NO142018B - PROCEDURE FOR THE PREPARATION OF A HIGH-VOLTAGE INSULATION - Google Patents

Description

Process for the production of pharmacologically active hydroxylamine derivatives.

This invention relates to methods for the production of hydroxylamine derivatives.

It has been found that hydroxylamine derivatives having the general formula

in which X represents a hydrogen or a halogen atom, and n denotes 1, 2 or 3, as well as addition salts of these derivatives constitute potential inhibitors for the enzymes responsible for decarboxylation of 3,4-dihydroxyphenylalanine (DO-PA ) and of 5-hydroxytryptophan (5HTP) and has an effect on the central nervous system both in vitro and in vivo when used on mammals, including humans. α-methyl DOPA is used in medicine and it has been demonstrated that it has a dopadecarboxylase inhibitory effect. The compounds according to the present invention show a far more potent depadecarboxylase inhibitory effect, which shows their usefulness for the treatment of mental illness accompanied by and occurring at abnormal levels of catecholamines and/or 5-hydroxytryptamine. According to the present invention, the process for the production of hydroxylamine derivatives of the general formula (1) comprises the feature of reacting hydrazine with a benzyloxyphthalimide having the general formula in which X and n have the above meanings and Y represents one that is closer defined below, after which, if necessary, the group Y is removed by hydrolysis. The process can be carried out by allowing at least two molar proportions of hydrazine to react with a benzyloxyphthalimide having the general formula

in which X and n have the meanings given above, and R represents an alkyl or an aryl radical. During this reaction, the phthaloyl group and the acyl group RCO are split off, by what can be called hydrazinolysis.

Alternatively, the method can be carried out by allowing hydrazine to react with a benzyloxyphthalimide which has the general formula in which X, n and R have the above meanings, after which the R-SO. group is hydrolysed away. The phthaloyl group is cleaved off by hydrazinolysis, but a further hydrolysis step, preferably using alkali metal hydroxide, is required to remove the R-SOa group.

The hydrazine is preferably used in

form of hydrazine hydrate.

The hydroxylamine derivatives formed by any of these methods can be converted into an acid addition salt using any of the methods known per se. For example, they can be converted to hydrochloride by reacting with ethanolic hydrogen chloride.

The reactions used for the production of compounds represented by the formulas I, II and III can be shown schematically in the manner below (where X, n and R have the meanings defined above).

The most active hydroxylamine derivatives according to the present invention are obtained by using N-(3-acetoxy-benzyloxy)-phthalimide, N-(3-benzyloxy-6-chloro-benzyloxy)-phthalimide, N-(3- benzenesulfonyloxy-4-chloro-benzyloxy)-phthalimide or N-(3-benzenesulfonyloxy-4-bromo-benzyloxy)-phthalimide.

These reactions can be carried out in the manner described in the following examples. In these examples, all temperatures are given in degrees Celsius.

Example 1. 3-acetoxy-benzyl bromide.

A solution of bromine (196.5 g = 1.225 mol) in carbon tetrachloride (400 ml) was added dropwise under reflux to a solution of m-tolyl acetate (184 g = 1.225 mol) in carbon tetrachloride (800 ml) over 4.5 hours . During the entire addition period, the mixture was irradiated from a 500 watt non-frosted tungsten ray bulb.

The solution was cooled and the solvent was distilled off under reduced pressure. The residue was fractionated carefully, using a 50 cm long, screw-shaped packed column, whereby, after a course of m-tolyl acetate, m-acetoxy-benzyl bromide was obtained, in the form of a colorless oil, boiling at 138-150° C at 14 mm. After redistillation, the whole fraction had bp 97-9°/0.15 mm, and gave a negligible residue in the still.

N-(3-acetoxy-benzyloxy)phthalimide.

m-acetoxy-benzyl bromide (4.6 g = 0.02 mol) was added to the red solution obtained by dissolving phthaloxime (3.25 g = 0.02 mol) and triethylamine (2.02 g = 0.02 mol) in acetonitrile (20 mL). The solution was heated under reflux for 15 minutes, during which time the color disappeared. On cooling, a solid precipitated out, which was separated by filtration. The filtrate was evaporated to dryness under reduced pressure, and the solid residue was combined with the original solid. After washing with water to remove triethylamine hydrobromide, the water-soluble solid was recrystallized from ethanol to give N-(3-acetoxy-benzyloxy)phthalimide (4.22 g = 67.5%) as colorless plates, which melted at 113° C.

3- hydroxy- benzyloxy- amine hydrochloride.

A solution of N-(3-acetoxy-benzyloxy)phthalimide (3.11 g = 0.01 mol) and 100% hydrazine hydrate (1.5 g = 0.03 mol) in ethanol (40 ml) was boiled during the return run (for 2 hours). The mixture was cooled, isopropanolic HCl (10.2 mL containing 0.25 g HCl per mL) was added, and the mixture was heated at reflux (for 15 minutes). The cooled mixture was filtered, the filtrate was evaporated to a small volume (approx. 10 ml) under reduced pressure, cooled and the precipitated solid (which essentially consisted of hydrazine dichloride) was filtered off. The filtrate was evaporated to dryness to give a white solid which was washed with water leaving a small amount of insoluble residue. The aqueous filtrate was recrystallized from glacial acetic acid, whereby 3-hydroxy-benzyloxy-amine hydrochloride (1.2 g = 69 per cent) was obtained in the form of colorless needles, which melted at 168.5-169.5°C.

Example 2.

3- benzoyloxy- 2, 4, 6- tribromobenzyl bromide.

To a boiling solution of 3-benzoyloxy-2,4,6-tribromotoluene (44 g = 0.098 mol) in carbon tetrachloride (200 ml) was added a solution of bromine (15.7 g = 0.098 mol) in carbon tetrachloride (100 ml ), with such a feed rate that no permanent coloration was formed. The reaction mixture was irradiated from a 500 watt unfrosted tungsten projection lamp to catalyze the bromination. After removal of the solvent under reduced pressure, a tough oil was obtained, which crystallized on standing overnight, and then obtained m.p. 112-114° C By recrystallization from ethanol, 37.7 g (73 per cent) of product was obtained with m.p. 116—117° C. A further recrystallization from ethanol did not raise the melting point.

N-( 3- benzoyloxy- 2, 4, 6- tribromo -

benzyloxy ) f thalimide.

A solution of 3-benzoyloxy-2,4,6-tribromo-benzyl bromide (5.28 g = 0.01 mol) phthaloxime (1.63 g = 0.01 mol) and triethylamine (1.01 g = 0.01 mol) in acetonitrile (20 mL) was refluxed until the red color disappeared (15 minutes). On cooling, a colorless precipitate was formed, which was filtered off, washed with water, dried and recrystallized from glacial acetic acid, whereby N-(3-benzoyloxy-2,4,6-tribromo-benzyloxy)phthalimide was obtained (4.3 g = 71 percent) in the form of colorless needles, which melted at 168-169° C. Further recrystallization from glacial acetic acid did not raise the melting point of the product.

4

2, 4, 6- tribromo- 3- hydroxy- benzyloxyamine.

N-(3-benzoyloxy-2,4,6-tribromo-benzyloxy)phthalimide (12.2 g = 0.02 mol) was added to a solution of 100% hydrazine hydrate (3 g = 0.06 mol) in ethanol (75 mL), and the suspension was heated under reflux. After a short period of time, the mixture became clear and solids began to separate. After 2-1/2 hours of heating, the mixture was cooled and isopropanolic HCl (16 mL containing 0.25 g HCl per mL) was added. The mixture was then heated under reflux for 15 minutes, then cooled and filtered. The filtrate was evaporated to dryness under reduced pressure, the solid residue was washed with ether, and dissolved in 2N sodium hydroxide solution. On acidification with acetic acid to pH 4, a white precipitate of crude 2,4,6-tribromo-3-hydroxy-benzyloxyamine was obtained, which was recrystallized from aqueous methanol, and then gave pink needles with m.p. 165-166° C. The yield was 5.15 g (= 68 percent).

2,4,6-tribromo-3-hydroxy-benzyloxyamine hydrochloride was prepared by dissolving the base in ethanol containing an excess of isopropanolic HCl and diluting with ether. By recrystallization from glacial acetic acid, the product was obtained in the form of colorless needles with m.p. 222—223° C (under decomposition).

Example 3.

3- benzoyloxy- 6- chloro- benzyl- bromide.

N-Bromosuccinimide (7.12 g = 0.04 mol)

was added to a solution of 3-benzoyloxy-6-chloro-toluene (9.86 g = 0.04 mol) and benzoyl peroxide (0.05 g) in carbon tetrachloride (100 ml) and the mixture was refluxed for 8 hours . The mixture was then cooled, the succinimide was filtered off, and the filtrate was evaporated under reduced pressure, leaving behind an oily residue (13 g) which solidified overnight at 0° C. Two recrystallizations from methanol/charcoal gave 3 -benzoyloxy-6-chloro-benzyl bromide (3.05 g = 23 per cent) in the form of pale yellow needles, which melted at 69-70° C.

N-(3- benzoyloxy- 6- chloro- benzyloxy) -

phthalimide.

A solution of 3-benzoyloxy-6-chloro-benzyl bromide (3 g = 0.009 mol), phthaloxime (1.51 g = 0.009 mol) and triethylamine (0.925 g = 0.009 mol) in acetonitrile (25 mL) was boiled under reflux until the red color disappeared (30 minutes). On cooling, a colorless substance precipitated out, which was filtered off, washed with water, dried and recrystallized from glacial acetic acid, whereby N-(3-benzoyloxy-6-chloro-benzyloxy)-phthalimide (3.2 g = 85 pst .) in the form of colorless microprisms of m.p. 170-171° C.

2- chloro- 5- hydroxy- benzyloxy amine hydrochloride.

A solution of N-(3-benzoyloxy-6-chloro-benzyloxy)phthalimide (2.5 g = 0.0062 mol) and 100% hydrazine hydrate (0.92 g = 0.0186 mol) in ethanol (40 ml) was refluxed for 2-1/2 hours. After some cooling, isopropanolic HCl (9 mL = 2.25 g HCl) was added, and the suspension was heated for a further 15 minutes under reflux, then cooled, and the solid was filtered off. The filtrate was evaporated to dryness under reduced pressure, the residue was dissolved in 2nHCl (25 ml), a small amount of insoluble residue was filtered off, and the solution was again evaporated to dryness under reduced pressure. The residue (2 g) was dissolved in water (15 mL), brought to pH 10 using 2N NaOH, and then to pH 4 using dilute acetic acid. The precipitate was filtered off, dried and dissolved by heating with an excess of isopropanolic HCl (5 ml = 1.2 g of HCl). On addition of ether, the hydrochloride precipitated out in the form of prisms, which melted at 168-170° C. On recrystallization from glacial acetic acid, 0.9 g (70 per cent) was obtained which melted at 171-172° C.

Example 4.

3- benzoyloxy- 4, 6- dibromo- benzyl bromide.

N-Bromosuccinimide (1.44 g = 0.0081

mol) was added to a solution of 3-benzoyloxy-4,6-dibromotoluene (3 g = 0.0081 mol) and benzoyl peroxide (0.02 g) in carbon tetrachloride (50 mL), and the suspension was refluxed in 2-1/2 hours. The mixture was then cooled, the succinimide was filtered off, and the filtrate was evaporated under reduced pressure, leaving an oil which solidified. Two recrystallizations from methanol gave 3-benzoyloxy-4,6-dibromobenzyl bromide (1.8 g = 50 percent) in the form of colorless needles with m.p. 88-89° C.

N-(3-benzoyloxy-4,6-dibromo-benzyloxy)phthalimide.

A solution of 3-benzoyloxy-4,6-dibromo, benzyl bromide (1.5 g = 0.0033 mol),

5

phthaloxime (0.545 g = 0.0033 mol) and triethylamine (0.335 g = 0.0033 mol) in acetonitrile (10 mL) were refluxed for 30 min. On cooling, a colorless solid precipitated out, which was filtered off, washed with water, dried and recrystallized from glacial acetic acid to give N-(3-benzoyloxy-4,6-dibromo-benzyloxy)-phthalimide (0, 9 g = 50 percent) in the form of a colorless micro-crystalline substance with m.p. 175-176° C.

2, 4- ibromo- 5- hydrolcsy- benzyloxy amine.

A solution of N-(3-benzoyloxy-4,6-dibromo-benzyloxy)-phthalimide (0.85 g = 0.0016 mol) and 100% hydrazine hydrate (0.24 g = 0.005 mol) in ethanol (10 mL ) was refluxed for 2y2 hours. After cooling to approx. 50°C, isopropanolic HCl (2.5 ml = 0.625 g Acl) was added and the resulting suspension was heated under reflux for 15 minutes and then allowed to cool to room temperature. The precipitate was filtered off, the filtrate was evaporated under reduced pressure, and the solid residue was dissolved in 2N HCl (30 mL) and filtered from a small insoluble residue. The filtrate was brought to pH 10 using 2N NaOH and then brought to pH 4 using dilute acetic acid; the residue was washed with water and dried, and 2,4-dibromo-5-hydroxy-benzyloxyamine (0.4 g) was obtained with m.p. 197-198° C.

The hydrochloride was prepared by dissolving the base (0.4 g) in ethanol (3 mL) and adding isopropanolic HCl (2 mL = 0.5 g HCl). On addition of ether (200 ml), the hydrochloride slowly precipitated in the form of colorless microneedles, which melted at 200° during cleavage. One recrystallization from glacial acetic acid gave 0.28 g (52 per cent) with m.p. 201—202 during cleavage.

Example 5.

3- benzoyloxy- 6- bromo- benzyl bromide.

A solution of bromine (60 g = 0.375

mol) in carbon tetrachloride (400 ml) was added dropwise to a gently boiling solution of 3-benzoyloxy-6-bromotoluene (109 g = 0.375 mol) in carbon tetrachloride (500 ml) under reflux, with such addition that no some permanent color appeared (3 hours). The reaction mixture was irradiated the whole time from a 500 watt "unfrosted" tungsten lamp.

The cooled solution was

pet under reduced pressure, the residue was dissolved in a mixture of chloroform (35 ml) and 60-80° petroleum ether (120 ml), filtered and cooled to 0° C. The crystalline phase was filtered off and recrystallized from methanol, whereby 3-benzoyloxy-6-bromo-benzyl bromide (65.3 g = 47 percent) was obtained in the form of colorless needles with m.p. 91— 92.5° C.

N-(3-benzoyloxy-6-bromo-benzyloxy)phthalimide.

A solution of 3-benzoyloxy-6-bromobenzyl bromide (9 g = 0.024 mol), phthaloxime (3.96 g = 0.024 mol) and triethylamine (2.46 g = 0.024 mol) in acetonitrile (40 mL) was boiled under reflux until the red color has disappeared. The solution was cooled, the resulting precipitate was filtered off, washed with methanol and recrystallized from glacial acetic acid to give N-(3-benzoyloxy-6-bromo-benzyloxy)-phthalimide (9.1 g = 83%) as small colorless needles with m.p. 155°C.

2- bromo- 5- hydroxy- benzyloxyamine.

N-(3-benzyloxy-6-bromo-benzyloxy)phthalimide (7.7 g = 0.017 mol) was added to a solution of 100% hydrazine hydrate (2.56 g = 0.051 mol) in ethanol (75 ml) , and the mixture was heated under reflux (2x2 hours). The mixture was cooled, ethanolic HCl (30 mL = 7 g HCl) was added, and the mixture was allowed to stand at room temperature for 1 hour. The precipitate formed was filtered off, the filtrate was evaporated to dryness, and the residue was triturated with ether, filtered, the solid dissolved

into 2N HCl (100 mL), filtered, and the filtrate

was evaporated to dryness. The solid remainder

(6.7 g) was suspended in water (45 ml), which was brought to pH = 10 using 5N sodium hydroxide solution (a clear final solution was obtained) and then brought to pH 4.5 using acetic acid. The suspension was cooled to 4-10°C for 1 hour, and the product was filtered off and dried (3.1 g;

m.p. 94—96° C).

This product was dissolved in an excess of ethanolic HCl, evaporated to dryness, and the residue recrystallized from glacial acetic acid to give 2-bromo-5-hydroxy-benzyloxy-ammonium chloride (2.5 g = 58 percent) as a colorless micro-crystalline substance, which melted at 184— 185° C (under decomposition).

Example 6.

3- benzenesulfonyloxy- 4- chlorobenzyl bromide.

3-benzenesulfonyloxy-4-chloro-toluene

(108 g = 0.383 mol) was dissolved in carbon tetrachloride (250 ml) and bromine vapor (61.5 g = 0.383 mol) was introduced over 9 hours into the gently refluxing solution together with a weak current of dry nitrogen. Below, the solution was irradiated from a 500 watt "unfrosted" tungsten bulb. The solution was filtered while hot, was cooled to 0° C., and the extract was filtered off, dried and recrystallized from methanol (5 parts w/w), whereby 3-benzenesulfonyloxy-4-chloro-benzyl bromide ( 54.35 g = 40 percent) in the form of colorless needles which melted at 103.5— 105° C.

N-(3-benzenesulfonyloxy-4-chloro-benzyloxy) phthalimide.

A solution of 3-benzenesulfonyl-oxy-4-chloro-benzyl bromide (10 g = 0.028

mol), phthaloxime (4.54 g = 0.028 mol) and triethylamine (2.8 g = 0.028 mol) in acetonitrile (100 mL) was refluxed until the red color had disappeared (1 hour). The solution was cooled for 1 hour to -^10° C, the precipitate was filtered off, washed with water and ethanol and dried, and 8.75 g of substance was obtained, which melted at 164.5-165.5° C.

Evaporation of the filtrate gave a solid which after washing with water and ethanol and recrystallization from acetonitrile (25 ml) melted at 164-165° C (1.35

g). Further recrystallizations of both products did not cause any rise of

their melting point. The overall yield of N-(3-benzenesulfonyloxy-4-chloro-benzyloxy)phthalimide was 10.1 g (82 percent).

3- benzenesulfonyloxy- 4- chloro-benzyloxyamine.

N-(3-benzenesulfonyloxy-4-chloro-benzyloxy-phthalimide (9.3 g = 0.021 mol)

was added to a solution of 100% hydrazine hydrate (1.05 g = 0.021 mol) in ethanol (100 ml), and the mixture was heated under reflux for 1y2 hours. The suspension was cooled, filtered, and the filtrate was evaporated to dryness. The residue was dissolved in chloroform (100 ml), filtered and the filtrate was evaporated, whereby a residue was obtained which by trituration with 60-80° petroleum ether (75

ml) gave a crude 3-benzenesulfonyloxy-4-chloro-benzyloxyamine (6.1 g) of m.p. 44— 46° C., which was not further purified.

4- chloro- 3- hydroxy- benzyloxyamine.

Crude 3-benzenesulfonyloxy-4-chloro-benzyloxyamine (6.1 g = 0.0195 mol) was added to a solution of potassium hydroxide (2.82 g = 0.044 mol) in methanol (30 mL). The mixture was heated under reflux for 5 minutes, then allowed to stand for 1 hour, and the precipitate was then filtered off, washed with methanol (5 ml) and the filtrate plus the washing liquid was evaporated under reduced pressure. The residue was dissolved in water (30 ml) and acidified to pH 4 with acetic acid. The precipitate was filtered off, dried, dissolved in a small excess of 5N ethanolic HCl, and the resulting solution was filtered into ether (200 mL) to give 4-chloro-3-hydroxy-benzyloxy-ammonium chloride (2.4 g = 59 per cent) in the form of colorless needles, which melted at 192.5-193.5° C (under decomposition). Upon recrystallization from glacial acetic acid, the melting point did not rise.

Example 7.

3- benzenesulfonyloxy- 4- bromo-benzyl bromide.

A solution of bromine (49 g = 0.306

mol) in carbon tetrachloride (100 ml) was added dropwise to a weak, refluxing, boiling solution of 3-benzenesulfonyl-oxy-4-bromo-toluene (100 g = 0.306 mol) in carbon tetrachloride (450 ml) at such a rate of addition that no permanent color appeared (5 hours). The reaction mixture was continuously irradiated from a 500 watt tungsten bulb.

The cooled solution was evaporated under reduced pressure and the residue (136 g) was used without further purification.

N-(3-benzenesulfonyloxy-4-bromo-benzyloxy)phthalimide.

A solution of crude 3-benzenesulfonyloxy-4-bromobenzyl bromide (122 g = 0.295 mol), phthaloxime (48.2 g = 0.295 mol) and triethylamine (30 g = 0.295 mol) in acetonitrile (500 mL) was boiled under reflux for 3 hours. The solution was evaporated under reduced pressure, and the residue was recrystallized from ethanol (500 ml) and acetic acid (100 ml), whereby N-(3-benzenesulfonyloxy-4-bromo-benzyloxy)phthalimide (100 g = 57% ) with m.p. 130—

135° C. After two recrystallizations from ethanol, a product was obtained in the form of colorless needles, which melted at 153.5-154° Celsius.

3- benzenesulfonyloxy- 4- bromo-benzyloxyamine.

N-(3-benzenesulfonyloxy-4-bromo-benzyloxy)phthalimide (105 g = 0.22 mol)

was added to a solution of 100% hydrazine hydrate (17 g = 0.33 mol) in ethanol (1.1) and the mixture was heated under reflux for 2 hours. The solution was evaporated to dryness under reduced pressure and chloroform (300 mL) was added to the residue. The solution was filtered and the filtrate evaporated to dryness. The residue was recrystallized from isopropanol (400 ml), whereby 3-benzenesulfonyloxy-4-bromo-benzyloxy-amine (20.4 g = 29 percent) was obtained with m.p. 82.5-83.5° C. After two recrystallizations from isopropanol, a product was obtained in the form of prisms, which melted at 84-85° C.

4- bromo- 3- hydroxy- benzyloxyamine. 3-benzenesulfonyloxy-4-bromo-benzyloxyamine (3.58 g = 0.01 mol) was added to a solution of potassium hydroxide (1.41 g = 0.025 mol) in methanol (20 mL) and the mixture was heated under reflux in 5 minutes. The solution was filtered, the filtrate evaporated and the residue dissolved in water (25 ml), and the resulting solution was acidified to pH 4 with acetic acid. The resulting precipitate was filtered off, dried and dissolved in 8.3 N ethanolic HCl (1 mL) and ethanol (4 mL). The solution was filtered and diluted with ether (50 mL), whereby a precipitate of 4-bromo-3-hydroxy-benzyloxyammonium chloride (1 g = 39

pst.) which melted at 202-203° C (under decomposition). Recrystallization from glacial acetic acid did not raise the melting point.

Samples:

Biochemical and pharmacological data for 0-(3-hydroxybenzyl)-hydroxyammonium chloride (NSD 1024) and 0-(4-bromo-3-hydroxybenzyl)-hydroxyammonium dihydrogen phosphate (NSD 1055) compared with data for α-methyl- 3, 4- dihydroxy- phenylamine. 1. Effect of 3, 4- dihydroxyphenylalanine/ 5- hydroxytryptophan decarboxylase in vitro. 50% inhibition concentrations were determined using 3,4-dihydroxy phenylalanine decarboxylase from guinea pig kidneys with 3,4-dihydroxyphenylalanine as substrate. The procedure was according to Hartman, Akawie of Clark, J. Biol. Chem. (1955) 216, 507. The results were expressed as molarity in relation to substrate:

2. Effect of 3, 4- dihydroxyphenylalanine/ 5- hydroxytryptophan decarboxy-

lase in vivo.

a) Effect of a single dose. 5-Hydroxytryptophan decarboxylase activity on mouse brains was measured 1 hour after administration of the compounds. The procedure was according to Bogdanski, Weissback and Udenfriend, J. Neuro-chem., (1957), 1, 272, with minor modifications. The following doses are required to induce 50 percent inhibition of the enzyme: b) Effect of several doses. Compounds were administered orally in mice in 5 doses of 20 mg/kg, each 12 hours apart. 5-hydroxy-tryptophan decarboxylase activity in the brain was measured for 1 hour after the last dose. "Under these conditions, N.S.D. 1024 gave 33 per cent inhibition and N.S.D. 1055 gave 68 per cent inhibition of the enzyme. 3. Suppression of 5-hydroxytryptophan induced tremor.

An in vivo assay was developed to demonstrate inhibition of brain decarboxylase. The tests exploit the arousal induced in mice by injection of 5-hydroxytryptophan after pretreatment with a monoamine oxidase inhibitor, a phenomenon first reported by Bogdanski, Weissback and Udenfriend, J. Pharmacol. (1958) 122, 182. The excitation produced appears to be mainly central in origin, a conclusion supported by experiments in which 25 microgram quantities of 5-hydroxytryptophan were injected intracisternally and produced head jerks within three minutes. This dose is approximately 1/5 of the dose required subcutaneously. The excitation is blocked by α-methyl-3,4-dihydroxyphenylalanine and by compounds that have been shown to be 3,4-dihydroxy-phenylalanine/5-hydroxytryptophan decarboxylase inhibitors in vitro,

The 5-hydroxytryptophan syndrome persists

of three steps:

(a) overactivity

(b) tremor or spasmodic shaking of the head (c) tremor of the whole body, so that the mouse

is unable to walk and this one

effect lasts for approx. 1 hour.

At high doses, 3,4-dihydroxyphenylalanine decarboxylase inhibitors completely protect mice from this syndrome. Using standard experimental procedures, the "threshold dose" for a compound was defined as the lowest dose at

which house exhibited step (b) but not

step (c) for the syndrome.

Claims (2)

1. Process for the production of pharmacologically active hydroxylamine derivatives having the general formula in which X represents a hydrogen or a halogen atom and n denotes 1, 2 or 3, as well as acid addition salts thereof, characterized by reacting hydrazine, preferably in the form of hydrazine hydrate, with a benzyloxyphthalimide having the general formula in which X and n have the above meanings and Y is one of the groups -COR and -SO,R, where R is an alkyl or aryl radical, and that, when Y means -SO.R, the group Y is hydrolysed away, after which if desired, the prepared base is converted into an acid addition salt. 2. Process according to claim 1, characterized in that N-(3-acetoxy-benzyloxy)-phthalimide, N-(3-benzyloxy-6-chloro-benzyloxy)phthalimide, N-(3 -benzenesulfonyloxy-4-chloro-benzyloxy)phthalimide or N-(3-benzenesulfonyloxy-4-bromo-benzyloxy)-phthalimide.