CS196334B2 - Process for the preparation of derivatives (N-aminoactyl) benzene - Google Patents

Abstract

The invention relates to a method for producing (α-aminoacetyl)benzene derivatives which have the ability to inhibit the formation of insoluble fibrin from fibrin.

Description

The invention relates to a method for producing (α-aminoacetyl)benzene derivatives which have the ability to inhibit the formation of insoluble fibrin from fibrin.

The subject of the invention is a process for the production of («-aminoacetyl) benzene derivatives of the general formula I

Y

HJhC X-A- CO-R (I) where

Y represents hydrogen or a C 1 to C 4 alkoxy group,

X represents oxygen, sulfur or a direct bond between the benzene nucleus and the A residue,

A represents a straight or branched chain C1 to C6 alkylene radical and

R represents a hydroxy group, an amino group, a C1 to C5 alkoxy group, a di-(C1 to C4 alkyl)amino group or an α-(C1 to C4 alkoxy)carbonyl-C1 to C4 alkylamino group or their pharmaceutically acceptable acid addition salts, or in the case of compounds of general formula I where R represents a hydroxy group, pharmaceutically acceptable base addition salts, characterized in that the compound of general formula II

Y

Q-CH _of CO-^^-XA-CO-R (II) where

Q represents a chlorine, bromine or iodine atom and

X, Y, A and R have the above meanings, are reacted with hexamethylenetetramine in an inert solvent or diluent, at 20 to 60 °C, and then the hexamine salt thus formed is acid hydrolyzed at a temperature of 40 to 100 °C, after which, in the case where a pharmaceutically acceptable acid addition salt is to be obtained, the compound of general formula I is reacted with an acid capable of providing a pharmaceutically acceptable cation, and in the case where a pharmaceutically acceptable base addition salt is to be obtained, the compound of general formula I, where R represents a hydroxy group, is reacted with a base capable of providing a pharmaceutically acceptable cation.

Those compounds of formula I where A is another symmetrical C1-C6-alkylene group contain an asymmetrically substituted carbon atom and consequently these compounds and similar compounds of formula I where R is a substituent containing an asymmetrically substituted carbon atom can be isolated as racemic and optically active forms. The present invention relates to both the racemic form of compounds of formula I containing one or more asymmetrically substituted carbon atoms and to all optical isomers which have the above useful property. Methods for resolving racemic forms and methods for determining the biological properties of individual optical isomers are generally known in the art of chemotherapeutics.

A particularly suitable value for R, when this symbol represents a C1 to C8-alkoxy group, is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or n-hexyloxy.

A particularly preferred meaning of the (C1-C4-alkoxy)carbonyl group, optionally present as a substituent in the radical A, is, for example, a methoxy or ethoxycarbonyl group.

A particularly suitable value of R when this symbol represents an α-(C1-C4 alkyl)carbonyl-C1-C4 alkylamino group is, for example, an α-(methoxycarbonyl)ethylamino group and a suitable di-(C1-C4 alkyl)amino group is, for example, a diethylamino group.

A particularly suitable value of C1-C4-alkoxy in the value of Y is, for example, methoxy.

A particularly suitable value of A, when this symbol represents a straight or branched C1 to C6-alkylene radical, is, for example, a methylene, ethylene or propylene group or a group of the formula —CH(CH3) — or —C(C3)2—.

Particularly suitable pharmaceutically acceptable addition salts are, for example, hydrohalides, for example hydrochlorides or hydrobromides, sulfates, phosphates or 2-hydroxyethylsulfonates or salts with carboxylic acids, for example citrates, lactates or acetates.

Particularly suitable base addition salts are, for example, alkali metal or alkaline earth metal salts, for example sodium, potassium or calcium salts, aluminum salts or salts of organic phases providing a pharmaceutically acceptable cation, for example triethanolamine.

A particular group of compounds of formula I are those compounds of formula I wherein A represents a methylene group and their pharmaceutically acceptable salts as defined above.

Within this particular group of compounds, one group of preferred compounds are those compounds in which X represents oxygen and their pharmaceutically acceptable salts as defined above, and a second group of preferred compounds are those compounds in which X represents sulfur and their pharmaceutically acceptable salts as defined above.

Yet another special group of compounds of general formula I consists of those compounds of general formula I in which X represents a direct bond between the benzene radical and the radical A, and their pharmaceutically acceptable salts as defined above.

In each of the above groups, R may have the meaning defined above, but preferably R represents a hydroxy, methoxy or α-(methoxycarbonyl)-ethylamino group. Furthermore, in each of the above groups of compounds, particularly suitable salts are, for example, acid addition salts, for example hydrochlorides.

Specific compounds of general formula I are described in the examples, and of these compounds, the following are of particular importance:

4-(Aminoacetyl)phenoxyacetic acid, methyl 4-(aminoacetyl)phenoxyacetate, methyl 4-(aminoacetyl)thiophenoxyacetate, and N-{3-[4-(aminoacetyl)phenyl]propionylalanine methyl ester and their pharmaceutically acceptable salts, as defined above, especially their acid addition salts.

The reaction with hexamine is conveniently carried out, for example, using equimolar amounts of the reaction components in an inert solvent or diluent, for example ether, tetrahydrofuran or chloroform, and at a temperature of, for example, 20 to 60°C, for example at room temperature or at a temperature close to this temperature.

The acidic hydrolysis of the intermediate adduct of the compound of formula II with hexamine is conveniently carried out as a separate step in an inert solvent or diluent, for example ethanol, and at a temperature of, for example, 40 to 100° C. A particularly suitable acid for use in the hydrolysis is, for example, hydrochloric acid, and the compound of formula I is conveniently isolated from the reaction mixture as an acid addition salt derived from the acid used for the hydrolysis.

If the desired compound of general formula I contains an alkoxy group, the corresponding alcohol is preferably used as solvent in the hydrolysis step in order to avoid re-esterification.

All starting materials can be obtained by well-known procedures that are applicable to the synthesis of analogous compounds.

The starting materials of general formula II can be obtained from aromatic compounds of general formula-

(in) where

X, Y, A and R are as defined above, by a Friedel-Grafts reaction using a haloacyl halide, for example chloroacetyl chloride or an acyl halide, followed by direct halogenation. Compounds of formula II, wherein Y is a C1-C6 alkoxy group, are preferably obtained by alkylation of the appropriate 4-hydroxy-3-(C1-C6 alkoxy)acetophenone, followed by direct halogenation as described in the examples.

Compounds of formula I may be converted into pharmaceutically acceptable acid addition salts as defined above by reaction with a suitable acid using conventional means compatible with the remaining substituents. Similarly, compounds of formula I wherein R is hydroxy may be converted into pharmaceutically acceptable base addition salts as defined above by reaction with a suitable base using conventional means compatible with the remaining substituents.

As already mentioned, the compounds of the general formula I inhibit the formation of insoluble fibrin from fibrin. The formation of thrombi or clots in blood plasma is a complex process, but during the final stages of this process, fibrin units are joined to form fully linked thrombin, this process being catalytically controlled by the enzyme fibrinoligase (factor XIIIa). As long as the thrombus still consists of different fibrin units, it can be easily and reversibly dispersed in a 1% (w/v) aqueous solution of monochloroacetic acid. However, once the thrombus is fully linked, it is insoluble in this monochloroacetic acid solution.

The ability of compounds of formula I to inhibit the formation of insoluble fibrin can be demonstrated "in vitro" by measuring the effect of the test compound on the solubility of fibrin clots in a 1% (w/v) aqueous solution of monochloroacetic acid. Fibrin clots are obtained by adding porcine thrombin to an aqueous buffered solution of radiolabeled ( ¹²⁵ I) human fibrinogen containing a physiologically effective amount of the enzyme fibrinoligase.

The ability of the compounds of formula I to inhibit the formation of insoluble fibrin can also be demonstrated by administering the test compound to rabbits and then measuring the solubility of fibrin clots formed by recalcification of rabbit blood plasma samples taken at intervals after administration of the test compound in 1% (w/v) aqueous monochloroacetic acid. In this test, the compounds of formula I increase the solubility of fibrin clots formed after administration at a dose of 100 mg/kg or less. In particular, methyl-4-(aminoacetyl)-phenoxyacetate shows activity when administered orally, and plasma samples taken 24 hours after administration of the compound form fibrin clots which are soluble in 1% (w/v) aqueous monochloroacetic acid.

The compounds of formula I therefore have the ability to inhibit the formation of fully assembled fibrin clots. This property is very important in the physiology of thrombus formation "in vivo", since when a thrombus is formed in the presence of a compound of formula I, it is then more easily dissolved by the influence of a protease, which may be present in the blood. For this reason, the compounds of formula I are useful for inhibiting the formation of thrombus and also for reducing the persistence of thrombus formed in the blood of warm-blooded animals.

The ability of the compounds of formula I to inhibit the formation of insoluble fibrin is also important in other physiological processes in which aggregated fibrin is deposited, since inhibition of this process can be used for therapeutic purposes. For example, in those tumors that require a fibrin network for their support, invasion of other tissues or spread or metastasis, the compounds of formula I are able to limit the disease process when used alone or in combination with cytotoxic agents, antimetabolites or immunomodulators. The use of the compounds of formula I is demonstrated by the effect of these compounds in limiting the spread and growth of chemically induced or transplanted tumors in immunosuppressed or normal rodents or in limiting the formation or development of tumor emboli or metastases. Experiments of the latter type are carried out on the ear chamber of rabbits,. which are injected with a transplantable metastatic tumor, and the test compounds are administered alone or together with other antitumor agents.

For use in inhibiting the formation of insoluble fibrin from fibrin in warm-blooded animals, the compounds of formula I may be administered intravenously or by infusion at a daily dose of 2.5 mg/kg to 25 mg/kg administered intermittently. Alternatively, the compounds may be administered orally, in which case a suitable daily dose is 5 to 50 mg/kg. In humans, the above dose, administered by injection, is equivalent to a total daily dose of 0.2 to 2.0 g. The above oral dose is equivalent to a total daily dose of 0.4 to 4.0 g. In any case, administration is continued as long as there is a risk of thrombus formation.

The compound of general formula I is used in preparations preferably in the form of pharmaceutically acceptable acid addition salts.

The invention is illustrated by the following examples, which, however, do not limit its scope in any way.

In examples

1) NMR spectra are measured in a solution of de-DMSO with tetramethylsilane as an internal standard,

2) room temperature means a temperature between 18 and 27 °C,

3) the petroleum ether used has a boiling point between 40 and 60 °C, unless otherwise stated,

4) the melting points given for acid addition salts are associated with decomposition and

5) If yields are given, they are not maximum achievable yields. The meaning of these data is illustrative only.

Example 1

To a solution of 4-(bromoacetyl)phenoxyacetic acid (26 g) in chloroform (150 ml) was added hexamine (14 g) with stirring. The mixture was stirred at room temperature for 3 days and then filtered. The solid was suspended in ethanol (250 ml), concentrated hydrochloric acid (50 ml) was added and the mixture was stirred at room temperature for 18 hours. The mixture was then filtered and the filtrate was diluted with diethyl ether (1500 ml). The solid thus formed was filtered off and washed with a mixture of ethanol and diethyl ether. 4-(aminoacetyl)phenoxyacetic acid hydrochloride with a melting point >250 °C was obtained.

NMR:

<S 7.0 to 7.14, 7.92 to 8.06 each 2H (aromatic protons),

4.5 (2H, NH3CH2CO) and

4.81 (2H, —OCH2—COOH).

Example 2.

A solution of methyl 4-(chloroacetyl)phenoxyacetate (6.7 g) in methylene chloride (100 ml) was stirred while hexamine (hexamethylenetetramine) (4.5 g) was added. The mixture was stirred for 3 days at room temperature. The resulting solid (9.0 g) was filtered off and stirred in methanol (60 ml) and concentrated hydrochloric acid (30 ml) at room temperature for 60 hours. The resulting solid (5.1 g) was filtered off and dissolved in cold methanol (100 ml). The solution was filtered and the filtrate was evaporated to 30 ml. After cooling, methyl 4-(aminoacetyl)phenoxyacetate hydrochloride (2.0 g, melting point 202-204 °C) was separated. Further portions of the substance were obtained from the mother liquors.

Examples 3 to 4 *

Using a similar procedure to that described in Example 1, 4-(4-(aminoacetyl)phenyl]propionic acid hydrochloride (Example 3) melting point 208°C, and 2-(4-(aminoacetyl]phenoxy]-2-methylpropionic acid hydrochloride (Example 4), melting point 188-190°C, are obtained in a yield of 32 ^% and 26%, respectively, when 3-[4-(chloroacetyl)phenyl]propionic acid or 2-(4-(chloroacetyl)phenoxy]-2-methylpropionic acid are used as starting materials.

3-(4-(Chloroacetyl)phenyl]propionic acid is obtained as follows:

A solution of 3-phenylpropionic acid (50 grams) in ethylene dichloride (200 ml) was added to chloroacetyl chloride (37.7 g) and aluminum chloride (48.9 g) in ethylene dichloride (550 ml) at room temperature with stirring for 1 hour.

The resulting mixture was stirred for 1 hour and then carefully poured into a mixture of ice (2 kg) and concentrated hydrochloric acid (55 ml). After stirring for another 16 hours, the crude product was filtered off and recrystallized from water. 3-[4-(chloroacetyl)phenyl]propionic acid with a melting point of 151-153 degrees Celsius was obtained.

2-(4-(Chloroacetyl)phenoxy]-2-methylpropionic acid is obtained in a similar manner as a solid having satisfactory microanalysis.

Examples 5 to 18

Using a similar procedure to that described in Example 2, the following compounds of general formula I are obtained as hydrochlorides in 23 to 48% yield from the corresponding α-chloro- or β-bromoacetofertones of general formula II (Q = Cl or Br). The corresponding alcohol is used as solvent in the hydrolysis step.

196

4

Example Y X 5 H About 6 H About 7 MeO About 8 H About 9 H About 10 H direct link 11 H direct link 12 H About 13 H About 14 H About 15 H direct link 16 H About 17 H About 18 H With

* substance isolated as a hygroscopic solid with satisfactory microanalysis:

calculated:

(+ ³ /mole of H2O):

50.2% C, 6.1% H, 4.9% N, found:

50.0% C, 5.9% H, 4.9% N.

-j- substance isolated as a hygroscopic solid with satisfactory microanalysis:

calculated:

(+ Know moles of HzO):

53.4 θ/o C, 6.3% H, 4.8% N.

found:

53.1% C, 6.2% H, 4.8% N.

Me = methyl Pr = propyl

Et = ethyl Bu = butyl

The required starting α-bromo- or α-chloroacetophenone derivatives can be obtained by the following procedures, or procedures analogous to them:

Isopropyl-4-(bromoacetyl)phenoxyacetate

Potassium carbonate (17.0 g) was added to a solution of isopropyl bromoacetate (24.0 g) and 4-hydroxyacetophenone (17.7 g) in acetone (200 ml). The mixture was refluxed for 24 hours, then cooled and filtered. The filtrate was evaporated to an oil which was dissolved in ether (150 ml). The solution was washed with sodium bicarbonate solution (2 x 30 ml), water (2 x 30 ml), dried and evaporated. The residual oil was distilled to give isopropyl-4-acetylphenoxyacetate, infrared (IR) maxima at 1750 and 1670 cm ⁴ .

A R Hydrochloride melting point (°C)

—CHz— i-PrO 167—170 —CHz— n-hexyl-0 122—126 —CHz— MeO 174—175 —CHz— EtO 188—190 —CHz— n-BuO 172—176 —CHz— EtO 183—185 — ( _CH2 )2— MeO 188 —CMez— EtO 108—109 —CHMe— EtO + — (CH2)3— MeO 165—169 — ( _CH2 )2- —iNH . CHMe . . What? 187—190 ch ₂ n-PrO 194—197 —CHMe— MeO * CH2 MeO 161—165 (monohydrate) Bromine (12 g) drips to the mixed solution of isopropyl-4-acetylphenoxyacetate (17.6 g) in benzene (200 ml) for 30 min-

nut. The solution was stirred for a further 15 minutes and then evaporated. The residue was recrystallized from ether/hexane to give isopropyl-4-(bromoacetyl)phenoxyacetate, mp 60-61°C.

Methyl 2-methoxy-4-(bromoacetyl)phenoxyacetate

Methyl bromoacetate is reacted with 2-methoxy-4-acetylphenol to form methyl 2-methoxy-4-acetylphenoxyacetate in the same manner as used to prepare isopropyl 4-acetylphenoxyacetate.

Copper (II) bromide (23.9 g) was then added to a solution of methyl 2-methoxy-4-acetylphenoxyacetate (12.8 g) in a mixture of methyl acetate (150 ml) and chloroform (150 ml). The mixture was stirred and heated under reflux until the copper (II) bromide was essentially completely removed. The mixture was cooled and filtered, and the filtrate was washed with brine (3 x 30 ml), dried and evaporated. The residue was chromatographed on silica gel to give methyl 2-methoxy-4-(bromoacetyl)-phenoxyacetate, m.p. 105-107°C.

n-Hexy 1-4-(bromoacetyl and phenoxyacetate

A mixture of 4-acetylphenoxyacetic acid (20.0 grams), n-hexanol (10.5 g) and concentrated sulfuric acid (2 ml) in benzene (100 ml) was heated under reflux for 6 hours, using a water separator. The mixture was then evaporated and the residue was dissolved in n-pentane (50 ml). The solution was washed with water (3 X 30 ml), sodium bicarbonate solution (1 X X 50 ml) and again with water (1 X 50 ml). The solution was then evaporated and the residue was chromatographed on alumina. n196334

-hexyl-4-acetylphenoxyacetate with infrared maxima at 1760 to 1680 cm ¹ .

Methyl 3-[4-(chloroacetyl)phenyl]propionate

A mixture of 3-phenylpropionic acid (50 g), methanol (250 ml) and concentrated sulphuric acid (12 ml) was heated to reflux for 12 hours and then the excess methanol was evaporated under reduced pressure. The residue was added to saturated aqueous sodium bicarbonate solution (100 ml) containing ice (400 g) and the pH was adjusted to 9 by addition of more sodium bicarbonate solution. The mixture was extracted with ether (5 x 100 ml) and the extracts were combined, washed with brine (2 x 50 ml), dried and evaporated. Methyl 3-phenylpropionate was obtained as an oil with a maximum at 1740 cm ¹ in the IR spectrum.

Aluminum chloride (225 g) was added to a rapidly stirred mixture of the above ester (41 g) and chloroacetyl chloride (113 g) in carbon disulfide maintained at 0°C. The mixture was allowed to warm to room temperature with stirring over 2 hours and the carbon disulfide was then evaporated. The residue was added to a mixture of ice (500 g) and concentrated hydrochloric acid (15 ml) and the mixture was extracted with methyl acetate (4 x 200 ml) and then with methylene dichloride (2 x 150 ml). The extracts were combined, washed with brine (2 x 100 ml), dried and evaporated. The residue obtained was recrystallized from a 2:1 mixture of diethyl ether and n-pentane. Methyl 3-[4-(chloroacetyl)phenyl]propionate, m.p. 90°C, was obtained.

Ethyl 2-(4-(bromoacetyl)-phenoxy]-2-methylpropionate

Ethyl 2-[4-(acetylphenoxy)-2-methylpropionate (10 mmol) in a chloroform solution (120 ml) was brominated at 35°C, with dropwise addition of a solution of bromine (10.5 mmol) in chloroform (20 ml). After 1 hour, the reaction mixture was filtered and the filtrate was washed with water (2 × 30 ml), dried and evaporated. Ethyl 3-(4-(bromoacetyl)phenoxy]-2-methylpropionate was obtained as an oil, which was pure according to analysis by thin layer chromatography (TLC) (on silica gel plates, elution with a mixture of 50% ether and 50% petrol).

Ethyl 2-[4-(chloroacetyl)phenoxy]propionate

Ethyl 2-phenoxypropionate (0.25 mmol) was dissolved in methylene chloride (20 ml) containing chloroacetyl chloride (0.26 mmol). The solution was cooled to 0 °C with rapid stirring and aluminum chloride (0.79 mol) was added portionwise over 30 minutes. The mixture was allowed to warm to room temperature with stirring over 16 hours. The solvent was evaporated and the residue was poured into a mixture of ice (300 g) and concentrated hydrochloric acid (15 ml). The mixture was extracted with methylene dichloride (5 × 100 ml), the extracts were washed with water (2 × 50 ml), dried and evaporated. After chromatography on alumina, ethyl 2-(4-chloroacetyl)phenoxy]propionate was obtained as a white solid having satisfactory microanalysis:

calculated:

57.7% C, 5.6% H, 13.1% N, found:

57.7% C, 5.5% H, 13.0% N.

Methyl 4-[-(chloroacetyl)phenoxy]butyrate

Methyl 4-phenoxybutyrate is reacted with acetyl chloride in a manner similar to that described above for the preparation of 3-(4-(chloroacetyl)phenyl]propionic acid, except that the crude product is triturated with petroleum ether. Methyl 4-[4-(chloroacetyl)phenoxy]butyrate is obtained as a crystalline solid which is pure by TLC analysis (on silica gel plates using a 50% ether/50% petroleum ether mixture as eluent).

N-{3-[4-(chloroacetyl]phenyl]propionylalanine methyl ester).

A solution of pivaloyl chloride (4.41 ml) in tetrahydrofuran (30 ml) was added to a stirred solution of 3-(4-(chloroacetyl)phenyl]propionic acid (9.7 g) and triethylamine (5.5 ml) in tetrahydrofuran (30 ml) and acetonitrile (40 ml) cooled to -15 °C. The resulting mixture was stirred at -15 °C for 1 hour. A suspension of DL-alanine methyl ester hydrochloride (5.0 g) in dimethylformamide (30 ml) containing triethylamine (5.5 ml) was then added over 15 minutes. The mixture was stirred at -15 °C for 1 hour and then at room temperature for 16 hours. Saturated sodium bicarbonate solution (30 ml) was added, the solution was stirred for 30 minutes and then evaporated in vacuo. The residue was mixed with water (150 ml) and extracted with chloroform (2 X 100 ml). The extracts were The mixture was washed with 10% hydrochloric acid (200 ml), water (200 ml), saturated sodium bicarbonate solution (200 ml) and water (200 ml), dried over magnesium sulfate and evaporated. The residue was recrystallized from toluene/petroleum ether to give N-{3-[4-(chloroacetyl)phenyl]propionylalanine methyl ester, m.p. 122-124 °C.

Methyl 4-(chloroacetyl)thiophenoxyacetate

A solution of methyl thiophenoxyacetate (60 g) in methylene chloride (100 ml) was added over 20 minutes to a stirred suspension of chloroacetyl chloride (45.2 g) and aluminum chloride (134 grams) in methylene chloride (400 ml) at room temperature.

The resulting solution was stirred overnight at room temperature and then poured into a mixture of ice (2 kg) and concentrated hydrochloric acid (50 ml). This mixture was then stirred for 1 hour at room temperature. The methylene chloride phase was separated, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from methanol to give methyl 4-(chloroacetyl)thiophenoxyacetate (60.1 g) with a melting point of 61-63 °C.

Example 10

By a similar procedure to Example 1, except that the concentrated hydrochloric acid is replaced by 50% aqueous sulfuric acid, methyl 4-(aminoacetyl)phenoxyacetate sulfate is obtained in the form of a solid with a melting point of 125 to 128 °C. Examples 20 to 21

By a similar procedure as in Example 2, but using N,N-diethyl-4-(chloroacetyl)phenoxyacetamide or N,N-diethyl-2-methoxy-4-(bromoacetyl)phenoxyacetamide as the starting material, N,N-diethyl-4-(aminoacetyl)phenoxyacetamide hydrochloride (Example 20j (melting point 78-80 °C), or N,N-diethyl-2-methoxy-4-(aminoacetyl)phenoxyacetamide hydrochloride (Example 20j (melting point 78-80 °C), is obtained.

Claims (3)

SUBJECT A process for the preparation of (N-aminoacetyl) benzene derivatives of the general formula I Y is ^H 2 ^N-CH 2 ^C0 ~ ^^ ~ ^ ~ ^C0 ~ ^A ~ ^R (I) wherein Y is hydrogen or Cl to Cd alkoxy, X represents oxygen, sulfur or a direct bond between the benzene ring and residue A, A represents a straight chained or branched C 1 -C 6 alkylene residue and R is hydroxy, amino, C 1 -C 5 alkoxy, di- (C 1 -C 1 alkyl amino) or α- (C 1 -C 4 alkoxy) carbonyl-C 1 -C 4 alkylamino or pharmaceutically acceptable acid addition salts thereof, or in the case of compounds of formula I wherein R represents a hydroxy group, a pharmaceutically acceptable base addition salt, characterized in that the compound of formula (II) amide hydrochloride (Example 21) (m.p. 113-116 ° C). The starting 4- (haloacetyl) phenoxyacetamides are obtained as follows: N, N-Diethy 1-4- (chloroacetyl) phenoxyacetamide Aluminum chloride (83.3 gj) was added in portions over 30 minutes to a rapidly stirred solution of N, N-diethylphenoxyacetamide (51.6 g) and chloroacetyl chloride (31.0 g) in methylene chloride (200 mL) at 0 ° C. After stirring for 16 hours at room temperature with stirring, the solvent was evaporated and the residue was poured into a mixture of ice (300 g) and concentrated hydrochloric acid (15 ml), extracted with methylene chloride (5X 100 ml) and the extracts washed with water (2X50). The residue was chromatographed on alumina to give N, N-diethyl-4- (chloroacetyl) phenoxyacetamide, m.p. 89-91 ° C. N, N-Diethyl-2-methoxy-4- (bromoacetyl) phenoxyacetamide N, N-Diethyl-2-methoxy-4-acetylphenoxyacetamide is reacted with copper (I) bromide in a similar manner as described above for the preparation of the starting material for the procedure of Example 6. N, N-diethyl-2-methoxy- 4- (bromoacetyl) phenoxyacetamide, m.p. 101-103 ° C. ynAlezu Y Q-CH 2 CO 4 ^-A - ^co - ^R (II) wherein Q represents a chlorine, bromine or iodine atom and X, Y, A and R are as defined above, reacted with hexamethylenetetramine in an inert solvent or diluent at 20 to 60 ° C, and then the resulting hexamine salt is acid hydrolyzed at 40 to 100 ° C, followed by to obtain a pharmaceutically acceptable acid addition salt, reacting a compound of formula I with an acid capable of providing a pharmaceutically acceptable cation and, if a pharmaceutically acceptable base addition salt is to be obtained, a compound of formula I wherein R is hydroxy, reacting with a base capable of providing a pharmaceutically acceptable cation. 2. Process according to claim 1, characterized in that the acid hydrolysis is carried out in the presence of alcohol and hydrochloric acid at a temperature of 40 to 100 ° C. 3. A process according to claim 1, wherein Y is hydrogen, X is oxygen, A is methylene and R is methoxy and acid hydrolysis is carried out in the presence of methanol.