of 184-187°.

・/4H20 Theory @C97 Summer, 88; H, 8, 17; N, 8.
99' experimental value C, 71, 91; H, 8, 24;
N, 8.94 Example 4 2-C3-(4-benzyl-1-piperidinyl)flopoxy]-N-ethylaniline In a suspension of 0.70 g of lithium aluminum hydride in anhydrous ether, N- [:2- [3-(4-
benzyl-1-piperidinyl)propoxycophenyl]
Add 1.84 g of acetamide and heat under reflux for 1 hour.

After the reaction, water is added and extracted with ether. After the ether layer was dehydrated, the solvent was distilled off to obtain 1.58 g of a pale yellow liquid. The fumarate is prepared by a conventional method. Recrystallization from ethanol gives a colorless prism product with a melting point of 171-173''.

Elemental analysis value C23H3□N20・'/2C4H404
Theoretical value C, 73, 14i H, 8, 35i N, 8
．． 82 Experimental value C, 73,09; H, 8,45;
N, 6.79 Example 5 N-C2-[:3-(4-benzyl-1-piperidinyl)propoxycophenyl]propionamide hydrochloride 2-[3-(4-benzyl-1-piperidinyl)propoxycoaniline 2.04g, triethylamine 1
．． To a mixture of 30 ml and 20 ml of chloroform, 0.70 ml of propionyl chloride is added while stirring while cooling with water, and the mixture is stirred for 1 hour. After the reaction, water is added and extracted with chloroform. After the chloroform layer is washed with water and dehydrated, the solvent is distilled off. The obtained residue was converted into a hydrochloride salt by a conventional method to obtain pale yellow crystals.
Obtain 70g. It is recrystallized from a mixture of ethanol and ether to obtain colorless prism crystals with a melting point of 87-8θ0.

Elemental analysis value C24H3□N20・HCl-H20 theoretical value C, 6B, 27; H, 8, 11i N, 8.4
4 Experimental values C, 611i, 23i H, 8, 2G;
N, 8.44 Example 6 N-C2-[3-(4-benzyl-1-piperidinyl)
propoxy]phenyl]benzamide 2-[3-(4-
benzyl-1-piperidinyl)propoquine coaniline 2
．． 04g,) ethyl 7mi 71.30ml1. Using a mixture of 201 ml of chloroform and 0.88 ml of benzoyl chloride, the same treatment as in Example 5 was carried out to obtain light brown crystals 2.
．． Obtain 04g. Recrystallized from ethanol, melting point 10
8-107' colorless needles are obtained.

Elemental analysis value C28H3□N20□ Theoretical value C,78,43i H,7,53i N,8
．． 54 Experimental value C, 78, 4G; H, F, 51;
N,lli,35Example 7 N-benzyl-2-C3-(4-benzyl-1-piperidinyl)propoxycoaniline 2-(:3-(4-
benzyl-1-piperidinyl)propoxy]aniline 1
．． A solution of 83 g and 0.70 sl of benzaldehyde in methanol 301 is heated under reflux for 2 hours. Then, add 1゜00g of boron hydride and add 2.5g of boron hydride at room temperature.
Stir for an hour. After the reaction, the solvent was distilled off, water was added to the resulting residue, and the mixture was extracted with benzene. After the benzene layer is washed with water and dehydrated, the solvent is distilled off. The resulting residue is treated with column chromatography (eluting with a mixture of alumina, chloroform and hexane) to obtain 0.88 g of a pale yellow liquid.

The fumarate is prepared by a conventional method. Recrystallization from ethanol gives colorless needle-shaped crystals with a melting point of 1345-135°5.

Elemental analysis value CHNO/SCHO Theoretical value C, 7G, 24; H, 7, 88; N, 5
．． 93 experimental value C, 7G, 29i H, 7, 82;
N, 5.94 Example 8 N-[2-[3-(4-benzyl-1-piperidinyl)
Propoxy]phenyl]cyclohexanecarboxamide 2-[3-(4-benzyl-1-piperidinyl)propoxycoaniline 2.04 g,) ethylamine 1.3
0m1. Chloroform 201 and cyclohexane carbonyl chloride 1. Example 5 Using a mixture of Log
Treat in the same manner as above to obtain 1.88 g of colorless crystals. Recrystallization from ethanol gives colorless needles with a melting point of 88-89''.

Elemental analysis value C28838N20□ Theoretical value C,77,38i H,8,81; N,l
li, 45 experimental value C, fu, 38; H, 8,84;
N, 8.30 Example 9 N-[:2-C3-(4-benzyl-1-piperidinyl)propoquine]phenylcocinnamamide hydrochloride 2-[3-(4-benzyl-1-piperidinyl)propoxyco Aniline 2.04g, triethylamine 1.
30m1. The mixture is treated in the same manner as in Example 5 using a mixture of 201 chloroform and 1.10 ml of cinnamoyl chloride to obtain 1.89 g of colorless crystals as the hydrochloride. Recrystallized from a mixture of chloroform and methanol to a melting point of 1.
Colorless needles of 90-192° are obtained.

Elemental analysis value C30H34N202・HC1 theoretical value C
,73,38i H,7,18; N,5.70 Experimental value C,73,04i H,7,29; N,5.5
3 Example 1O N-1-C3-(4-benzyl-1-piperidinyl)propoxy]phenylcophenylpropionamide hydrochloride 2- [:3- (4-benzyl-1-piperidinyl)
2.04 g of propoxycoaniline, 1) ethylamine
．． A mixture of 30 sl, 201 chloroform and 1.27 g of hydrocinnamoyl chloride was treated in the same manner as in Example 5 to obtain 2.78 g of colorless crystals as the hydrochloride.

Recrystallize from ethanol to obtain colorless needle crystals with a melting point of 180-186@ Elemental analysis value C30N36 N202-
HCl theoretical value C, 73,08; H, 7,58;
N, 5. li8 experimental value C,73,08i H,7,6
4i N, 5.56 Table 1 shows the physical property values of the example compounds.

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R is a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a lower alkanoyl group, a benzoyl group, a cinnamoyl group, a phenyl lower alkanoyl group) or a cyclohexylcarbonyl group) and a pharmacologically acceptable acid addition salt thereof.