JPH05320113A - Novel phenylacetamide derivative and process for producing the same - Google Patents

Abstract

(57) [Summary] [Structure] A novel phenylacetamide derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof. [Chemical 11] [Wherein, X is a hydrogen atom, a halogen atom, hydroxy, nitro, amino, R ¹ , NR ¹ R ² , NHR ¹ or OR
¹ (wherein R ¹ and R ² are substituted or unsubstituted C _1-8
An alkyl, cycloalkyl or benzyl group)
Y is the same or different when p is greater than 1, and is a hydrogen atom, a halogen atom, methylenedioxy, hydroxy, trifluoromethyl, R ³ or OR ³ (in the formula,
R ³ represents a substituted or unsubstituted C _1-8 alkyl or benzyl group); n is an integer of 1 to 6;
Is an integer of 1 to 5] [Effect] The above compounds are used as analgesics and antiphlogistics.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel phenylacetamide derivative having excellent analgesic and anti-inflammatory effects or a pharmacologically acceptable salt thereof and a method for producing the same.

[0002]

PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION Heretofore, capsaicin represented by the following general formula (A):
It is known that (trans-8-methyl-N-vanillyl-6-nonenamide) has an analgesic effect.

[0003]

[Chemical 3]

The capsaicin is of the genus Cayenne .
It is a spicy ingredient contained in the juice of plants.
In No. 313,958, the natural cupsaicin and the synthetic cupsaicin are described as drugs having an analgesic effect. In addition, Yaksh et al. [Science 206 , 4
81-483 (1979)] and the literature [The Alkaloids, Vol. XXIII, 22.
7-299 (1984), Academic Press], studies of capsaicin and its derivatives chemically and pharmaceutically.

European Patent 282,127 describes
It is described that the aminoethoxybenzylamine derivative represented by the following structural formula (B) has anti-inflammatory and analgesic effects.

[0006]

[Chemical 4]

In addition, TR LaHann et al., US Pat. No. 4,424,205 (European Patent 89,7).
No. 10) describes analgesic or anti-irritant compounds of the following general formula (C).

[0008]

[Chemical 5]

[Wherein R ^a is a linear or branched C ₃
A -C ₁₁ alkyl, alkynyl or aralkyl group, a linear or branched C ₃ -C ₂₂ alkenyl group, or a linear or branched C ₆ -C ₁₁ cycloalkyl or cycloalkenyl group, R ₁ and R ₂ One of them is OH,
The remaining one is OH or H.

British Patent No. 2, JM Janusz et al.
No. 168,975 describes an arlanamide represented by the following general formula (D).

[0011]

[Chemical 6]

[In the formula, R ^b represents H, OH, OCH ₃ or OCH ₂ CH ₃ , R ^c represents H or CH ₃ , and n represents an integer of 0 to 12]

Gardner et al., US Pat. No. 5,0,5.
No. 45,565 has the general formula (E):

[0014]

[Chemical 7]

[Wherein R ^d is hydrogen, hydroxy or methoxy; R ^e is an alkyl group]

A β-aminoethyl-substituted phenyl compound represented by the formula: has been described.

In the specification of said Gadner patent, the term alkyl includes a straight carbon chain optionally substituted with an aryl group, said aryl group optionally comprising a halogen atom, hydroxy, C _1-16 alkoxy, Amino, nitro, cyano, phenyl, benzyl, benzyloxy,
It is defined as including phenyl substituted with trifluoromethyl, formylamino, carboxylate or C _1-6 alkyl.

However, the alkyl-substituted phenylacetamide derivative of the above-mentioned general formula (E) of the above-mentioned Gadner patent is substituted with N-n-alkyl having a phenyl group at the terminal of the n-alkyl group as in the present invention. No specific compound and its effect are disclosed for the obtained phenylacetamide derivative.

In the above-mentioned prior art, the capsaicin derivative and the like are characterized in that a carbonyl group is bonded to a saturated or unsaturated alkyl group having 3 to 24 carbon atoms or an unsubstituted ω-phenylalkyl group. However, these compounds generally have a side effect of making the skin red due to severe skin irritation, and have a problem of strong toxicity.

[0020]

Therefore, a compound having excellent pharmacological and physiological activities, but having little irritation and toxicity has been demanded.

As a result of researching compounds for solving the above-mentioned problems, the present inventors have found a novel phenylacetamide derivative which exhibits excellent anti-inflammatory and analgesic activities and has little skin irritation and toxicity, and the present invention It came to completion.

Therefore, the main object of the present invention is to provide a novel phenylacetamide derivative represented by the following general formula (I).

[0023]

[Chemical 8]

[In the formula, X represents a hydrogen atom, a halogen atom, hydroxy, nitro, amino, R ¹ , NR ¹ R ² , NHR.
¹ or OR ¹ group (in the formula, R ¹ and R ² are each a substituted or unsubstituted C _1-8 alkyl, cycloalkyl or benzyl group); Y is the same when p is greater than 1; Differently, hydrogen atom, halogen atom, methylenedioxy, hydroxy, trifluoromethyl, R
³ or OR ³ group (wherein R ³ is a substituted or unsubstituted C _1-8 alkyl or benzyl group); n is an integer of 1 to 6 and p is an integer of 1 to 5 ]

In the present specification, unless otherwise specified,
Phenylacetamide derivatives are considered to include their pharmacologically acceptable salts.

Further, the present invention provides a method for producing these compounds and an analgesic and anti-inflammatory agent containing these compounds as an active ingredient.

The present invention will be described in detail below.

Among the compounds of the present invention, preferred compounds are those represented by the above general formula (I), wherein X is a hydrogen atom, halogen atom, hydroxy, nitro, amino or OR ¹ group, and Y is p is 1 or less. When larger, they are the same or different and are a hydrogen atom, a halogen atom, a trifluoromethyl or R ³ group, wherein R ¹ and R ³ are as defined above, and n is an integer of 2 to 5. , P is an integer of 1 to 3.

Among the compounds of the present invention, the most desirable compound is the above-mentioned general formula (I), wherein X is a halogen atom, hydroxy, nitro, amino or OR ¹ group and Y is p
When 2 is the same or different, it is a hydrogen atom, a halogen atom, a trifluoromethyl or R ³ group, wherein R ¹ and R ³ are each a substituted or unsubstituted C _1-5 alkyl, and n Is 3 or 4 and p is 1 or 2
Is a compound.

Examples of the salt of the compound of the general formula (I) of the present invention include salts with inorganic acids such as hydrochloric acid, hydrogen bromide, sodium hydrogensulfate and carbonic acid, or formic acid, acetic acid, oxalic acid, benzoic acid. , Salts with organic acids such as, citric acid, tartaric acid, gluconic acid, gentisic acid, fumaric acid and lactobionic acid.

Next, a method for producing the compound of the present invention will be described.

The phenylacetamide derivative of the general formula (I) and its salt are prepared by reacting (i) an amine compound of the following general formula (II) with p-hydroxyphenylacetic acid of the following general formula (III),
Obtaining a compound of the following general formula (IV); (ii) reacting a compound of the general formula (IV) with 1,2-dibromoethane to obtain a compound of the following general formula (V); (iii) general The compound of formula (V) was treated with sodium azide (Na
N ₃ ) to obtain a compound of general formula (VI) below; and (iv) converting an azido compound of general formula (VI) into a compound of general formula (I) of the present invention. it can.

[0033]

[Chemical 9]

[Wherein X, Y, n and p are the same as defined above]

In the above production process, the reaction of step (i) is carried out without solvent in the presence of a catalyst at 130 to 160 ° C. for 2 hours.
It is carried out by heating for 5 to 5 hours. At this time, 3Å, 4Å or 5Å molecular sieve powder, preferably 4Å molecular sieve powder can be used.

The reaction of step (ii) is usually carried out in a solvent such as tetrahydrofuran in the presence of a base such as NaH.
It is carried out by heating at the boiling point of the solvent.

Further, the reaction of step (iii) is generally carried out in a benzene solvent by heating at the boiling point of the solvent in the presence of a catalyst such as tetra-n-butylammonium bromide.

The reaction of the final step (iv) is carried out by reduction under hydrogen pressure using Pd-C as a catalyst or to obtain a compound of the general formula (I) in which X is nitro. Is in water and tetrahydrofuran solvent,
It can be carried out by reacting the product obtained in step (iii) with triphenylphosphine.

In step (i) above, the compound of general formula (IV) is obtained as an intermediate for preparing the final compound of the present invention, which also has analgesic and anti-inflammatory effects. Therefore, compounds of general formula (IV) can also be considered as belonging within the scope of the invention.

In the preparation of the compound of the present invention, the amine compound of the general formula (II) used as a starting material is prepared by a conventional method from the compound of the following general formula (VII) or (VIII),
For example, it can be obtained by a reduction method using alanate such as lithium aluminum hydride (LiAlH ₄ ) or hydrogenation using a metal catalyst such as palladium or Raney nickel.

[0041]

[Chemical 10]

[Wherein Y, n and p are the same as defined above]

Further, the compound of the general formula (III) can be easily obtained from commercial products and can be produced with partial protection.

The following compounds can be mentioned as specific examples of the phenylacetamide derivative of the general formula (I) of the present invention which can be produced by the above-mentioned method.

N- [3- (3,4-dimethylphenyl)
Propyl] -4- (2-aminoethoxy) -3-hydroxyphenylacetamide; N- [2- (3,4-dimethylphenyl) ethyl] -4- (2-aminoethoxy)
-3-Hydroxyphenylacetamide; N- (3-phenylpropyl) -4- (2-aminoethoxy) -3-
Hydroxyphenylacetamide; N- [3- (3-methylphenyl) propyl] -4- (2-aminoethoxy) -3-hydroxyphenylacetamide; N- [3
-(4-Methylphenyl) propyl] -4- (2-aminoethoxy) -3-hydroxyphenylacetamide;

N- [3- (4-chlorophenyl) propyl] -4- (2-aminoethoxy) -3-hydroxyphenylacetamide; N- [3- (3,4-dichlorophenyl) propyl] -4- (2 -Aminoethoxy) -3
-Hydroxyphenylacetamide; N- [3- (4-
Fluorophenyl) propyl] -4- (2-aminoethoxy) -3-hydroxyphenylacetamide; N-
[3- (3,4-Methylenedioxyphenyl) propyl] -4- (2-aminoethoxy) -3-hydroxyphenylacetamide; N- [3- (3-methoxyphenyl) propyl] -4- (2- Aminoethoxy) -3-hydroxyphenylacetamide;

N- [3- (3-trifluoromethylphenyl) propyl] -4- (2-aminoethoxy) -3-
Hydroxyphenylacetamide; N- [3- (3,5
-Dimethylphenyl) propyl] -4- (2-aminoethoxy) -3-hydroxyphenylacetamide; N-
[3- (3-Ethylphenyl) propyl] -4- (2-
Aminoethoxy) -3-hydroxyphenylacetamide; N- (4-phenylbutyl) -4- (2-aminoethoxy) -3-hydroxyphenylacetamide; N-
[4- (3,4-Dimethylphenyl) butyl] -4-
(2-aminoethoxy) -3-hydroxyphenylacetamide;

N- (5-phenylpentyl) -4- (2
-Aminoethoxy) -3-hydroxyphenylacetamide; N- [3- (3,4-dimethylphenyl) propyl] -4- (2-aminoethoxy) -3-nitrophenylacetamide; N- [2- (3, 4-Dimethylphenyl) ethyl] -4- (2-aminoethoxy) -3-nitrophenylacetamide; N- (3-phenylpropyl) -4- (2-aminoethoxy) -3-nitrophenylacetamide; N- [3- (3-Methylphenyl) propyl] -4- (2-aminoethoxy) -3-nitrophenylacetamide;

N- [3- (4-methylphenyl) propyl] -4- (2-aminoethoxy) -3-nitrophenylacetamide; N- [3- (4-chlorophenyl) propyl] -4- (2- Aminoethoxy) -3-nitrophenylacetamide; N- [3- (3,4-dichlorophenyl) propyl] -4- (2-aminoethoxy) -3
-Nitrophenylacetamide; N- [3- (4-fluorophenyl) propyl] -4- (2-aminoethoxy) -3-nitrophenylacetamide; N- [3-
(3,4-Methylenedioxyphenyl) propyl] -4
-(2-aminoethoxy) -3-nitrophenylacetamide;

N- [3- (3-methoxyphenyl) propyl] -4- (2-aminoethoxy) -3-nitrophenylacetamide; N- [3- (3-trifluoromethylphenyl) propyl] -4- (2-aminoethoxy)
-3-nitrophenylacetamide; N- [3- (3,
5-Dimethylphenyl) propyl] -4- (2-aminoethoxy) -3-nitrophenylacetamide; N-
[3- (3-Ethylphenyl) propyl] -4- (2-
Aminoethoxy) -3-nitrophenylacetamide;
N- (4-phenylbutyl) -4- (2-aminoethoxy) -3-nitrophenylacetamide;

N- [4- (3,4-dimethylphenyl)
Butyl] -4- (2-aminoethoxy) -3-nitrophenylacetamide; N- (5-phenylpentyl)-
4- (2-aminoethoxy) -3-nitrophenylacetamide; N- [3- (3,4-dimethylphenyl) propyl] -4- (2-aminoethoxy) -3-aminophenylacetamide; N- [2 -(3,4-Dimethylphenyl) ethyl] -4- (2-aminoethoxy) -3-
Aminophenylacetamide; N- (3-phenylpropyl) -4- (2-aminoethoxy) -3-aminophenylacetamide;

N- [3- (3-methylphenyl) propyl] -4- (2-aminoethoxy) -3-aminophenylacetamide; N- [3- (4-methylphenyl) propyl] -4- (2 -Aminoethoxy) -3-aminophenylacetamide; N- [3- (4-chlorophenyl) propyl] -4- (2-aminoethoxy) -3-aminophenylacetamide; N- [3- (3,4-dichlorophenyl) ) Propyl] -4- (2-aminoethoxy) -3-aminophenylacetamide; N- [3-
(4-Fluorophenyl) propyl] -4- (2-aminoethoxy) -3-aminophenylacetamide;

N- [3- (3,4-methylenedioxyphenyl) propyl] -4- (2-aminoethoxy) -3
-Aminophenylacetamide; N- [3- (3-meoxyphenyl) propyl] -4- (2-aminoethoxy) -3-aminophenylacetamide; N- [3-
(3-Trifluoromethylphenyl) propyl] -4-
(2-Aminoethoxy) -3-aminophenylacetamide; N- [3- (3,5-dimethylphenyl) propyl] -4- (2-aminoethoxy) -3-aminophenylacetamide; N- [3- ( 3-Ethylphenyl) propyl] -4- (2-aminoethoxy) -3-aminophenylacetamide;

N- (4-phenylbutyl) -4- (2-
Aminoethoxy) -3-aminophenylacetamide;
N- [4- (3,4-dimethylphenyl) butyl] -4
-(2-Aminoethoxy) -3-aminophenylacetamide; N- (5-phenylpentyl) -4- (2-aminoethoxy) -3-aminophenylacetamide; N
-[3- (4-Chlorophenyl) propyl] -4- (2
-Aminoethoxy) phenylacetamide; N- [3-
(4-chlorophenyl) propyl] -4- (2-aminoethoxy) -3-fluorophenylacetamide;

N- [3- (4-chlorophenyl) propyl] -4- (2-aminoethoxy) -3-chlorophenylacetamide; N- [3- (4-chlorophenyl) propyl] -4- (2-aminoethoxy) ) -3-Methoxyphenylacetamide; N- [3- (2,4-dichlorophenyl) propyl] -4- (2-aminoethoxy)-
3-methoxyphenylacetamide; N- [3- (3,
4-dichlorophenyl) propyl] -4- (2-aminoethoxy) -3-methoxyphenylacetamide; N-
[3- (4-Fluorophenyl) propyl] -4- (2
-Aminoethoxy) -3-methoxyphenylacetamide;

N- [3- (3,4-methylenedioxyphenyl) propyl] -4- (2-aminoethoxy) -3
-Methoxyphenylacetamide; N- [3- (3-methoxyphenyl) propyl] -4- (2-aminoethoxy) -3-methoxyphenylacetamide; N- [3-
(3-Benzyloxyphenyl) propyl] -4- (2
-Aminoethoxy) -3-methoxyphenylacetamide; N- [3- (3,4-dimethoxyphenyl) propyl] -4- (2-aminoethoxy) -3-methoxyphenylacetamide; and N- [3- (3 -Trifluoromethylphenyl) propyl] -4- (2-aminoethoxy) -3-methoxyphenylacetamide.

The present invention also provides an analgesic and anti-inflammatory agent containing, as an active ingredient, one or more of the phenylacetamide derivatives represented by the general formula (I) and a pharmacologically acceptable carrier.

The term "pharmacologically acceptable carrier" as used herein refers to one or more solid or liquid filler, diluents or encapsulating agents suitable for administration to humans or animals. To do. The carrier used in the present invention is
In a normal formulation, it is a component that hardly reduces the efficacy of the pharmaceutical composition. Further, as the pharmacological carrier, one having a sufficiently low toxicity to be administered to a treatment subject is suitable.

Therefore, such carriers include sugar, starch,
Cellulose and its derivatives, powdered tragacanth gum, malt, gelatin, talc, magnesium stearate, calcium sulfate, vegetable oil, polyol, alginic acid, pyrogen-free water, isotonic saline phosphate buffer solution, cocoa butter ( Suppository bases) and emulsifiers, as well as pharmacologically acceptable non-toxic substances used for other formulation can be used. Wetting agents and lubricants such as sodium lauryl sulfate, as well as colorants, fragrances, excipients,
Tableting agents, stabilizers, antioxidants and preservatives may also be suitably mixed. Ingredients such as analgesics, muscle relaxants and other additives can be admixed with the pharmacological carrier used in the compositions of the present invention.

The pharmacological carrier suitable in the present invention is basically determined by the administration mode. The compounds of the invention may be administered by injection, orally or topically. When the compound of the invention is administered by injection, a preferred carrier is pH 4
There is sterile saline. For topical administration of the compounds, carriers, which are suitable for use as creams, jellies, tapes, etc. are desirable. As a pharmacological carrier for oral administration, those suitable for tablets and capsules are desirable.

The total amount of the carrier may occupy 0.1 to 99.99999%, mainly 50% to 99.9999% of the weight of the pharmaceutical composition of the present invention.

The dose of the compound of the present invention is generally 1 μg.
To 10 g, preferably 1 μg to 3,50
0 mg, more preferably 1 μg to 1,000
mg, most preferably 1 μg to 600 mg. Pharmaceutically suitable carriers for the formulation of oral and injectable single dosage forms and topical single dosage forms are known. The choice can be made in view of the attendant considerations such as taste, cost and / or storage stability, these considerations being not limiting for the purposes of the present invention only. ..

As described above, the phenylacetamide derivative of the general formula (I) of the present invention in which variously substituted ω-phenylalkyl groups are bonded to the carbonyl group and the pharmacologically acceptable salt thereof are conventional. It has superior analgesic and anti-inflammatory effects to the compounds.

[0064]

EXAMPLES A method for producing a starting material will be described below with reference to examples.

Reference Example 1: Synthesis of 3- (3,4-dimethylphenyl) propylamine 70.0 ml diethyl malonate 400 ml absolute ethanol
10.0 g of sodium metal is added to the solution, stirred for 30 minutes and then cooled to 0 ° C. To this solution was added 66.5 g of 3,4-dimethylbenzyl chloride, the mixture was stirred at room temperature for 1 hour and then heated at the boiling point for 4 hours, and the reaction mixture was concentrated under reduced pressure to give a residue. After dissolving this in ethyl ether,
Wash with water. To the residue obtained by further concentrating the organic layer, 500 ml of water and 170 g of KOH are added, and the mixture is heated at the boiling temperature for 24 hours. After concentrating under reduced pressure until the amount of the mixture is almost halved, 200 ml of sulfuric acid was gradually added to the mixture, and the boiling point was adjusted to 2
Heat for 4 hours. The resulting solution was extracted twice with 300 ml of ethyl ether, the solvent was distilled off under reduced pressure, and the residue was recrystallized from boiling hexane to give 42.1 g of white solid 3- (3,4-dimethylphenyl) propionic acid. Obtained (yield 55
%). Boiling point 82 ° C; NMR (CDCl ₃ , 300 MHz) δ: 2.22 (s, 3H, CH ₃ ), 2.24 (s, 3H,
CH ₃ ), 2.66 (t, J = 8Hz, 2H, ArCH ₂ ), 2.89 (t, J = 8Hz, 2
H, CH ₂ CO), 6.93-7.70 (m, 3H, ArH).

A mixture of 18.5 g of 3- (3,4-dimethylphenyl) propionic acid obtained above and 50 ml of thionyl chloride was refluxed for 2 hours and then concentrated under reduced pressure. 1 residue obtained
Dissolved in 00 ml of ethyl ether, this solution is added to a mixture of 200 ml of ethyl ether, 150 ml of water and 50 ml of 30% aqueous ammonia solution with good stirring. The organic layer is separated and the water bath is extracted twice with 150 ml portions of dichloromethane. The organic layers were combined and concentrated under reduced pressure, the resulting residue was dissolved in 150 ml of tetrahydrofuran, and this solution was dissolved in 8.0 g of LiAlH ₄ and 200 ml of tetrahydrofuran.
After being added to the mixture with and heated at boiling point for 6 hours. After 30 ml of 30% NaOH aqueous solution and 20 ml of water were gradually added to the reaction mixture, the tetrahydrofuran layer was separated from the mixture, dissolved in 300 ml of solid residue in water and extracted twice with 200 ml of ethyl ether each time. The tetrahydrofuran solution separated above and the ethyl ether solution were combined and concentrated, and the residue was evaporated under reduced pressure to give 13.4 g of 3-
(3,4-Dimethylphenyl) propylamine was obtained (yield 70%). Boiling point 140-150 ° C / 0.5 mmHg; NMR (CDCl ₃ , 300 MHz) δ: 1.32 (br s, 2H, NH ₂ ), 1.74 (qui
nt, J = 7Hz, 2H, CH ₂ ), 2.23 (s, 3H, CH ₃ ), 2.24 (s, 3H,
CH ₃ ), 2.59 (t, J = 7Hz, 2H, ArCH ₂ ), 2.72 (t, J = 7Hz, 2H,
CH ₂ N), 6.91-7.06 (m, 3H, ArH).

Reference Example 2: Synthesis of 3- (3-methylphenyl) propylamine The title compound was prepared in the same manner as in Reference Example 1, except that 3-methylbenzyl chloride was used instead of 3,4-dimethylbenzyl chloride. Was produced (yield 82%). Boiling point 150 ° C / 0.3 mmHg; NMR (CDCl ₃ ) δ: 1.20 (br s, 2H, NH ₂ ), 1.76 (m, 2H, C
H ₂ ), 2.33 (s, 3H, ArCH ₃ ), 2.61 (t, J = 7Hz, 2H, ArC
H ₂ ), 2.72 (t, J = 7Hz, 2H, CH ₂ NH ₂ ), 6.48-7.20 (m, 4H,
ArH).

Reference Example 3: Synthesis of 3- (4-methylphenyl) propylamine The title compound was obtained by the method described in Reference Example 1 above using 4-methylbenzyl chloride instead of 3,4-dimethylbenzyl chloride. It was produced (yield 73%). Boiling point 130 ° C./0.4 mmHg; NMR (CDCl ₃ ) δ: 1.55 (br s, 2H, NH ₂ ), 1.75 (m, 2H, C
H ₂ ), 2.32 (s, 3H, ArCH ₃ ), 2.61 (t, J = 7Hz, 2H, ArC
H ₂ ), 2.72 (t, J = 7Hz, 2H, CH ₂ NH ₂ ), 7.01 (m, 4H, ArH).

Reference Example 4: Synthesis of 3- (3,5-dimethylphenyl) propylamine 3,5-dimethyl chloride instead of 3,4-dimethylbenzyl chloride
The title compound was produced in the same manner as in Reference Example 1 using dimethylbenzyl (yield 71%). Boiling point 150 ° C / 0.3 mmHg; NMR (CDCl ₃ ) δ: 1.48 (br s, 2H, NH ₂ ), 1.74 (quint, J = 7H
z, 2H, CH ₂ ), 2.21 (s, 6H, 2ArCH ₃ ), 2.56 (t, J = 7Hz, 2
H, ArCH ₂ ), 2.70 (t, J = 7Hz, 2H, CH ₂ NH ₂ ), 6.81 (s, 3H,
ArH).

Reference Example 5: Synthesis of 2- (3,4-dimethylphenyl) ethylamine 6.8 g of 90% sodium cyanide was added to 6.5 ml of distilled water.
After dissolving with heating, the solution is added with a solution of 15.5 g of 3,4-dimethylbenzyl chloride in 20 ml of absolute ethanol and heated at the boiling point for 10 hours. This solution was cooled to room temperature, 50 ml of distilled water was added, and the mixture was extracted twice with 150 ml of ethyl ether each time, and then the organic solvent was removed to give 11.5 g.
There was obtained 3,4-dimethylbenzyl cyanide (yield 79%). This was dissolved in 50 ml of anhydrous tetrahydrofuran to prepare a mixture of 6.0 g of LiAlH _{4 and} 150 ml of anhydrous tetrahydrofuran.
Add slowly to the ml dispersion and heat to boiling for 14 hours.
After cooling the reaction mixture to room temperature, 1N NaOH 1
6 ml and 8 ml of distilled water are slowly added, the mixture is filtered through Celite and the residue is dissolved in a mixture of 250 ml of ethyl ether and 250 ml of ethyl alcohol. The filtrate is 5N-N
After alkalinizing with aqueous aOH solution, it is extracted with dichloromethane (200 ml × 2) and the solvent is distilled off under reduced pressure.
The residue was distilled under reduced pressure to obtain 5.6 g of the title compound (yield 4
8%).

Reference Example 6: Synthesis of 3- (4-chlorophenyl) propylamine 6.75 g of 4-chlorocinnamic acid and CuSO ₄ .5H ₂ O
A mixture of 0.3 g dispersed in 50 ml of ethanol is stirred at room temperature for 10 minutes, 23 ml of 95% hydrazine is added, and the mixture is stirred for 18 hours while passing 1 liter of air per minute. The mixture is filtered through Celite and 30 ml of 1N NaOH are added. The resulting solution is washed twice with 30 ml of dichloromethane, then acidified with concentrated hydrochloric acid and extracted 4 times with 100 ml of ethyl acetate each time. Dry over magnesium sulfate and evaporate the solvent to give 3-
6.05 g of (4-chlorophenyl) propionic acid was obtained (89% yield).

5.90 g of 3- (4-chlorophenyl) propionic acid obtained above was dissolved in 6 ml of thionyl chloride, heated under reflux for 2 hours and concentrated under reduced pressure, and the residue obtained was dissolved in 100 ml of ethyl ether. This solution was added to NH ₄ OH in an ice bath.
After adding dropwise to 150 ml, the mixture is stirred at room temperature for 1 hour. After extracting twice with 200 ml each of dichloromethane, the organic layer was washed with 100 ml of a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and the solvent was evaporated to obtain 4.62 g of 3- (4-chlorophenyl) propionic acid amide. (Yield 78%).

4.62 g of the amide thus obtained was dissolved in 50 ml of anhydrous tetrahydrofuran and the solution was treated with LiA.
Slowly add dropwise to a dispersion of 2.4 g of 1H _{4 in} 150 ml of anhydrous tetrahydrofuran and heat to reflux for 2 hours. After cooling to room temperature, treat with 10 ml of 1N NaOH and filter through Celite. The residue was dissolved in 150 ml of distilled water and filtered through Celite, and the filtrate was 100 ml of ethyl ether.
Extraction was performed three times, and the organic layers were combined, dried over magnesium sulfate, concentrated, and distilled under reduced pressure to obtain 3.12 g of the title compound as a colorless liquid (yield 73%). Boiling point 140 ° C / 3.4 mmHg.

Reference Example 7: 3- (4-fluorophenyl)
Synthesis of Propylamine Using 4-fluorocinnamic acid instead of 4-chlorocinnamic acid, the title compound was obtained in the same manner as in Reference Example 6 above. NMR (CDCl ₃ ) δ: 1.35 (s, 2H, NH ₂ ), 1.73 (m, 2H, CH ₂ ),
2.65 (m, 4H, 2CH ₂ ), 6.71 (m, 2H, ArH), 7.03 (m, 2H, A
rH).

Reference Example 8: Synthesis of 3- (2,4-dichlorophenyl) propylamine By the same method as in Reference Example 6 above, 2,4-dichlorocinnamic acid was used instead of 4-chlorocinnamic acid. The title compound was obtained. Boiling point 116 ° C./0.75 mmHg; NMR (CDCl ₃ ) δ: 1.13 (s, 2H, NH ₂ ), 1.81 (m, 2H, CH ₂ ),
2.78 (m, 4H, 2CH ₂ ), 7.27 (m, 3H, ArH).

Reference Example 9: Synthesis of 3- (3,4-dichlorophenyl) propylamine By the same method as in Reference Example 6 above, 3,4-dichlorocinnamic acid was used instead of 4-chlorocinnamic acid. The title compound was obtained. NMR (CDCl ₃ ) δ: 1.45 (s, 2H, NH ₂ ), 1.72 (quint, J = 7.4H
z, 2H, CH ₂ ), 2.60 (t, J = 7.8Hz, 2H, CH ₂ N), 2.70 (t, J =
7.1Hz, 2H, ArCH ₂ ), 7.00 (dd, J = 2.1, 8.1Hz, 1H, ArH),
7.26 (d, J = 2.0Hz, 1H, ArH), 7.31 (d, J = 8.2Hz, 1H, A
rH).

Reference Example 10: Synthesis of 3- (3,4-methylenedioxyphenyl) propylamine 10% of 10.0 g of 3,4-methylenedioxycinnamic acid
To a solution of 130 ml of NaOH and 80 ml of distilled water, 5% Pd
After the addition of 1.0 g of -C, the reaction is carried out at a pressure of 40 psi until the hydrogen gas is no longer exhausted, filtered through Celite, acidified with concentrated hydrochloric acid and cooled to room temperature. The produced solid was filtered, washed twice with 100 ml of cold water each time, and dried to obtain 9.8 g of 3- (3,4-methylenedioxyphenyl) propanoic acid (yield 97%). NMR (CDCl ₃ , 200 MHz) δ: 2.62 (t, J = 7Hz, 2H, CH ₂ ), 2.88
(t, J = 7Hz, 2H, CH ₂ N), 5.93 (s, 2H, CH ₂ O ₂ ), 6.63-6.7
6 (s, 3H, ArH).

A mixture of 8.23 g of propionic acid and 5.3 ml of thionyl chloride is heated under reflux for 2 hours. After concentration under reduced pressure, the residue was dissolved in 100 ml of anhydrous ethyl ether, gradually added dropwise to 150 ml of ammonia water in an ice bath, stirred for 1 hour at room temperature, and then extracted with 200 ml of ether three times.
Dry over magnesium sulfate, evaporate the solvent and remove 3- (3,
7.89 g of 4-methylenedioxyphenyl) propionic amide was obtained (96% yield).

6.0 g of the above amide was dissolved in 100 ml of anhydrous tetrahydrofuran, and this solution was added to LiAlH ₄ 2.
The mixture was added dropwise to a suspension of 4 g of anhydrous tetrahydrofuran in 150 ml, and the mixture was heated under reflux for 2 hours, 10 ml of 1N NaOH was added, and the mixture was filtered through Celite. 200 ml distilled water
Dissolve in and extract twice with 200 ml of ethyl ether each time. The organic layers were combined, dried over magnesium sulfate, concentrated, and then distilled under reduced pressure to obtain 4.71 g of 3- (3,4-methylenedioxyphenyl) propylamine (yield 85%). NMR (CDCl ₃ , 200 MHz) δ: 1.34 (br s, 2H, NH ₂ ), 1.72 (m,
J = 7Hz, 2H, CH ₂ ), 2.57 (t, J = 7Hz, 2H, CH ₂ ), 2.71 (t,
J = 7Hz, 2H, CH ₂ N), 5.91 (s, 2H, CH ₂ O ₂ ), 6.59-6.74 (s,
3H, ArH).

Reference Example 11: Synthesis of 3- (3-trifluorophenyl) propylamine Using 3-trifluoromethylcinnamic acid instead of 3,4-methylenedioxycinnamic acid, the above Reference Example 10 was used. The title compound was obtained by a method similar to. NMR (CDCl ₃ ) δ: 1.40-2.10 (m, 4H, CH ₂ , NH ₂ ), 2.40-2.90
(m, 4H, 2CH ₂ ), 7.30 (s, 4H, ArH).

Reference Example 12: Synthesis of 3- (3-benzyloxyphenyl) propylamine Using Reference Example 10 using 3-benzyloxycinnamic acid instead of 3,4-methylenedioxycinnamic acid. The title compound was obtained in a similar manner.

Reference Example 13: Synthesis of 3- (3-methoxyphenyl) propylamine The same as Reference Example 10 except that 3-methoxycinnamic acid was used instead of 3,4-methylenedioxycinnamic acid. The method afforded the title compound. NMR (CDCl ₃ ) δ: 1.24 (s, 2H, CH ₂ ), 1.72 (m, 2H, CH ₂ ),
2.61 (m, 4H, 2CH ₂ ), 3.68 (s, 3H, OCH ₃ ), 6.71 (m, 3H,
ArH), 7.18 (m, 1H, ArH).

Reference Example 14: Synthesis of 3- (3,4-dimethoxyphenyl) propylamine 3,4-Methylenedioxycinnamic acid instead of 3,4-
The title compound was obtained by the same method as in Reference Example 10 using dimethoxycinnamic acid (yield 73%).

Reference Example 15: Synthesis of 3- (4-methoxyphenyl) propylamine The same as Reference Example 10 except that 4-methoxycinnamic acid was used instead of 3,4-methylenedioxycinnamic acid. The title compound was obtained by the method (yield 94%). NMR (CDCl ₃ ) δ: 1.21 (s, 2H, NH ₂ ), 1.71 (m, 2H, CH ₂ ),
2.57 (t, J = 7Hz, 2H, CH ₂ ), 2.69 (t, J = 7Hz, 2H, CH ₂ ),
3.75 (s, 3H, OCH ₃ ), 6.81-7.10 (m, 4H, ArH).

Reference Example 16: 4- (3-methylphenyl)
Synthesis of butylamine 3-Methylbenzyl chloride in 300 ml of anhydrous toluene 14.
0 g and 50.0 g of ethyl acrylate are dissolved and the mixture is heated to 110 ° C. Separately, AIBN (2,2 '
3.0 g of azobisisobutyronitrile) and 32.0 g of hydrogenated tri-n-butyltin were dissolved in 200 ml of anhydrous toluene and this solution was added to the mixture over 2 hours. After heating the reaction mixture further for 2 hours at boiling point,
The residue obtained by cooling to ambient temperature and distilling off the solvent under reduced pressure was purified by silica gel column chromatography to give 4-
Ethyl (3-methylphenyl) butyrate was obtained.

This ester was mixed with 100% 10% KOH aqueous solution.
After adding 12 ml and heating at the boiling point for 12 hours, the organic layer is washed with 50 ml of ethyl ether, the aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl ether (100 ml × 3). The organic solvent was distilled off under reduced pressure to obtain 9.6 g of emulsion liquid 4- (3-methylphenyl) butyric acid (yield 55%).

4- (3-methylphenyl) thus obtained
A mixture of 3.3 g of butyric acid and 10 ml of thionyl chloride was heated at the boiling point for 2 hours and then concentrated under reduced pressure, and the residue obtained was dissolved in 50 ml of ethyl ether.
l, 300 ml of water and 20 ml of 30% aqueous ammonia are added with stirring, then the organic layer is separated and extracted with dichloromethane (50 ml x 2). Next, the organic layers were combined and evaporated to dryness under reduced pressure to obtain a residue. This residue was dissolved in 40 ml of tetrahydrofuran, and then LiAlH ₄ 0.9
Add to a mixture of 4 g and 60 ml of tetrahydrofuran and heat at boiling point for 5 hours. To this mixture was slowly added 10 ml of 10% aqueous NaOH solution. The tetrahydrofuran layer was separated, the residue was dissolved in 100 ml of water, and ethyl ether (5
It was extracted with 0 ml × 2). The separated tetrahydrofuran layer and ethyl ether layer were combined and concentrated under reduced pressure, and the residue obtained was distilled under reduced pressure to obtain 1.48 g of the title compound (yield 79%). Boiling point 145 to 150 ° C./0.35 mmHg; NMR (CDCl ₃ ) δ: 1.49 (m, 2H, NH ₂ ), 1.59-1.67 (m, 4H, 2C
H ₂ ), 2.33 (s, 3H, ArCH ₃ ), 2.59 (t, J = 7Hz, 2H, ArC
H ₂ ), 2.70 (t, J = 7Hz, 2H, NHCH ₂ ), 6.97-7.20 (m, 4H, Ar
H).

Reference Example 17: Synthesis of 4- (3,4-dimethylphenyl) butylamine By the same method as in Reference Example 16 above, except that 3,4-dimethylbenzyl chloride was used instead of 3-methylbenzyl chloride. The compound was prepared.

Reference Example 18: Synthesis of 3-benzyloxy-4-hydroxyphenylacetic acid 3,4-dihydroxyphenylacetic acid ethyl ester
79 g of the product is dissolved in anhydrous acetone, 4.48 g of potassium carbonate and 4.15 ml of benzyl bromide are added thereto, and the mixture is heated under reflux until the starting material is consumed. The solvent is distilled off under reduced pressure, and 50 ml of water is added to the obtained residue. The mixture is acidified with concentrated hydrochloric acid and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate and then evaporated to dryness under reduced pressure, and the resulting residue was purified by column chromatography to give 3-
3.80 g of benzyloxy-4-hydroxyphenylacetic acid ethyl ester was obtained (yield 45%). NMR (CDCl ₃ , 200MHz) δ: 1.24 (t, J = 7Hz, 3H, CH ₃ ), 3.45
(s, 2H, CH ₂ CO), 4.12 (q, J = 7Hz, 2H, OCH ₂ ), 5.05 (s,
2H, CH ₂ Ph), 6.77-7.35 (m, 6H, ArH).

5.35 g of the above ester was added to a mixed solution of 50 ml of water and 1.49 g of sodium hydroxide, and the mixture was stirred for 30 hours for 2 hours.
After heating under reflux for a minute, the mixture was acidified with concentrated hydrochloric acid and concentrated under reduced pressure to give a solid, which was purified with a Soxhlet extractor to give 4.27 g of the target compound as a yellow solid (yield 89%). Melting point 130-133 ° C; NMR (CDCl ₃ , 200 MHz) δ: 3.45 (s, 2H, CH ₂ Ar), 5.09 (s, 2
H, OCH ₂ ), 6.75-7.40 (m, 6H, ArH).

The following examples illustrate some methods of making compounds of general formula (I).

Example 1: N- [3- (3,4-dimethylphenyl) propyl] -4- (2-aminoethoxy)-
Synthesis of 3-methoxyphenylacetamide Step 1. Synthesis of N- [3- (3,4-dimethylphenyl) propyl] -4-hydroxy-3-methoxyphenylacetamide 3- (3,4-dimethylphenyl) obtained in Reference Example 1
A mixture of 1.39 g of propylamine, 1.50 g of 4-hydroxy-3-methoxyphenylacetic acid and 0.60 g of powder 4Å molecular sieve was stirred at a temperature of 150 to 160 ° C. for 4 hours and then dissolved in 10 ml of dichloromethane. After purification by column chromatography, 2.43 g of the title compound was obtained (yield 90%). NMR (CDCl ₃ ) δ: 1.72 (m, 2H, CH ₂ ), 2.21 (s, 6H, 2ArC
H ₂ ), 2.49 (t, J = 7Hz, 2H, ArCH ₂ ), 3.22 (q, J = 7Hz, 2H,
ArCH ₂ ), 3.47 (s, 2H, CH ₂ CO), 3.87 (s, 3H, OCH ₃ ), 5.4
4 (s, 1H, NH), 5.78 (s, 1H, OH), 6.68-7.04 (m, 6H, Ar
H).

Step 2. N- [3- (3,4-dimethylphenyl) propyl] -4- (2-bromoethoxy) -3
Synthesis of-(methoxyphenylacetamide) 1.80 g of the amide obtained in Step 1 above was dissolved in a mixed solvent of 60 ml of tetrahydrofuran and 10 ml of 2,2-dibromoethane, added with 2.2 g of 50% NaH and heated at the boiling point for 12 hours. Then, the reaction mixture was poured into 200 ml of water and extracted with dichloromethane (150 ml × 2).
The solvent was removed under reduced pressure, the residue was purified by column chromatography, and then recrystallized from dichloromethane-hexane to obtain 1.53 g of the title compound (yield 63%). Melting point 105 ° C; NMR (CDCl ₃ ) δ: 1.73 (quint, J = 7Hz, 2H, CH ₂ ), 2.21 (s,
6H, 2ArCH ₂ ), 2.50 (t, J = 7Hz, 2H, ArCH ₂ ), 3.22 (q, J
= 7Hz, 2H, NCH ₂ ), 3.48 (s, 2H, CH ₂ CO), 3.66 (t, J = 6H
z, 2H, CH ₂ Br), 3.86 (s, 3H, OCH ₃ ), 4.32 (t, J = 6Hz, 2
H, OCH ₂ ), 5.38 (br s, 1H, NH), 6.73-7.05 (m, 6H, Ar
H).

Step 3. N- [3- (3,4-dimethylphenyl) propyl] -4- (2-azidoethoxy) -3
Synthesis of methoxyphenylacetamide To a solution of 1.16 g of 4- (2-bromoethoxy) phenylacetamide obtained in step 2 above in 20 ml of benzene,
0.90 g of NaN ₃ and tetra-n-butylammonium
Add 0.17 g of bromide and heat at boiling point for 24 hours. The reaction mixture is diluted with 100 ml of dichloromethane, washed with 100 ml of water and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography and recrystallized from dichloromethane-hexane to obtain 1.03 g of the desired compound (yield 97%). Melting point 105 ° C; NMR (CDCl ₃ ) δ: 1.73 (quint, J = 7Hz, 2H, CH ₂ ), 2.22 (s,
6H, 2ArCH ₂ ), 2.50 (t, J = 7Hz, 2H, ArCH ₂ ), 3.23 (q, J
= 7Hz, 2H, NCH ₂ ), 3.49 (s, 2H, CH ₂ CO), 3.64 (t, J = 5H
z, 2H, OCH ₂ ), 3.86 (s, 3H, OCH ₃ ), 4.18 (t, J = 5Hz, 2
H, CH ₂ N ₃ ), 5.40 (br s, 1H, NH), 6.73-7.06 (m, 6H, Ar
H).

Step 4. N- [3- (3,4-dimethylphenyl) propyl] -4- (2-aminoethoxy) -3
Synthesis of methoxyphenylacetamide To a solution of 1.00 g of 4- (2-azidoethoxy) phenylacetamide obtained in step 3 above in 100 ml of ethyl acetate was added 0.30 g of 10% Pd-C to give about 40 psi.
Under hydrogen pressure for 5 hours. Pd-C was removed from this reaction product through Celite, the solvent was distilled off under reduced pressure, and the residue was recrystallized from dichloromethane-hexane to obtain 0.88 g of the desired compound (yield 94%). Melting point 125 ° C NMR (CDCl ₃ ) δ: 1.72 (m, 4H, CH ₂ , NH ₂ ), 2.21 (s, 6H, 2
ArCH ₃ ), 2.49 (t, J = 7Hz, 2H, ArCH ₂ ), 3.11 (q, J = 5Hz,
2H, OCH ₂ ), 3.22 (q, J = 7Hz, 2H, NCH ₂ ), 3.49 (s, 2H, C
H ₂ CO), 3.85 (s, 3H, OCH ₃ ), 4.04 (t, J = 5Hz, 2H, CH
₂ N), 5.42 (br s, 1H, NH), 6.71-7.03 (m, 6H, ArH).

Examples 2-35 Various compounds were synthesized by the same method as in Example 1.
The results are shown in Table 1.

Example 36: N- [3- (3,4-dimethylphenyl) propyl] -4- (2-aminoethoxy)
Synthesis of 3-hydroxyphenylacetamide Step 1. Synthesis of N- [3- (3,4-dimethylphenyl) propyl] -3-benzyloxy-4-hydroxyphenylacetamide 3-Benzyloxy-4-hydroxyphenylacetic acid instead of 4-hydroxy-3-methoxyphenylacetic acid Was used in the same manner as in Step 1 of Example 1 to give the title compound (yield 87%). Melting point 63-66 ° C NMR (CDCl ₃ , 200 MHz) δ: 1.70 (m, J = 7Hz, 2H, CH ₂ ), 2.1
9 (s, 6H, 2CH ₃ ), 2.45 (t, J = 7Hz, 2H, CH ₂ ), 3.18 (q, J
= 5.1Hz, 2H, CH ₂ N), 3.41 (s, 2H, CH ₂ Ar), 5.02 (s, 2H,
CH ₂ ), 5.63 (b, 1H, NH), 6.68-7.35 (m, 6H, ArH).

Step 2. N- [3- (3,4-dimethylphenyl) propyl] -3-benzyloxy-4- (2-
Synthesis of bromoethoxy) phenylacetamide The title compound was obtained by the same method as in Step 2 of Example 1 above (yield 85%). Melting point 73-75 ° C; NMR (CDCl ₃ , 200 MHz) δ: 1.71 (m, J = 7Hz, 2H, CH ₂ ), 2.2
2 (s, 6H, 2CH ₃ ), 2.50 (t, J = 7Hz, 2H, CH ₂ ), 3.19 (q, J
= 6.7Hz, 2H, CH ₂ NH), 3.45 (s, 2H, CH ₂ CO), 3.65 (t, J =
6.4Hz, 2H, CH ₂ Br), 4.35 (t, J = 6.4Hz, 2H, CH ₂ O), 5.1
4 (s, 2H, OCH ₂ Ph), 5.25 (b, 1H, NH), 6.73-7.47 (m, 6
H, ArH).

Step 3. N- [3- (3,4-dimethylphenyl) propyl] -3-benzyloxy-4- (2-
Synthesis of azidoethoxy) phenylacetamide The title compound was obtained by the same method as in Step 3 of Example 1 above (yield 84%). Melting point 105-106 ° C; NMR (CDCl ₃ , 200 MHz) δ: 1.64 (m, J = 6.5 Hz, 2H, CH ₂ ),
2.21 (s, 6H, 2CH ₃ ), 2.49 (t, J = 8Hz, 2H, CH ₂ ), 3.20
(q, J = 6.8Hz, 2H, CH ₂ N), 3.45 (s, 2H, CH ₂ Ar), 3.61
(t, J = 5Hz, 2H, CH ₂ N ₃ ), 4.20 (t, J = 5.1Hz, 2H, OCH ₂ ),
5.11 (s, 2H, OCH ₂ Ph), 5.30 (b, 1H, NH), 6.74-7.45
(m, 6H, ArH).

Step 4. N- [3- (3,4-dimethylphenyl) propyl] -4- (2-aminoethoxy) -3
-Synthesis of hydroxyphenylacetamide The title compound was obtained by the same method as in Step 4 of Example 1 above (yield 87%). Melting point 144-147 ° C; NMR (CDCl ₃ , 200 MHz) δ: 1.65 (m, J = 6.6 Hz, 2H, CH ₂ ),
2.10 (s, 6H, 2CH ₃ ), 2.40 (t, J = 8Hz, 2H, CH ₂ ), 2.95
(t, J = 5Hz, 2H, CH ₂ N), 3.18 (m, J = 6.7Hz, 2H, CH ₂ NC
O), 3.35 (s, 2H, CH ₂ Ar), 3.92 (t, J = 5Hz, 2H, OCH ₂ ),
5.85 (b, 1H, NH), 6.68-7.31 (m, 6H, ArH).

Examples 37 to 39 Various compounds were synthesized by the same method as in Example 36. The results are shown in Table 1.

Example 40: N- [3- (3,4-Dimethylphenyl) propyl] -4- (2-aminoethoxy)
Synthesis of 3-Aminophenylacetamide Step 1. Synthesis of N- [3- (3,4-dimethylphenyl) propyl] -4-hydroxy-3-nitrophenylacetamide 7.0 g 4-hydroxy-3-nitrophenylacetic acid and 8.11 g (COCl) ₂ in 15 ml dichloromethane. The suspension is heated under reflux for 2 hours and then concentrated under reduced pressure. The obtained residue was further dissolved in dichloromethane, 4.14 g of triethylamine and 6.37 g of 3- (3,4-dimethylphenyl) propylamine were added thereto, and the mixture was stirred at room temperature for 5 hours. After the solvent was evaporated and evaporated, the residue was purified by column chromatography and recrystallized from dichloromethane-hexane to give 10.98 g of the title compound (yield 9
0%). Melting point 103 ° C .; NMR (CDCl ₃ , 200 MHz) δ: 1.77 (m, J = 7 Hz, 2H, CCH ₂ C),
2.23 (s, 6H, CH ₃ ), 2.55 (t, J = 8Hz, 2H, CH ₂ Ar), 3.15
(t, J = 5.0Hz, 2H, CH ₂ NH ₂ ), 3.29 (q, J = 6.7Hz, 2H, NHC
H ₂ ), 3.46 (s, 2H, CH ₂ CO), 4.15 (t, J = 5.0Hz, 2H, OC
H ₂ ), 5.40 (b, 1H, NH), 6.86-7.75 (m, 6H, ArH).

Step 2. N- [3- (3,4-dimethylphenyl) propyl] -4- (2-bromoethoxy) -3
-Synthesis of nitrophenylacetamide By the same method as in Step 2 of Example 1 above, the title compound was obtained (yield 94%). Melting point 93 ° C .; NMR (CDCl ₃ , 300 MHz) δ: 1.80 (quint, J = 7 Hz, 2H, CH ₂ ),
2.23 (s, 6H, 2CH ₃ ), 2.57 (t, J = 8Hz, 2H, CH ₂ Ar (C
H ₃ ) ₂ ), 3.25 (q, J = 6.8Hz, 2H, CH ₂ NH), 3.46 (s, 2H, CH
₂ CO), 3.68 (t, J = 6.5Hz, 2H, CH ₂ Br), 3.45 (t, J = 6.5H
z, 2H, CH ₂ O), 5.38 (br, 1H, NH), 6.86-7.72 (m, 6H, A
rH).

Step 3. N- [3- (3,4-dimethylphenyl) propyl] -4- (2-azidoethoxy) -3
-Synthesis of nitrophenylacetamide The title compound was obtained by the same method as in Step 3 of Example 1 above (yield 97%). Melting point 89 ° C .; NMR (CDCl ₃ , 300 MHz) δ: 1.80 (quint, J = 7Hz, 2H, CH ₂ ),
2.27 (s, 6H, 2CH ₃ ), 2.57 (t, J = 8Hz, 2H, 2CH ₃ ), 3.27
(q, J = 6.8Hz, 2H, CH ₂ NCO), 3.48 (s, 2H, CH ₂ CO), 3.69
(t, J = 4.9Hz, 2H, CH ₂ N ₂ ), 4.25 (t, J = 4.9Hz, 2H, CH
₂ O), 5.40 (br, 1H, NH), 6.88-7.75 (m, 6H, ArH).

Step 4. N- [3- (3,4-dimethylphenyl) propyl] -4- (2-aminoethoxy) -3
-Synthesis of aminophenylacetamide The title compound was obtained by the same method as in Step 4 of Example 1 above (yield 94%). Melting point 98 ° C; NMR (CDCl ₃ , 300 MHz) δ: 1.72 (quint, J = 7Hz, 2H, CH ₂ ),
2.20 (s, 6H, 2CH ₃ ), 2.48 (t, J = 8Hz, 2H, 2CH ₃ ), 3.10
(t, J = 5.2Hz, 2H, CH ₂ NH ₂ ), 3.20 (q, J = 6.7Hz, 2H, CH ₂ N
CO), 3.42 (s, 2H, CH ₂ CO), 4.03 (t, J = 5.2Hz, 2H, CH
₂ O), 5.44 (br, 1H, NH), 6.52-7.29 (m, 6H, ArH).

Examples 41 to 49 Various compounds were synthesized by the same method as in Example 40. The results are shown in Table 1.

Example 50: N- [3- (3,4-Dimethylphenyl) propyl] -4- (2-aminoethoxy)
Synthesis of 3-nitrophenylacetamide To a solution of 685 mg of the azide obtained in Step 3 of Example 40 in 6 ml of tetrahydrofuran was added 437 mg of triphenylphosphine, and the mixture was stirred at room temperature for 2 hours, and then 0.1 ml of water was added.
Was added and the mixture was further stirred at room temperature for 4 hours. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography and recrystallized from dichloromethane-hexane to obtain 525 mg of the target compound as a yellow precipitate (yield 82%). Melting point 98 ° C; NMR (CDCl ₃ , 200 MHz) δ: 1.77 (m, J = 7Hz, 2H, CCH ₂ C),
2.23 (s, 6H, CH ₃ ), 2.55 (t, J = 8Hz, 2H, CH ₂ Ar), 3.15
(t, J = 5.0Hz, 2H, CH ₂ NH ₂ ), 3.29 (q, J = 6.7Hz, 2H, NHC
H ₂ ), 3.46 (s, 2H, CH ₂ CO), 4.15 (t, J = 5.0Hz, 2H, OC
H ₂ ), 5.40 (br s, 1H, NH), 6.86-7.75 (m, 6H, ArH).

Examples 51 to 56 Various compounds were synthesized in the same manner as in Example 50. The results are shown in Table 1.

[0109]

[Table 1]

[0110]

[Table 2]

[0111]

[Table 3]

[0112]

[Table 4]

[0113]

[Table 5]

[0114]

[Table 6]

The first column of Table 1 shows the numbers of the examples, and n, Yp and X shown in the second to fourth columns are the same as those defined in the general formula (I), and the fifth to fifth columns. 7
The data shown in the columns are the intermediates used in the preparation of the final compounds of general formula (I), ie, general formula (IV),
The yield and melting point of each of the compounds of (V) and (VI) are shown, and the eighth column shows the yield and melting point of the final compound of general formula (I).

The following formulation examples illustrate the method of formulating the pharmaceutical composition of the present invention.

Formulation Example 1 Tablets are prepared using conventional methods such as mixing and direct compression. The compounding ingredients are as follows.

Patients to whom one tablet should be analgesic (sex: male,
Oral administration twice a day (age: 42, body weight: 67 kg) showed a usual analgesic effect.

Formulation Example 2 A capsule for oral administration is manufactured by incorporating the following ingredients.

The compound of Example 8 was dissolved in sesame oil using an ultrasonic device, and then filled into soft gelatin capsules by a conventional method known in the art. Two capsules, each containing 27 mg of the composition, were given analgesic and anti-inflammatory effects when administered to an adult man weighing 63 kg (age: 35) to be treated.

Formulation Example 3 A syrup for oral administration is manufactured by mixing the following components. Ingredient Amount Compound of Example 1 250 g Benzoic acid solution 20 ml Compound polishing solution 10 ml Formulation water 20 ml Lemon syrup 200 ml Syrup Amount to make up to 1,000 ml

The above ingredients are mixed to form a syrup, which is then packaged under sterile conditions in a 6 oz. Bottle. When 1 spoon of the formulation was administered to an adult man weighing 70 kg (age: 27), it showed analgesic and anti-inflammatory effects.

Formulation Example 4 A composition for injection administration having the following composition was produced. Ingredients Amount Composition 1: Compound of Example 8 0.01% Aqueous acetic acid (1.30%) 95.45% Dextrose 4.54% Composition 2: Compound of Example 8 0.05% Aqueous sodium acetate (1 .18%) 85.95% Aqueous acetic acid (2.0%) 10.00% Benzyl alcohol 4.04%

Before performing the oral surgery for the third molar extraction,
Composition 20.0 for an adult woman weighing 52 kg (age: 29)
A local anesthetic effect was obtained during the operation by injecting 5 ml.

Formulation Example 5 A composition for topical administration was produced by mixing the following components.

The compound of Example 1 was dissolved in the solution of the remaining components, and 0.4 ml of this solution was administered to a site of 80 cm ^{2 on} the anterior arm of an adult man weighing 60 kg and maintained for 2 days. The local analgesic effect was obtained. Little or no skin irritation could be observed.

[Activity test] The physiological activity of the compounds synthesized in the above Examples is measured by the following method.

1. Waddle test 1) Test animal Charles Liver Bleeding Laboratory (Charle)
Strain Breeding Lab), and KTC-ICR mouse, which was supplied from Laboratory Animal Room of Korea Institute for Chemical Research, is used for the experiment. The final product test mice produced by Examples 1-35 weighed 20-25 g and the final product test mice produced by Examples 36-56 ranged in weight 10-15 g. .. After being supplied with these, the experiment was carried out after adapting to the experimental environment while freely supplying water and feed for one week, and the lighting was kept for 12 hours.

2) Test method The experiment was conducted in two ways, namely, acetic acid-induced writhing (Writhin
g) Test method and phenyl-1,4-benzoquinone (P
BQ) Induced writhing test method.

The acetic acid-induced writhing test solution was prepared as in Examples 1 to 1.
5 of any of the final products prepared according to No. 35 was added to a saline solution containing 1 wt% of Tween 80.
It is prepared by dissolving it so that the concentration will be mg / ml, and diluting it successively with a saline solution. Using 5 ICR mice for each test group, 0.3 ml of this test solution
It is orally administered in a dose of 30 g. After 60 minutes, 0.9%
The acetic acid solution was intraperitoneally administered in a volume of 0.1 ml / 30 g of body weight, and after 3 minutes, the number of writhings based on 10 minutes of acetic acid administration was measured. For comparison, first, a physiological saline solution alone is orally administered to a control group. After 60 minutes, a 0.9% acetic acid solution is intraperitoneally administered to the control group.

Furthermore, the PBQ-induced writhing test solution was added,
After preparation by dissolving one of the products synthesized according to Examples 36 to 56 in a mixture of Tween 80, alcohol and distilled water (1: 5: 94), 5 animals per test group were prepared. ICR mice are orally administered in a volume of 0.3 ml / 30 g body weight. 0.02 after 60 minutes
The% PBQ solution is intraperitoneally administered in a volume of 0.1 ml per 30 g of test animal body weight.

After 5 minutes, the number of writhings generated in 5 minutes is measured by the PBQ solution administered at 40 ° C. For comparison, Tween 80, a mixture of alcohol and distilled water alone is orally administered to the control group, and 60 minutes later, the PBQ solution is intraperitoneally administered to the control group according to the above method.

3) Measurement of analgesic effect The number of writhing in the test drug administration group and the control group are compared, and the analgesic effect is measured as a wheezing suppression rate. That is, when the number of writhing in the control group is "A" and the number of writhing in the test drug administration group is "B", the rate of writhing inhibition is shown as follows.

Wheezing suppression rate (I.W.) (%) =
[(A−B) / (A)] × 100

The amount of test drug required to reduce the frequency of wheezing in the control group by 50%, ie B = 0.5A or I.D. W. = 50% is taken as ED ₅₀ (mg / kg body weight). Therefore, the smaller this value is, the stronger the analgesic action is. Table 1 shows the experimental results.

2. Behavioral Observation Various behavioral changes observed in test animals are observed in order to confirm the presence or absence of side effects or toxicity of the compound of the general formula (I).

After administration of the test solution and the control solution to the test animal, sedative effect, ptosis, dyspnea, vasodilation, convulsions, excessive salivation, urinary symptoms, etc. were observed and the degree of such changes was observed. Is indicated by a numerical grade.

The normal values of urination, hypersalivation and sedation are 0, and the normal values of convulsions, ptosis, dyspnea and vasodilation are 4. The higher the number, the more severe the side effects.

The results are shown in Table 2 below.

[0140]

[Table 7]

[0141]

[Table 8]

3. Randal-Selitt
o) Test According to the method described in the paper [Arch, Int. Phamacodyn. 11 , 409 (1957)], the Randall-Selit test was conducted as follows.

Charles Riva Sprague Dawli albino rats (male, weight 120-170 g) were used. Brewer on the plantar of the rat hind paw
Inflammation was induced by injecting 0.1 ml of a 20% suspension of yeast. Paper [Winter & Flataker, J. Pharm. Exp. The
r. 148 , 373 (1965)] was used to measure the threshold value. Pain threshold was measured as the pressure in mmHg required to elicit the desired response (eg, audible jarring and / or flapping) when pressurized on the paw.

From the air line to the neddle valve
Air pressure was applied through ve) to a pressure gauge connected by a 20 ml glass syringe and T-tube. The syringe was equipped with a short bullet-teflon peg-connected plunger.

Pressure was applied to the rat paw at a rate of 10 mmHg / sec. Drugs were administered within 2 hours after yeast injection. The threshold response was measured 2 hours after drug administration.

The results are shown in Table 3 in comparison with the results obtained with the yeast treated saline control group.

The analgesic activity was shown as a reaction inhibition rate.

[0148]

[Equation 1]

Two hours after the yeast injection and one hour before the start of the test,
Oral administration of the compound of Example 1 at a dose of 5 mg / kg suppressed the yeast-induced hyperalgesia.

[0150]

[Table 9]

4. Tail-flick test D'Amour and Smith's paper [J. Phar
m. Exp. Ther. 72 , 74 (1941)] using the modified tail-flick analysis method in mice.
Radiant heat was applied by intensively irradiating the tail with a high-intensity light beam.

The reaction time, defined by the onset of stimulation and the tail-flick interval, was measured electrically (approximately 0.1.
Seconds). The beam intensity was set so that an average adjusted reaction time of 3.8 ± 0.4 seconds was obtained. Within 15 seconds, the animals with unresponsive tails were removed to determine the 15-second reaction latency.

The inhibition rates (analgesic effect) of the compound of Example 1 and the standard compound are shown in Table 4.

The inhibition rate was determined by the following formula.

[0155]

[Equation 2]

Morphine used as a control substance was active in this test, whereas the non-steroidal anti-inflammatory agent had no effect.

As can be seen from these results, Example 1
Is more effective than morphine, and the compound of Example 1
Of the compound acts as a central analgesic.

[0158]

[Table 10]

5. Hot-Plate Test Mice were placed on an aluminum plate held at 55 ± 0.5 ° C by a heat regulator (Harvard). Height 15 cm,
The mouse was enclosed on a heating plate using a 15 cm diameter glass cylinder.

Paw swelling was used as the end point for response latency determination (measured at approximately 0.1). Unreacted animals were removed within 30 seconds and a 30 second-reaction latency was determined.
The inhibition rates of the compound (po) and morphine (sc) of Example 1 were measured in the hot-plate test by the same formula as that used in the tail-flick test, and the results are shown in Table 5. This result shows that the compound (po) of Example 1 is effective to the extent of morphine (sc), and further that the compound of Example 1 acts as a central analgesic.

[0161]

[Table 11]

6. Tail-pinch test in rats with hyperalgesia induced by Freund's supplemental solution 120-170 g rat (Sprague-Dawli strain)
Was used.

Difco Laborato
ries: Dried Mycobacterium butyricu (Detroit, Michigan)
m ) was ground in a mortar, suspended in liquid paraffin, sterilized in an autoclave, and then injected into the tail end using a 1-inch 21-gauge injection needle (containing 0.5 mg in 0.1 ml, s.
c.).

The animals treated in this way show a hypersensitivity reaction due to the pressure applied on the tail within a few hours after the injection, and were therefore used for the analgesic test 18 to 24 hours after the injection. The test for tail hypersensitivity reaction is as follows.

The animal was held loosely in one hand and lightly pressed to the site of injection with the finger of the other hand. This slight pressure or "tail-pinch" causes the animal to make a "chucky sound". Such stimulation was applied 5 times at intervals of 4 seconds. If the animal did not make a "chorus sound" even if it was applied 5 times, it was considered to have analgesic activity and was evaluated as 1. 0 if sound is emitted more than once
Evaluated to.

The analgesic activity was determined by the following formula.

[0167]

[Equation 3]

After oral administration of the compound of Example 1, 2
A tail-pinch test was performed after a lapse of time to determine the inhibition rate associated with the capacity of the drug-induced hyperalgesia, and the results are shown in Table 6.

[0169]

[Table 12]

7. Anti-inflammatory test 100-120g rat (Sprague Dawli,
Female) was used. Twenty minutes after the administration of the test drug, carrageenin was injected into the plantar of the right hind paw (0.1 ml of 1% solution,
sc). Three hours later, the volume of edema was measured with a volume meter (Rehma Vo
lumeter 2060).

The inhibition rate was calculated by the following formula.

[0172]

[Equation 4]

The amount of test compound required to obtain 50% inhibition was expressed as ED ₅₀ .

The suppressing effect of the compounds of Examples 1 and 8 is 7th.
As shown in the table, it was equivalent to the effect of ketoprohen, but far superior to the effects of aspirin or naprozen.

[0175]

[Table 13]

8. Local anti-inflammatory effect test Rats (Sprague Dawli, female) weighing 100 to 120 g were used. Administering the test compound transdermally,
20 minutes later (7 hours later in the case of double dose experiment)
Carrageenin was injected into the plantar of the right hind paw (0.1 ml of a 1% solution, sc). The volume of edema was measured with a volume meter after 1 hour in the case of the single dose experiment and 24 hours in the case of the double dose experiment, and the same formula was used for the anti-inflammatory effect test. The inhibition rate was calculated.

As shown in Table 8, the inhibitory effect of the compound of Example 1 was slightly better than that of naprozene.

[0178]

[Table 14]

9. Toxicity test Further, after 5 oral administration of the test compound of the present invention to 5 ICR mice (male: 5 weeks old) and 5 ICR strain mice (female: 5 weeks old) in various amounts stepwise The test compound was subjected to an acute toxicity test and observed for 14 days. LD this
_The value is shown as ₅₀ .

The LD ₅₀ values of the test compounds are shown in Table 9 below.

[0181]

[Table 15]

10. Mutation test The method developed by Maron and Ames [see Mutation Research, 1983, 113 , 173-175].
And histidine-requiring Salmonella typhimurium TA9 that requires histidine for growth according to
8 and TA100 were used to perform a mutagenicity test on the compound of Example 1. In the case of the compound of Example 1,
The number of mutant colonies did not increase at the concentrations of 3.2, 16, 80 and 40 μg / plate.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (31) Priority claim number 19641/1991 (32) Priority date November 6, 1991 (33) Priority claim country South Korea (KR) (31) Priority claim number Japanese Patent Application No. 3 −130114 (32) Priority Day 3 (1991) June 1 (33) Priority claiming country Japan (JP) (72) Inventor Jejun Kwon South Korea, Daesonshi, Yousung, Dryongdong 431-6 Bondi, Hyundai Apartment 103 Don 604 Ho (72) Inventor Kim Hyun Shuk Republic of Korea, Daisonsi, Junk, Munha Dong 1-15 (72) Inventor Hong Misuk Republic of Korea, Daisonshi, Yousungk, Jan Dong 100 (72) Inventor Im Hyzon South Korea, Busansi, Haeundek, Zesong Dong, Green Apartment 48 Dong 501ho (72) Inventor Iku Hwangsuk Republic of Korea, Chung Chung Namdo, Chung Ansi, Gusung Dong 402-1

Claims (9)

[Claims] 1. A phenylacetamide derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof. [Chemical 1] [Wherein, X is a hydrogen atom, a halogen atom, hydroxy, nitro, amino, R ¹ , NR ¹ R ² , NHR ¹ or OR
¹ group (in the formula, R ¹ and R ² are each a substituted or unsubstituted C _1-8 alkyl, cycloalkyl or benzyl group); Y is the same or different when p is greater than 1; Atom, halogen atom, methylenedioxy,
Represents a hydroxy, trifluoromethyl, R ³ or OR ³ group, where R ³ is a substituted or unsubstituted C _1-8 alkyl or benzyl group; n is an integer from 1 to 6; p is Is an integer from 1 to 5] 2. X is a hydrogen atom, halogen atom, hydroxy, nitro, amino or OR ¹ group; Y is the same or different when p is greater than 1;
A halogen atom, a trifluoromethyl or R ³ group; R ¹ and R ³ are as defined in claim 1; n is an integer of 2 to 5; p is an integer of 1 to 3. The described compound or a salt thereof. 3. X is a halogen atom, hydroxy, nitro, amino or OR ¹ group; Y is the same or different when p is 2 and is a hydrogen atom, halogen atom, trifluoromethyl or R ³ group. Wherein R ¹ and R ³ are each a substituted or unsubstituted C _1-5 alkyl; n is 3 or 4; p is 1 or 2; or a salt thereof. .. 4. The compound according to claim 3, wherein X is a methoxy group, or a salt thereof. 5. The compound according to claim 3, wherein X is a hydroxy group, or a salt thereof. 6. The compound according to claim 3, wherein X is a nitro or amino group. 7. The salt is an inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogensulfate, carbonic acid, and formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gentisic acid, The salt of the compound according to claim 1, which is selected from salts with organic acids such as fumaric acid and lactobionic acid. 8. (i) An amine compound represented by the following general formula (II) and p-hydroxyphenylacetic acid represented by the following general formula (III) in the presence of 3Å, 4Å or 5Å molecular sieve powder at 130 ° C. or higher. Reacting at 160 ° C. for 2 to 5 hours to obtain a compound of the following general formula (IV); (ii) reacting a compound of the general formula (IV) with 1,2-dibromoethane to give a compound of the following general formula (V (Iii) a compound of the general formula (V) with sodium azide (Na
N ₃ ) to obtain a compound of the following general formula (VI); and (iv) reducing the compound of the general formula (VI) under hydrogen pressure in the presence of a catalyst. A process for producing a compound of general formula (I), which comprises the step of converting to a compound of I). [Chemical 2] [Wherein, X, Y, n and p are the same as defined in claim 1] 9. An analgesic and anti-inflammatory agent comprising the phenylacetamide derivative of the general formula (I) according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.