KR820001615B1 - Process for the preparation of n-phenethyl acetamide - Google Patents

Abstract

The title compds. (I; X1 = lower alkoxy; X2 = H, loweralkoxy; R = phenyl, pyridyl, pyrimidinyl,benzoyl), useful asanti-stress ulcer agents, were prepd. by the reaction of II and R-NHCH2-COY(COY = carboxyl). Thus, 0.36 g 3.4-dimethoxy-phenethylamine and 0.46 g N-(2-carbamoyl-5-chlorophenyl)glycine were reacted at 175-185≰C for 6 hr in N2 gas to give o.44 g 2-(2-carbamoyl-5-chlorrphenylamino)-N-(3,4-dimethoxy-phenethyl)acetamide(m.p. 167.5-169≰C).

Description

Method for preparing N-phenethyl acetamide compound

The present invention relates to N-phenethylacetamide compounds of formula (I), which are useful as gastric ulcer inhibitors for humans and animals, and to methods for preparing pharmaceutically harmless salts or hydrates thereof.

Wherein X ₁ is a lower alkoxy group, X ₂ is a hydrogen atom or a lower alkoxy group and R is a phenyl group, a pyridyl group, a pyrimidinyl group or a benzoyl group, each of which is a halogen atom, a carbamoyl group, a lower alkoxy group It may have one or more substituents selected from sulfamoyl group, amino group, lower alkylamino group, lower alkylthio group, hydroxy group and lower alkoxycarbonyl group.

To date, known compounds with structures similar to the compounds of the invention, 3,4-dihydroxyphenethylamine (abbreviated as dopamine), are described in the following references: LSGoodman and A. Gilmam, The Pharmacological Basis of Therapeutics, (Fourth Edition), P, 234,1970]

However, this compound was unsuitable for clinical use because of its high side effects and insufficient activity.

Accordingly, an object of the present invention relates to a method for preparing a compound of formula (I) and a hydrate or pharmaceutically harmless salt thereof, which is excellent in inhibiting gastric ulcer and can be used clinically safely without causing harmful side effects. .

Other objects will be described later in detail.

The compound of the present invention can be prepared by the following scheme.

In the general formula, -COY represents a carboxyl group or functional group thereof (eg, ester, carboxylic anhydride, etc.), and X ₁ , X ₂ and R are as described above. The term "lower" described in X ₁ , X ₂ and R represents a site having 1 to 6 carbon atoms.

The compound of the present invention is prepared by reacting phenethylamine of formula (II) with a carboxylic acid or functional derivative thereof (III) in the presence or absence of a solvent.

Specifically, phenethylamine of formula (II) is heated with carboxylic acid or its lower alkyl ester (III) at 110 ° C. to 190 ° C. for 1 to 10 hours. When the substituent -COY in the compound of formula (III) is a carboxylic anhydride, the phenethylamine of formula (II) is cooled in a suitable solvent or for about 1 hour to several hours at room temperature (e.g. The reaction is carried out by reacting with carboxylic anhydride. The most suitable solvent for this reaction is dimethyl-formamide, which is advantageously carried out in the presence of an acid acceptor such as triethylamine.

The compounds of the present invention may also be prepared by heating the ammonium salts of the general formula (VI) at about 110 ° C to 190 ° C for about 1 to 10 hours.

X ₁ , X ₂ and R in the general formula are as described above.

Ammonium salts of formula (VI) are readily obtained by mixing equimolar amounts of compounds of formula (II) and compounds of formula (II) at room temperature.

The desired compound of the present invention can be separated and purified by conventional methods such as extraction, chromatography, recrystallization, and the like.

According to the process described above, the compounds of the invention are usually obtained as free bases, but if necessary can also be obtained in the form of their pharmaceutically toxic acid addition salts according to known methods.

Among the starting materials, the compound of formula (III) is a novel compound and known reactions, for example, by reacting an amine of formula (V) with a compound of formula (VII) (described in the examples described below): It can manufacture.

(Where Z is a halogen atom and-COY is as described above).

Examples of compounds of the invention of particular interest are as follows.

2- (3-carbamoylphenylamino) -N- (3,4-dimethoxy-feethyl) acetamide, 2- (2-carbamoyl-5-chlorophenylamino) -N- (3,4-dimeth Methoxyphenethyl) acetamide and 2- (phenylamino) -N- (3,4-dimethoxyphenethyl) acetamide,

Further investigation of the pharmaceutical preparation of the representative compound of the present invention, 2- (3-carbamoylphenylamino) -N- (3,4-dimethylphenethyl) acetamide, shows the free base and / or acid addition salt of this compound. It can be seen that it can be converted to a novel hydrate having three molecules of crystal water by treatment with water.

Specifically, to prepare a hydrate, the free base and / or acid addition salts are suspended or dissolved in water and stirred at room temperature or at an elevated temperature (below the boiling point of the suspension or solution) for about 10 minutes to 20 hours and then at the same temperature or It is left under cooling to precipitate crystals of the hydrate. The resulting crystals are collected by filtration and air dried at room temperature to give the desired hydrate. When dissolving the free base and / or acid addition salt in water, the solubility of the compound is increased by adding a suitable hydrophilic solvent such as lower alcohol, acetone, dioxane and the like.

2- (3-carbamoylphenylamino) -N- (3,4-dimethoxyphenethyl) acetamide obtained is a novel compound having three molecules of crystal water, and the presence of crystal water is determined by elemental analysis, melting point, It can be confirmed by differential thermal analysis, infrared absorption spectroscopy, X-ray analysis and the like. Hydrates of the present invention are particularly effective in preparing pharmaceutical compositions containing one of the compounds of the present invention, as they have stable chemical and physical properties, which are important factors in making pharmaceutical formulations such as capsules, tablets, powders, granules, and the like. . The stability of the hydrate of the present invention can be confirmed by the following method.

That is, as a result of the isothermal absorption curve measurement, it can be seen that the hydrates of the present invention are very stable with each other under high humidity at an elevated temperature because they do not have relative critical humidity. In addition, irradiation with thin layer chromatography showed that the hydrate was stable for 48 hours in methanol at room temperature. This fact means that methanol can be used as a solvent to make pharmaceutical preparations. Furthermore, the mixtures of the hydrates of the present invention and various additives (e.g. carriers, diluents, etc.) are stable even if they are left under accelerated conditions, i.e., at elevated temperatures for one month under high humidity or for one month under 2,500 lux of light irradiation. You can see that. The stability of the mixture of hydrates with various additives is described in Table 1 below.

TABLE 1

Reference 1. The meanings of ―, ＋, and ＋ are as follows.

－: No change in color ±: Slight change in color +: Clear change in color

Reference 2. Prepare a sample by mixing 100 mg of hydrate well with 100 mg of additive except magnesium stearate or talc. If magnesium stearate or talc is used as an additive, 10 mg of hydrate is used.

The compound of the present invention has an excellent and characteristic gastric ulcer inhibitory effect that cannot be expected from known drugs.

In order to demonstrate the superiority of the compounds of the present invention, the pharmaceutical properties of several representative compounds of the compounds of the present invention were defined as sulfide [N-[(1-ethyl-2-pyrrolidinyl) methyl], one of the representative gastric ulcer inhibitors. -2-methoxy-5-sulfamoylbenzamide]. In this experiment the test compound was administered in the form of free base, hydrochloride or hydrate.

As shown in Tables 2 to 4, it can be seen that the N-phenethylacetamide derivative of the present invention has a remarkably excellent effect on gastric ulcers, particularly neurological ulcers.

TABLE 2

TABLE 3

TABLE 4

Reference 1. * means "the difference with the control is significant (P <0.05)".

** means that the difference with the control has significance (P <0.01).

2. Inhibitory effects on neurological ulcers are described in the Japanese Journal of Pharmacoogy, Vol. Immersion Restriction Law as described in 18, 9 (1968)

Measured according to (Water Immersion Restraint Method).

3. As test animals, seven rats weighing approximately 300 g are used for each dosage unit.

4. Intraperitoneal injection or oral administration of test compound 30 minutes prior to immersion restriction.

5. Immerse and limit test animals in water for 20 hours at 21 ° C (Tables 2 and 3), and immerse and limit 7 hours at 21 ° C (Table 4).

REFERENCE 6. The compounds described in the above table and the following table are as follows.

Compound 1: 2- (2-carbamoyl-5-chlorophenylamino) -N- (3,4-dimethoxyphenethyl) acetamide

Compound 2: 2- (3-carbamoylphenylamino) -N- (3,4-dimethoxy-phenethyl) acetamide hydrochloride

Compound 3: 2- (phenylamino) -N- (3,4-dimethoxyphenethyl) -acetamide hydrochloride

Compound 4: 2- (3-carbamoylphenylamino) -N- (3,4-dimethoxyphenethyl) acetamide.3H ₂ O

Moreover, the ulcer inhibiting mechanism of the compounds of the present invention is very characteristic. That is, the superior ulcer inhibitory effect of the compound of the present invention is basically due to the central action, whereas the ulcer inhibitory effect of the conventional ulcer inhibitor is due to peripheral action.

Thus, the compounds of the present invention are very useful as unique forms of ulcer inhibitors. The central action of the compounds of the present invention can be confirmed by experimentation of the inhibitory effect of gastric acid secretion on rats using a modified method of "Shield's Method" described in British Journal of Pharmacology, Vol 13,54 (1958). Can be. In this experiment, the compounds of the present invention significantly inhibit centrally regulated gastric acid secretion induced by insulin administration, or do not inhibit gastric acid secretion induced by topically acting capronium chloride. The results of this experiment are shown in Tables 5 and 6 below.

TABLE 5

TABLE 6

As mentioned above, it is well known that dopamine structurally similar to the compounds of the present invention has an ulcer inhibitory effect. Pharmacological Basis of Therapeutics, 4th Edition, 234 (1970).

However, since dopamine is unable to cross the blood brain barrier, its ulcer suppression effect is not due to central action. Therefore, the mechanism of ulcer suppression effect of dopamine is fundamentally the mechanism of ulcer suppression action of the compound of the present invention. It is also known that dopamine is potent in the cardiovascular system and therefore used to treat shock syndromes (see Pharmacometrics, Vol. 8, 835 846 (1974)). It is not suitable to use

When the compound of the present invention is orally administered with 2 g / kg (LD50) of body weight in mice, the compound of the present invention is preferable as a low toxicity ulcer inhibitor in humans and animals.

When administering a compound of the invention, it may be formulated into any desired pharmaceutical formulation, such as a capsule, tablet, powder, injection, or suppository, which may be prepared by conventional techniques.

Suitable dosages are from 50 to 450 mg in adults, with suitable carriers and diluents such as lactose, sucrose, sorbitol, starch, gelatin, magnesium stearate, polyethylene glycol, etc. Dosing once or in divided doses.

The following examples are intended to illustrate the invention in more detail, and all percentages, parts, and parts are by weight unless otherwise indicated.

Example 1

0.46 g of N- (2-carbamoyl-5-chlorophenyl) glycine is added to 0.36 g of 3,4-dimethoxyphenethyl amine and the mixture is stirred at 175 to 185 ° C. for 6 hours under a nitrogen atmosphere. After cooling the mixture is dissolved in 50 ml of chloroform and the chloroform solution is filtered to remove insoluble matter. The filtrate is washed with 5% hydrochloric acid, 5% aqueous sodium carbonate solution and water and dried. The solvent was evaporated under vacuum and the residue was chromatographed on silica gel (15 g) column and eluted with a mixture of chloroform and methanol (50: 1 volume ratio). Concentrate the eluate to afford 0.44 g of colorless acicular 2- (2-carbamoyl-5-chlorophenylamino) -N- (3,4-dimethoxyphenethyl) acetamide.

Melting Point: 167.5 ~ 169 ℃

Example 2

2.3 g of N- (2-carbamoyl-5-chlorophenyl) -glycine was dissolved in 600 ml of ethyl acetate with stirring, and 1.8 g of 3,4-dimethoxyphenethylamine was dissolved in 20 ml of ethyl acetate. The solution was added dropwise while stirring to form 3,4-dimethoxy-phenethylamine N- (2-carbamoyl-5-chlorophenyl) glycine salt as crystals. The crystals are collected by filtration and dried to yield 3.9 g of salt with a melting point of 181 to 185 ° C.

Elemental Analysis: C ₁₉ H ₂₄ O ₅ N ₃ Cl

Calculated Value: C 55.68% H 5.90% N 10.25%

Found: C 55.70% H 5.92% N 10.26%

Under nitrogen atmosphere, the 2.0 g of the obtained salt is melted at 190 to 200 ° C. for 1 hour. After cooling the resulting mixture is dissolved in 100 ml of chloroform. After filtering the insoluble material, the filtrate is washed with 5% hydrochloric acid, 50% aqueous sodium carbonate solution and water and dried. The solvent was evaporated in vacuo and the residue was purified by silica gel (30 g) column chromatography and eluted with a mixture of chloroform and methanol (50: 1 volume ratio). The solids are concentrated to give 2- (2-carbamoyl-5-chlorophenyl amino) -N- (3,4-dimethoxyphenethyl) acetamide as crude crystals. The crude crystals obtained are recrystallized from a mixture of methanol and diethyl ether to give 1.2 g of pure crystals having a melting point of 167 to 168 ° C.

Example 3

3.6 g of 3,4-dimethoxyphenethylamine and 4.2 g of N- (3-carbamoylphenyl) glycine methyl ester are mixed, melted at 110 to 120 ° C. under nitrogen atmosphere, and left for 6 hours at the same temperature. do. After cooling, the reaction solution is dissolved in methanol, and 20 ml of methanol containing 5% hydrogen chloride (by weight) is added thereto. The resulting mixture was evaporated under reduced pressure, dried and the residue was recrystallized from a mixture of methanol and diethyl ether to give 2- (3-carbamoylphenylamino) -N- (3,4 having a melting point of 140 to 155 占 폚 (decomposition). 5.0 g of -dimethoxyphenethyl) -acetamide hydrochloride is obtained.

Elemental Analysis: C ₁₉ H ₂₄ O ₄ N ₃ Cl

Calculated Value: C 57.94% H 6.14% N 10.67%

Found: C 57.64% H 6.08% N 10.77%

To 3.0 g of 2- (3-carbamoylphenylamino) -N- (3,4-dimethoxyphenethyl) acetamide hydrochloride, 20 ml of 5% aqueous sodium carbonate solution and 125 ml of chloro-form are added and the mixture of the hydrochloride Stir at room temperature until crystals are completely dissolved. The chloroform layer is separated, washed with water, dried and the solvent is evaporated to dryness in vacuo. The residue was recrystallized from a mixture of methanol and dimethyl ether to give 2.3 g of 2- (3-carbamoyl-phenylamino) -N- (3,4-dimethoxyphenethyl) acetamide having a melting point of 133 to 135 ° C. do.

Elemental Analysis: C ₁₉ H ₂₃ O ₄ N ₃

Calculated Value: C 63.85% H 6.48% N 11.76%

Found: C 63.59% H 6.40% N 11.71%

Example 4

To a solution of 5.0 g of N- (3-carbamoylphenyl) glycine in 65 ml of tetrahydrofuran, a mixture of 2.3 ml of trichloromethylchloroformate and 10 ml of tetrahydrofuran was added dropwise under reflux. After refluxing for another 3 hours, the reaction solution was concentrated under reduced pressure, and 30 ml of petroleum ether was added dropwise while cooling and stirring. The precipitates are collected by filtration, washed with petroleum ether and dried to give 5.3 g of N- (3-carbamoylphenyl) -N-carboxyglycine anhydride as colorless crystals having a melting point of 160 to 170 ° C (decomposition). 5.3 g of the obtained compound was gradually added to a mixture of 4.4 g of 3,4-dimethoxyphenethylamine, 4.9 g of triethylamine, and 30 ml of dimethylformamide under ice-cooling, and the reaction solution was gradually warmed and stirred for 1.5 hours. do. First, 25 ml of 10% hydrochloric acid is added to acidify the reaction solution, and then 5.3 g of sodium carbonate is added to make it alkaline. The alkaline solution is concentrated under reduced pressure. The residue is dissolved in 70 ml of chloroform, washed with a small amount of water, dried and the solvent is evaporated to dryness in vacuo. The residue was chromatographed on silica gel (40 g) and eluted with a mixture of chloroform and methanol (100: 1 volume ratio). Concentrate the eluate to afford 2- (3-carbamoylphenylamino) -N- (3,4-dimethoxyphenethyl) acetamide. As described in Example 4, the free base is reacted with a 5% methanol solution of hydrogen chloride to convert the free base to the corresponding hydrochloride. This salt was recrystallized from a mixture of methanol and diethyl ether to give 2- (3-carbamoylphenylamino) -N- (3,4-dimethoxyphenethyl) acetamide hydrochloride having a melting point of 140 to 155 占 폚 (decomposition). g is obtained.

Example 5

To a solution of 1.0 g of 2- (3-carbamoylphenylamino) -N- (3,4-dimethoxyphenethyl) acetamide in 50 ml of methanol, a solution of 0.96 g of picric acid in 20 ml of ethanol was added. do. The mixture is appropriately concentrated under reduced pressure and left to yield 1.0 g of a peak rate having a melting point of 115 to 120 DEG C (decomposition).

Elemental analysis: C ₂₅ H ₂₆ O ₁₁ N ₆

Calculated Value: C 51.20% H 4.47% N 14.33%

Found: C 51.23% H 4.51% N 14.63%

[Examples 6 to 33]

In the same manner as described in any of Examples 1 to 4, various other N-phenethylamine derivatives are prepared. The results are summarized in Table 7 below.

TABLE 7

Example 34

To 5.0 g of 2- (3-carbamoylphenylamino) -N- (3,4-dimethoxyphenethyl) acetamide hydrochloride, 50 ml of water heated to 55-60 ° C. are added and the mixture is dissolved until the hydrochloride is completely dissolved. Heat and stir at the same temperature. After the mixture was left overnight, the precipitated crystals were collected by filtration, washed with water, and then air dried by standing at room temperature for 10 minutes to give 2- (3-carbamoylphenylamino) -N- (3, having a melting point of 53.5-55.5 ° C. 4.2 g of 4-dimethoxyphenethyl) acetamide-3hydrate are obtained as colorless needles.

The infrared absorption spectrum (KBr) of the obtained trihydrate shows an absorption band in the vicinity of 3100 to 3600 cm &lt; -1 &gt; due to the crystal water.

Elemental analysis: C ₁₉ H ₂₉ O ₇ N ₃

Calculated Value: C 55.46% H 7.10% N 10.21%

Found: C 55.29% H 7.15% N 10.32%

Determination of the number of crystals by differential thermal analysis: C ₁₉ H ₂₃ O ₄ N ₃ ㆍ 3H ₂ O

Calculated Value: H ₂ O, 13.1%

Found: H ₂ O, 13.0%

Example 35

When vigorously stirring a solution of 1 g of 2- (3-carbamoylphenylamino) -N- (3,4-dimethylphenethyl) acetamide hydrochloride in 20 ml of water, the mixture immediately becomes a viscous liquid, which then forms crystals. do. After stirring for 30 minutes, the crystals were collected by filtration, washed with water, and then air dried by standing at room temperature for 10 days to give 2- (3-carbamoylphenylamino) -N- (3, having a melting point of 51 to 56 ° C. 0.88 g of 4-dimethoxyphenethyl) acetamide-3hydrate is obtained in the form of crystalline powder.

Example 36

To 3.0 g of 2- (3-carbamoylphenylamino) -N- (3,4-dimethoxyphenethyl) acetamide hydrochloride, 20 ml of 50% aqueous sodium carbonate solution and 125 ml of chloroform are added until the hydrochloride is completely dissolved. The mixture is stirred at room temperature. The chloroform layer is separated, washed with water, dried and the solvent is concentrated to dryness under reduced pressure. The residue was recrystallized from a mixture of methanol and diethyl ether to give 2.3 g of 2- (3-carbamoylphenylamino) -N- (3,4-dimethoxyphenethyl) acetamide having a melting point of 133 to 135 ° C.

Elemental Analysis: C ₁₉ H ₂₃ O ₄ N

Calculated Value: C 63.85% H 6.48% N 11.76%

Found: C 63.59% H 6.40% N 11.71%

100 ml of water was added to 0.2 g of powdered 2- (3-carbamoylphenylamino) -N- (3,4-dimethoxyphenethyl) acetamide, and the mixture was stirred at 60 to 65 DEG C for 30 minutes to obtain powder. Dissolve completely. The mixture is concentrated under reduced pressure at 60 ° C. and left overnight at room temperature until the residual liquid is 40 ml. The precipitated colorless needles were collected by filtration, washed with water and air dried by standing at room temperature to give 2- (3-carbamoylphenylamino) -N- (3,4-dimethoxyphenethyl) having a melting point of 54 to 57 ° C. 0.13 g of acetamide is obtained.

Example A

To a mixture of 0.34 g 2-amino-4-chlorobenzamide, 0.57 g monochloroacetic acid, 0.90 g sodium iodide and 0.24 magnesium oxide was added 2 ml of dimethylformamide and stirred at 90 to 100 ° C. for 2.5 hours. do. After cooling, the reaction mixture is poured into 50 ml of 2.6% aqueous sodium carbonate solution. The resulting precipitate is filtered off and the filtrate is extracted with 50 ml of chloroform. Acidification by the addition of concentrated hydrochloric acid to the aqueous layer precipitates crystals. The crystals were collected by filtration and recrystallized from aqueous methanol to give 0.20 g of melting (phosphorus N- (2-carbamoyl-5-chlorophenyl) glycine as needles with a melting point of 217 to 222 ° C.

Elemental Analysis: C ₉ H ₉ O ₃ N ₂ Cl

Calculated Value: C 47.28% H 3.97% N 12.25%

Found: C 47.11% H 3.74% N 12.32%

Although the invention has been described in detail by way of examples, it is apparent to those skilled in the art that various changes and modifications can be made without departing from the scope of the invention.

Claims (1)

A method for producing N-phenethylacetamide of the following general formula (I), characterized by reacting a phenethylamine compound of the following general formula (II) with a compound of the following general formula (III)

In the general formula, X ₁ is a lower alkoxy group, X ₂ is a hydrogen atom or a lower alkoxy group, R is a phenyl group, a pyridyl group, a pyrimidinyl group or a benzoyl group, each of which is a halogen atom, a carbamoyl group , Lower alkoxy group, sulfamoyl group, amino group, lower alkylamino group, lower alkylthio group, hydroxy group and lower alkoxycarbonyl group may have one or more substituents, -COY is a carboxyl group or Functional group.