JP3021187B2 - Novel phenylacetamide derivatives and their preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

2. Description of the Related Art Heretofore, capsaicin represented by the following general formula (A) has been described.
It is known that (trans-8-methyl-N-vanillyl-6-nonenamide) has an analgesic effect.

[0003]

Embedded image

[0004] The capsaicin is Cayenne .
It is a spicy component contained in plant juice.
No. 313,958 describes the natural and synthetic capsaicins as drugs having an analgesic action. In addition, Yaksh et al. [Science 206 , 4
81-483 (1979)] and the literature [The Alkaloids, Vol. XXIII, 22
7-299 (1984), Academic Press] discusses capsaicin and its derivatives chemically and pharmacologically.

[0005] EP 282,127 discloses that
It is described that the aminoethoxybenzylamine derivative of the following structural formula (B) has anti-inflammatory and analgesic effects.

[0006]

Embedded image

[0007] Further, US Pat. No. 4,424,205 to TR LaHann et al.
No. 10) describes an analgesic or anti-irritant compound represented by the following general formula (C).

[0008]

Embedded image

[Wherein ^Ra 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, wherein R ₁ and R ₂ One of them is OH,
One of the remainder is OH or H.

[0010] British Patent No. 2, from JM Janusz et al.
168,975 describes an aralcanamide represented by the following general formula (D).

[0011]

Embedded image

Wherein 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.

[0013] US Patent No. 5,095 to Gardner et al.
No. 45,565 includes a general formula (E):

[0014]

Embedded image

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

There is described a phenyl compound substituted with β-aminoethyl represented by the formula:

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

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

In the above 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 reddening the skin due to severe skin irritation, and have a problem of high toxicity.

[0020]

Accordingly, a need has arisen for a compound which has excellent pharmacological and physiological activities, but has little irritation and toxicity.

The present inventors have studied compounds for solving the above-mentioned problems, and as a result, have found a novel phenylacetamide derivative which shows excellent anti-inflammatory and analgesic activities and has almost no skin irritation and toxicity. It was completed.

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

[0023]

Embedded image

Wherein X is a hydrogen atom, a halogen atom, hydroxy, nitro, amino, R ¹ , NR ¹ R ² , NHR
¹ or an OR ¹ group wherein R ¹ and R ² are each an unsubstituted C _1-8 alkyl, cycloalkyl or benzyl group; Y is the same or different when p is greater than 1 , A hydrogen atom, a halogen atom, methylenedioxy, hydroxy, trifluoromethyl, R ³ or OR
³ groups, wherein R ³ is an unsubstituted C _1-8 alkyl or benzyl group; n is an integer from 1 to 6,
p is an integer of 1 to 5]

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

Hereinafter, the present invention will be described in detail.

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

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 hydrogen sulfate and carbonic acid, or formic acid, acetic acid, oxalic acid and benzoic acid , Citric acid, tartaric acid, gluconic acid, gentisic acid, fumaric acid and salts with organic acids such as 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 a salt thereof are: (i) reacting 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 the compound of the general formula (IV) with 1,2-dibromoethane to obtain a compound of the following general formula (V); (iii) general Compounds of formula (V) are converted to sodium azide (Na
N ₃ ) to obtain a compound of the following general formula (VI); and (iv) converting an azide compound of the general formula (VI) into a compound of the general formula (I) of the present invention. it can.

[0033]

Embedded image

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 at 130 ° C. to 160 ° C. in the presence of a catalyst without a solvent.
The heating is performed for 5 to 5 hours. At this time, a 3Å, 4Å or 5Å molecular sieve powder, preferably a 4Å molecular sieve powder can be used as the catalyst.

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

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

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

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

[0041]

Embedded image

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

The compound of the formula (III) can be easily obtained from commercially available products, and can be produced with partial protection.

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

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
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
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 comprising as an active ingredient one or more of the above-mentioned phenylacetamide derivatives of the general formula (I) and a pharmacologically acceptable carrier.

The term "pharmaceutically acceptable carrier" as used herein refers to one or more solid or liquid fillers, diluents or encapsulating agents suitable for administration to humans or animals. I do. Carrier used in the present invention,
It is a component that hardly reduces the efficacy of the pharmaceutical composition in a normal preparation. The pharmacologically preferred carrier has a sufficiently low toxicity for administration to the subject to be treated.

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

The pharmacological carrier suitable in the present invention is basically determined by the mode of administration. The compounds of the present invention can be administered by injection, orally or topically. When the compounds of the present invention are administered by injection, the preferred carrier is pH 4
There is sterile saline. When the compound is to be administered topically, a carrier suitable for use as a cream, jelly, tape or the like is desirable. As a pharmacological carrier for oral administration, those suitable for tablets and capsules are desirable.

The total amount of the carrier may account for 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 g
0 mg, more preferably 1 μg to 1,000 mg.
mg, most preferably from 1 μg to 600 mg. Pharmacological carriers suitable for the formulation of single dosage forms for oral administration and injection and single dosage forms for topical administration are known. These can be selected as appropriate, taking into account additional considerations such as taste, cost and / or storage stability, and these considerations are not limited to the sole purpose of the present invention. .

As described above, the phenylacetamide derivative of the general formula (I) of the present invention having a carbonyl group to which variously substituted ω-phenylalkyl groups are bonded, and the pharmaceutically acceptable salts thereof, Has better analgesic and anti-inflammatory effects than compounds.

[0064]

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

Reference Example 1: Synthesis of 3- (3,4-dimethylphenyl) propylamine 70.0 ml of diethyl malonate and 400 ml of absolute ethanol
10.0 g of metallic sodium are added to the solution, stirred for 30 minutes and cooled to 0 ° C. 66.5 g of 3,4-dimethylbenzyl chloride was added to the solution, and the mixture was stirred at room temperature for 1 hour, heated at the boiling point for 4 hours, and concentrated under reduced pressure to obtain a residue. After dissolving this in ethyl ether,
Wash with water. To the residue obtained by further concentrating the organic layer were added 500 ml of water and 170 g of KOH, and the mixture was heated at the boiling point for 24 hours. The mixture was concentrated under reduced pressure until the amount of the mixture was reduced to almost half.
Heat for 4 hours. The resulting solution was extracted twice with 300 ml portions 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 3- (3,4-dimethylphenyl) propionic acid as a white solid. (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 the previously obtained 3- (3,4-dimethylphenyl) propionic acid and 50 ml of thionyl chloride was refluxed for 2 hours and concentrated under reduced pressure. The residue obtained is 1
Dissolve in 00 ml of ethyl ether and add this solution to a mixture of 200 ml of ethyl ether, 150 ml of water and 50 ml of 30% aqueous ammonia 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 obtained 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.
And then heat at boiling for 6 hours. After slowly adding 30 ml of a 30% aqueous NaOH solution and 20 ml of water to the reaction mixture, the tetrahydrofuran layer is separated from the mixture, dissolved in 300 ml of a solid residue and extracted twice with 200 ml each of ethyl ether. The tetrahydrofuran solution separated above and the ethyl ether solution were combined and concentrated.
(3,4-Dimethylphenyl) propylamine was obtained (yield 70%). NMR (CDCl ₃ , 300 MHz) δ: 1.32 (brs, 2H, NH ₂ ), 1.74 (quick)
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 (82% yield). Boiling point 150 ° C./0.3 mmHg; NMR (CDCl ₃ ) δ: 1.20 (brs, 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 prepared by the method described in Reference Example 1 above, using 4-methylbenzyl chloride instead of 3,4-dimethylbenzyl chloride. Manufactured (73% yield). Boiling point 130 ° C./0.4 mmHg; NMR (CDCl ₃ ) δ: 1.55 (brs, 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 Instead of 3,4-dimethylbenzyl chloride,
The title compound was produced in the same manner as in Reference Example 1 using dimethylbenzyl (yield 71%). NMR (CDCl ₃ ) δ: 1.48 (brs, 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.
Then, a solution of 3,4-dimethylbenzyl chloride (15.5 g) in absolute ethanol (20 ml) was added to the solution, and the mixture was heated at the boiling point for 10 hours. The solution was cooled to room temperature, 50 ml of distilled water was added, and the mixture was extracted twice with 150 ml each of ethyl ether.
(Yield 79%) 3,4-dimethylbenzyl cyanide was obtained. This was dissolved in 50 ml of anhydrous tetrahydrofuran, and 6.0 g of LiAlH _{4 was} added to 150 ml of anhydrous tetrahydrofuran.
After slowly adding to the ml dispersion, heat at the boiling point for 14 hours.
After cooling the reaction mixture to room temperature, 1N NaOH1
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 making the solution alkaline with an aqueous aOH solution, the mixture 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%).

[0071] Reference Example 6: 3- (4-chlorophenyl) Synthesis of propylamine 4- chlorocinnamic cinnamic acid 6.75g and CuSO ₄ · 5H ₂ O
A mixture of 0.3 g in 50 ml of ethanol is stirred at room temperature for 10 minutes, 23 ml of 95% hydrazine are added and the mixture is stirred for 18 hours while passing 1 liter of air per minute. The mixture is filtered through celite, to which 30 ml of 1N NaOH are added. The resulting solution is washed twice with 30 ml of dichloromethane, acidified with concentrated hydrochloric acid and extracted with four 100 ml portions of ethyl acetate. Dry over magnesium sulfate and evaporate the solvent to give a yellow solid 3-
6.05 g of (4-chlorophenyl) propionic acid were 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, concentrated under reduced pressure, and the residue obtained was dissolved in 100 ml of ethyl ether. The solution is placed in an ice bath with NH ₄ OH
After dropwise addition 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 solution of sodium bicarbonate, dried over magnesium sulfate, and the solvent was evaporated to obtain 4.62 g of 3- (4-chlorophenyl) propionamide. (78% yield).

After dissolving 4.62 g of the amide thus obtained in 50 ml of anhydrous tetrahydrofuran, the solution was added to LiA.
A solution of 2.4 g of lH _{4 in} 150 ml of anhydrous tetrahydrofuran is gradually added dropwise and refluxed 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 to give 100 ml of ethyl ether.
The organic layer was combined, dried over magnesium sulfate, concentrated, and distilled under reduced pressure to give 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 The title compound was obtained in the same manner as in Reference Example 6, except that 4-fluorocinnamic acid was used instead of 4-chlorocinnamic acid. 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 In the same manner as in Reference Example 6, except that 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 In the same manner as in Reference Example 6, except that 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
5% Pd in a solution of 130 ml of NaOH and 80 ml of distilled water
After the addition of 1.0 g of -C, the mixture is reacted at a pressure of 40 psi until hydrogen gas is no longer consumed, filtered through celite, acidified with concentrated hydrochloric acid and cooled to room temperature. The resulting solid was filtered, washed twice with 100 ml each of cold water, 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 = 7 Hz, 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 the above-mentioned 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 aqueous ammonia in an ice bath, stirred at room temperature for 1 hour, and extracted three times with 200 ml each of ether.
After drying over magnesium sulfate, the solvent was distilled off and 3- (3,3)
7.89 g of 4-methylenedioxyphenyl) propionamide was obtained (96% yield).

The above amide (6.0 g) was dissolved in anhydrous tetrahydrofuran (100 ml), and this solution was dissolved in LiAlH ₄ .
4 g of a suspension in 150 ml of anhydrous tetrahydrofuran was added dropwise, and the mixture was heated under reflux for 2 hours. After adding 10 ml of 1N NaOH, the mixture was filtered through celite. The residue is distilled water 200ml
And extract twice with 200 ml each of ethyl ether. The organic layers were combined, dried over magnesium sulfate, concentrated and 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 The above Reference Example 10 was carried out using 3-trifluoromethylcinnamic acid instead of 3,4-methylenedioxycinnamic acid. The title compound was obtained in the same manner as in. 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 The same procedure as in Reference Example 10 was carried out except that 3-benzyloxycinnamic acid was used 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 procedure as in Reference Example 10 was carried out except that 3-methoxycinnamic acid was used instead of 3,4-methylenedioxycinnamic acid. The title compound was obtained by the method. 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 Instead of 3,4-methylenedioxycinnamic acid, 3,4-
The title compound was obtained in the same manner as in Reference Example 10 using dimethoxycinnamic acid (yield 73%).

Reference Example 15: Synthesis of 3- (4-methoxyphenyl) propylamine The same procedure as in Reference Example 10 was carried out except that 4-methoxycinnamic acid was used instead of 3,4-methylenedioxycinnamic acid. The title compound was obtained by the method (94% yield). 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 tri-n-butyltin hydride were dissolved in 200 ml of anhydrous toluene and this solution was added to the mixture over 2 hours. After heating the reaction mixture at the boiling point for another 2 hours,
After cooling to ambient temperature, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to give 4-
Ethyl (3-methylphenyl) butyrate was obtained.

A 10% aqueous KOH solution was added to this ester.
After the mixture was heated at the boiling point for 12 hours, the organic layer was washed with 50 ml of ethyl ether, the aqueous layer was 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 an emulsion liquid of 4- (3-methylphenyl) butyric acid (yield 55%).

The 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, concentrated under reduced pressure, and the residue obtained was dissolved in 50 ml of ethyl ether.
After adding to a mixture of 300 ml of water and 20 ml of 30% aqueous ammonia with stirring, the organic layer was separated and extracted with dichloromethane (50 ml × 2). Next, the organic layers were combined and evaporated to dryness under reduced pressure to obtain a residue. The residue was dissolved in 40 ml of tetrahydrofuran and then dissolved in LiAlH ₄ 0.9
4 g and a mixture of 60 ml of tetrahydrofuran are heated at the boiling point for 5 hours. To this mixture was slowly added 10 ml of a 10% aqueous NaOH solution. The tetrahydrofuran layer was separated, and the residue was dissolved in 100 ml of water.
0 ml × 2). The separated tetrahydrofuran layer and ethyl ether layer were combined, 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 = 7 Hz, 2H, NHCH ₂ ), 6.97-7.20 (m, 4H, Ar
H).

Reference Example 17: Synthesis of 4- (3,4-dimethylphenyl) butylamine The title compound was prepared in the same manner as in Reference Example 16 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 was dissolved in anhydrous acetone, and 4.48 g of potassium carbonate and 4.15 ml of benzyl bromide were added thereto, and the mixture was heated under reflux until the starting material was 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 extracted with dichloromethane. After the organic layer was dried over magnesium sulfate, the residue obtained by evaporating to dryness under reduced pressure 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 , 200 MHz) δ: 1.24 (t, J = 7 Hz, 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 placed in a mixture of 50 ml of water and 1.49 g of sodium hydroxide, and the mixture was treated for 2 hours and 30 hours.
After heating under reflux for one minute, the mixture was acidified with concentrated hydrochloric acid and concentrated under reduced pressure to obtain a solid, which was purified by a Soxhlet extractor to obtain 4.27 g of the target compound as a yellow solid (89% yield). 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 for preparing 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 powdered 4-molecular sieve was stirred at a temperature of 150 to 160 DEG C. for 4 hours, and dissolved in 10 ml of dichloromethane. Purification by column chromatography gave 2.43 g of the title compound (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 the above step 1 was dissolved in a mixed solvent of 60 ml of tetrahydrofuran and 10 ml of 2,2-dibromoethane, and 2.2 g of 50% NaH was added, followed by heating at the boiling point for 12 hours. Thereafter, the reaction mixture was poured into 200 ml of water and extracted with dichloromethane (150 ml × 2).
The solvent was removed under reduced pressure, and 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 = 7 Hz, 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 the above Step 2 in 20 ml of benzene,
0.90 g of NaN ₃ and tetra n-butyl ammonium
Add 0.17 g of bromide and heat at boiling 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 = 7 Hz, 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, and the pressure was reduced to about 40 psi.
Under hydrogen pressure of 5 hours. The Pd-C was removed from the 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 to 35 Various compounds were synthesized in the same manner 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 and the title compound was obtained in the same manner as in Step 1 of Example 1 (yield 87%). 63-66 ° C. NMR (CDCl ₃ , 200 MHz) δ: 1.70 (m, J = 7 Hz, 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 in the same manner as in Step 2 of Example 1 (yield: 85%). 73-75 ° C .; NMR (CDCl ₃ , 200 MHz) δ: 1.71 (m, J = 7 Hz, 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 in the same manner as in Step 3 of Example 1 (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 in the same manner as in Step 4 of Example 1 (yield 87%). Mp 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 in the same manner 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 of 4-hydroxy-3-nitrophenylacetic acid and 8.11 g of (COCl) ₂ in 15 ml of dichloromethane The suspension is heated under reflux for 2 hours and then concentrated under reduced pressure. The obtained residue was further dissolved in dichloromethane, and thereto were added 4.14 g of triethylamine and 6.37 g of 3- (3,4-dimethylphenyl) propylamine, and the mixture was stirred at room temperature for 5 hours. After evaporating the solvent by evaporation, the residue was purified by column chromatography and recrystallized from dichloromethane-hexane to obtain 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 The title compound was obtained in the same manner as in Step 2 of Example 1 (yield 94%). 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 in the same manner as in Step 3 of Example 1 (yield 97%). 89 ° C .; NMR (CDCl ₃ , 300 MHz) δ: 1.80 (quint, J = 7 Hz, 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 in the same manner as in Step 4 of Example 1 (yield 94%). Melting point 98 ° C; NMR (CDCl ₃ , 300 MHz) δ: 1.72 (quint, J = 7 Hz, 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 in the same manner 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 azide obtained in Step 3 of Example 40 in 6 ml of tetrahydrofuran was added 437 mg of triphenylphosphine, the mixture was stirred at room temperature for 2 hours, and then 0.1 ml of water was added.
And 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 desired compound as a yellow precipitate (yield: 82%). Mp _{98 ℃; NMR (CDCl 3,} 200MHz) 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 in Table 1 shows the number of each embodiment, and n, Yp and X shown in the second to fourth columns are the same as those defined in the general formula (I), 7
The data shown in the columns are the intermediates used for the preparation of the final compound of the general formula (I), ie, the 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 produced using conventional methods, for example, mixing and direct compression. The components are as follows.

Patients to be analgesic for one tablet (sex: male,
(Age: 42, body weight: 67 kg) was orally administered twice daily, and showed a normal analgesic effect.

Formulation Example 2 A capsule for oral administration is produced by blending the following components.

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

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

After mixing the above ingredients to form a syrup, it is wrapped in a 6 oz. Bottle under sterile conditions. When one spoonful of the formulation was administered to an adult male weighing 70 kg (age: 27), it exhibited analgesic and anti-inflammatory effects.

Formulation Example 4 A composition for injection administration having the following composition was produced. Ingredient 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 oral surgery for the third molar extraction,
Composition 20.0 for adult woman weighing 52 kg (age: 29)
Injection of 5 ml gave a local anesthetic effect during surgery.

Formulation Example 5 A composition for topical administration was prepared 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 product was administered to a site of 80 cm ^{2 in} the forearm of an adult man weighing 60 kg, which was administered for 2 days. When it did, the local analgesic effect was obtained. Little or no skin irritation could be observed.

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

1. Writhing test 1) Test animal Charles River Breeding Laboratory (Charle, USA)
s River Breeding Lab) and a KTC-ICR strain mouse supplied from the Laboratory Animal Room of Korea Chemical Research Laboratory are used for the experiments. Test mice for the final product prepared according to Examples 1-35 weighed 20-25 g, and test mice for the final product prepared according to Examples 36-56 weighed 10-15 g. . After being supplied, the animals were adapted to the experimental environment for one week while freely supplying water and feed, and then subjected to the experiment. The illumination was maintained for a 12-hour cycle.

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

The acetic acid-induced writhing test solutions were prepared in Examples 1 to
35 in a saline solution containing 1 wt% of Tween 80.
It is prepared by dissolving to a concentration of mg / ml and diluting it sequentially with a saline solution. Using 5 ICR mice per test group, the test solution was added at 0.3 ml /
Oral administration in a volume of 30 g body weight. 0.9% after 60 minutes
After intraperitoneal administration of the acetic acid solution in a volume of 0.1 ml / body weight of 30 g, the number of writhing based on the administration of acetic acid for 10 minutes after 3 minutes is measured. For comparison, first, a physiological saline solution alone is orally administered to a control group. Sixty minutes later, a 0.9% acetic acid solution is intraperitoneally administered to the control group.

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

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

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

Writhing inhibition rate (IW) (%) =
[(AB) / (A)] x 100

The amount of test drug required to reduce the frequency of writhing in the control group by 50%, ie B = 0.5A or I.D. W. ED ₅₀ (mg / kg body weight) = 50%. Therefore, a smaller value means a stronger analgesic effect. The experimental results are shown in Table 1.

[0136] 2. Behavior Observation To confirm the presence or absence of side effects or toxicity of the compound of the general formula (I), various behavioral changes observed in test animals are observed.

After administration of the test solution and the control solution to the test animals, symptoms such as sedation, ptosis, dyspnea, vasodilation, convulsions, hypersalivation and urination are observed, and the degree of such changes is observed. Was shown in numerical grade.

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

The results are shown in Table 2 below.

[0140]

[Table 7]

[0141]

[Table 8]

3. Randal-Selitt
o) Test The Randall-Cerrit test was performed as described below by the method described in the paper [Arch, Int. Phamacodyn. 11 , 409 (1957)].

Albino rats (male, body weight 120-170 g) of the species Charles Riva Sprague-Dawley were used. Brewer on rat's hind foot sole
Inflammation was induced by injection of 0.1 ml of a 20% suspension of yeast. Dissertation [Winter & Flataker, J. Pharm. Exp. The
r. 148 , 373 (1965)], the threshold was measured. Pain threshold was measured as the pressure in mmHg required to elicit the desired response (eg, audible sharp sound and / or flapping) when pressure was applied to the foot.

From the air line, a needle valve (neddle val
Through ve), pneumatic pressure was applied to a pressure gauge connected by a 20 ml glass syringe and T-tube. The syringe was equipped with a short bullet-plunger to which a Teflon peg was connected.

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

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

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 yeast-induced hyperalgesia.

[0150]

[Table 9]

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

The response time, defined as the stimulus onset and the tail-flick interval, was measured electrically (approximately 0.1).
Seconds). The beam intensity was set to obtain an average adjusted reaction time of 3.8 ± 0.4 seconds. Animals with unresponsive tails were removed within 15 seconds to determine a 15 second-response latency.

Table 4 shows the inhibition rate (analgesic effect) of the compound of Example 1 and the standard compound.

The suppression rate was determined by the following equation.

[0155]

(Equation 2)

Although morphine used as a control substance showed activity in this test, non-steroidal anti-inflammatory drugs had no effect.

As can be seen from these results, Example 1
Is more effective than morphine,
Act as central analgesics.

[0158]

[Table 10]

[0159] 5. Hot-plate test Mice were mounted on aluminum plates maintained at 55 ± 0.5 ° C. by a thermoregulator (Harvard). Height 15cm,
The mice were surrounded on a hot plate using a 15 cm diameter glass cylinder.

Forefoot 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 response latency was determined.
The inhibition rate of the compound (po) and morphine (sc) of Example 1 was measured in a hot-plate test according to the same formula as that used in the tail-flick test, and the results are shown in Table 5. This result indicates that the compound (po) of Example 1 is as effective as morphine (sc), and that the compound of Example 1 acts as a central analgesic.

[0161]

[Table 11]

6. Tail-pinch test on rats with hyperalgesia induced by Freund's adjuvant 120-170 g rats (Sprague-Dawley)
Was used.

[0163] Difco Laborato
ries: Dried Mycobacterium butyricu obtained from 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 used for analgesic tests 18 to 24 hours after the injection. A test for a tail hypersensitivity reaction is as follows.

The animal was held gently in one hand and lightly pressurized at the site of injection with the finger of the other hand. The animal made a "chucking sound" by applying light pressure or "tail-pinch" in this manner. Such stimuli were given five times at 4 second intervals. When the animal did not emit a “chumbling sound” at least once out of five times, the animal was considered to have analgesic activity and scored as 1. 0 if one or more sounds were emitted
Was evaluated.

Analgesic activity was determined by the following formula.

[0167]

(Equation 3)

After oral administration of the compound of Example 1, 2
After the time elapsed, a tail-pinch test was performed to determine the inhibition rate related to the amount of the hyperalgesia induced by the drug, and the results are shown in Table 6.

[0169]

[Table 12]

[0170] 7. Anti-inflammatory effect test 100-120 g rat (Sprague-Dawley,
Female) was used. Twenty minutes after the administration of the test drug, carrageenin was injected into the sole of the right hind foot (0.1 ml of a 1% solution,
sc). Three hours later, the volume of the edema was measured using a volume meter (Rehma Vo
lumeter 2060).

The suppression rate was determined by the following equation.

[0172]

(Equation 4)

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

The inhibitory effects of the compounds of Examples 1 and 8 were
As shown in the table, the effect of ketoprohen was equal, but far superior to that of aspirin or naprozen.

[0175]

[Table 13]

8. Local anti-inflammatory effect test Rats (Sprague-Dawley, female) weighing 100 to 120 g were used. Administering the test compound transdermally,
20 minutes later (1 hour after 7 hours in the case of a double dose experiment)
And carrageenin was injected into the plantar of the right hind paw (0.1 ml of a 1% solution, sc). After one hour in the case of a single dose experiment and 24 hours in the case of a double dose experiment, the volume of the edema was measured with a volume meter, and the same formula as that used in the anti-inflammatory effect test was obtained. 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 naprozen.

[0178]

[Table 14]

9. Toxicity test In addition, after oral administration of various amounts of the test compound of the present invention to five ICR mice (male: 5 weeks old) and 5 ICR mice (female: 5 weeks old) stepwise. The test compounds were subjected to an acute toxicity test and observed for 14 days. This is LD
Indicated by ₅₀ values.

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

[0181]

[Table 15]

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

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI C07C 237/20 C07C 237/20 (31) Claimed priority number 19641/1991 (32) Priority date November 6, 1991 (1991) .11.6) (33) Priority claiming country South Korea (KR) (31) Priority claim number Japanese Patent Application No. 3-130114 (32) Priority date June 1, 1991 (1991.6.1) (33) ) Priority claiming country Japan (JP) (72) Inventor Jae Jun Kwon The Republic of Korea, Daeongsi, Yusong, Dolyeongdong 431-6 Bondi, Hyundaiapart 103 Dong 604ho (72) Inventor Kim Hyun Suk, Korea , Mun Haddon 1-15 (72) Inventor Hong Mi-sook Republic of Korea, Daeung-si, Yusong, Jandong 100 (72) Inventor Im Hee-zong Korea, Busa Shi, Heundeku, Ze Seo London, Green Apartment 48 Dong 501 Ho (72) inventor Lee Kwang congratulation Korea, Chungcheongnam-do, Chung Anshi, Gusondon 402-1 (56) Reference Korean J. Med. Chem. , Vol. 1, No. 1 (Dec. 1991) p. 36-p. 43 (58) Fields surveyed (Int. Cl. ⁷ , DB name) CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (9)

(57) [Claims] 1. A phenylacetamide derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof: [Wherein, X is a hydrogen atom, a halogen atom, hydroxy, nitro, amino, R ¹ , NR ¹ R ² , NHR ¹ or OR
¹ group (wherein, R ¹ and R ² are each unsubstituted C _1-8 alkyl, cycloalkyl or benzyl group) der
Ri; p is 1 to 5 integer; Y is water atom, a halogen atom, methylenedioxy, hydroxy, trifluoromethyl, R ³ or OR ³ group (wherein, R ³ is unsubstituted C _{1 -8} alkyl or benzyl group),
When p is greater than 1, Y may be the same or different
Well; n is Ru integer der of 1 to 6]. Wherein X is a hydrogen atom, a halogen atom, hydroxy, nitro, amino or OR ¹ group; p is not 1
3 of an integer; Y is selected from the group consisting of water atom, halogen atom, trifluoromethyl or R ³ groups, p is greater than 1
Integer of from n is 2 to 5; Y is also well be the same or different in the case have; have the same meanings R ¹ and R ³ are as defined in Claim 1
The compound according to claim 1, which is or a salt thereof. 3. X is a halogen atom, hydroxy, nitro, amino or OR ¹ group ; p is 1 or 2.
Ri; Y is selected from the group consisting of water atom, halogen atom, trifluoromethyl or R ³ groups, when p is 2, Y is also the same
Different and are well; wherein R ¹ and R ³ are each unsubstituted C _1-5 alkyl; n is Ru 3 or 4 der compound or salt thereof according to claim 1, wherein. 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 according to claim 1, wherein said salt is an inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, 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 an organic acid such as fumaric acid and lactobionic acid. (I) An amine compound represented by the following general formula (II) and p-hydroxyphenylacetic acid represented by the following general formula (III) are reacted at 130 ° C. in the presence of 3 の, 4Å or 5Å molecular sieve powder. Reacting at 160 ° C. for 2 to 5 hours to obtain a compound of the following general formula (IV); (ii) reacting the compound of the general formula (IV) with 1,2-dibromoethane to obtain a compound of the following general formula (V) (Iii) converting the compound of general formula (V) to 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 to obtain a compound of the following general formula (VI) Converting the compound of formula (I) into a compound of general formula (I)
A method for producing a compound of the formula: Embedded image [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 pharmaceutically acceptable salt thereof as an active ingredient.