HK1086548B - Deuterated catecholamine derivatives and medicaments comprising said compounds - Google Patents

Description

Deuterated catecholamine derivatives and medicaments containing said compounds

The present invention relates to deuterated catecholamine derivatives and to medicaments containing these compounds.

Known representatives of catecholamines, such as L-dopa (levodopa) and its carbonates, are used in particular for the treatment of parkinson's disease and restless leg syndrome. Such a medicament containing levodopa is for exampleL-dopa affects dopamine levels in brain nerve cells. Unlike dopamine itself, L-dopa can pass through the blood brain barrier and be converted to dopamine in the brain.

Furthermore, levodopamine is administered in combination with active additives in the medicament. Levodopamine is used in combination with a peripheral decarboxylase inhibitor, with an inhibitor of catechol-O-methyltransferase (COMT), with an inhibitor of monoamine oxidase (MAO) and an inhibitor of dopamine-beta-hydroxylase.

Decarboxylase inhibitors used in this connection are, for example, D, L-serine-2- (2, 3, 4-trihydroxybenzyl) hydrazide (benserazide), (-) -L- α -hydrazino-3, 4-dihydroxy- α -methylhydrocinnamic acid (carbidopa), L-serine-2- (2, 3, 4-trihydroxybenzyl) hydrazide, glycine-2- (2, 3, 4-trihydroxybenzyl) hydrazide) Hydrazide and L-tyrosine-2- (2, 3, 4-trihydroxybenzyl) hydrazide. Examples of combined preparations consisting of levodopa and a decarboxylase inhibitor are, inter alia(levodopa and benserazide hydrochloride) and(levodopa and carbidopa).

An example of a COMT inhibitor is entacapone (C: (C))) And cabergoline, commonly used MAO inhibitors are selegiline hydrochloride, moclobemide, and tranylcypromine.

As inhibitors of dopamine-beta-hydroxylase, calcium 5-butylpyridinecarboxylate and calcium 5-pentylpicolinate are described (DE 2049115).

The object of the present invention is to provide deuterated catecholamine derivatives having improved pharmacokinetic and/or pharmacodynamic properties relative to known compounds, and to provide catecholamine derivatives which can be used for the prophylaxis of psychotic disorders, in particular schizophrenia, and which can be used for the preparation of medicaments for the prophylaxis of psychotic disorders.

It has surprisingly been found that the deuterated catecholamine derivatives according to the invention have significantly better pharmacokinetic and/or pharmacodynamic properties than the non-deuterated compounds and that they can also be used for the prophylaxis of psychiatric disorders and for the preparation of medicaments for the prophylaxis of psychiatric disorders.

Thus, this object is achieved according to the invention by providing compounds of the general formula I:

formula I

Wherein R is¹Is H or D, R²Is H or D, R³Is H, D, C₁-C₆Alkyl or C₅-C₆Cycloalkyl, deuterated C₁-C₆Alkyl or deuterated C₅-C₆Cycloalkyl radical, R⁴Is H or D, and R⁵Is H or D.

Deuterated catecholamine derivatives according to formula I are preferred, wherein R is¹Is H or D, R²Is H or D, R³Is H, D, C₁-C₆Alkyl or C₅-C₆Cycloalkyl, deuterated C₁-C₆Alkyl or deuterated C₅-C₆Cycloalkyl radical, R⁴Is H or D, and R⁵Is D.

Particularly preferred are deuterated catecholamine derivatives according to formula I, wherein R¹Is H or D, R²Is D, R³Is D, C₁-C₆Alkyl or C₅-C₆Cycloalkyl, deuterated C₁-C₆Alkyl or deuterated C₅-C₆Cycloalkyl radical, R⁴Is H or D, and R⁵Is D.

Further preferred are deuterated catecholamine derivatives according to formula I, wherein R¹Is H or D, R²Is D, R³Is H, D, C₁-C₆Alkyl or C₅-C₆Cycloalkyl, deuterated C₁-C₆Alkyl or deuterated C₅-C₆Cycloalkyl radical, R⁴Is H or D, and R⁵Is D.

Of particular interest are deuterated catecholamine derivatives according to formula I, wherein R¹Is H or D, R²Is D, R³Is C₁-C₆Alkyl or C₅-C₆Cycloalkyl radical, R⁴Is H or D, and R⁵Is D.

Of further interest are deuterated catecholamine derivatives according to formula I, wherein R¹Is H or D, R²Is D, R³Is methyl, R⁴Is H or D, and R⁵Is D.

Of particular interest are deuterated catecholamine derivatives according to formula I, wherein R¹Is H or D, R²Is D, R³Is ethyl, R⁴Is H or D, and R⁵Is D.

Deuterated catecholamine derivatives according to formula I are preferred, wherein R is¹Is H or D, R²Is D, R³Being an all-deuterium ethyl group, R⁴Is H or D, and R⁵Is D.

Further preferred are deuterated catecholamine derivatives according to formula I, wherein R¹Is H or D, R²Is H or D, R³Being an all-deuterium ethyl group, R⁴Is H or D, and R⁵Is D.

Further preferred are deuterated catecholamine derivatives according to formula I, wherein R¹Is H or D, R²Is H or D, R³Being an all-deuterium ethyl group, R⁴Is D, and R⁵Is H or D.

Particularly preferred are the following deuterated catecholamine derivatives according to formula I:

l-2-amino-3, 3-dideuterio-3- (3, 4-dihydroxyphenyl) propionic acid,

l-2-amino-3, 3-dideuterio-3- (3, 4-dihydroxyphenyl) propionic acid methyl ester,

ethyl L-2-amino-3, 3-dideuterio-3- (3, 4-dihydroxyphenyl) propionate,

cyclohexyl L-2-amino-3, 3-dideuterio-3- (3, 4-dihydroxyphenyl) propionate,

l-2-amino-3, 3-dideuterio-3- (3, 4-dihydroxyphenyl) propionic acid deuterium methyl ester,

l-2-amino-3, 3-dideuterio-3- (3, 4-dihydroxyphenyl) propionic acid deuterium ethyl ester,

l-2-amino-3, 3-dideuterio-3- (3, 4-dihydroxyphenyl) propionic acid deuterium cyclohexyl ester,

l-2-amino-2, 3, 3-tridedeuterium-3- (3, 4-dihydroxyphenyl) propionic acid,

l-2-amino-2, 3, 3-tridedeuterium-3- (3, 4-dihydroxyphenyl) propionic acid methyl ester,

l-2-amino-2, 3, 3-tridedeuterium-3- (3, 4-dihydroxyphenyl) propionic acid ethyl ester,

cyclohexyl L-2-amino-2, 3, 3-tridedeuterium-3- (3, 4-dihydroxyphenyl) propionate,

l-2-amino-2, 3, 3-tridedeuterium-3- (3, 4-dihydroxyphenyl) propionic acid deuterium methyl ester,

l-2-amino-2, 3, 3-trideuterio-3- (3, 4-dihydroxyphenyl) propionic acid deuterium ethyl ester,

l-2-amino-2, 3, 3-tridedeuterium-3- (3, 4-dihydroxyphenyl) propionic acid deuterium cyclohexyl ester,

l-2-amino-2, 3, 3-tridedeuterium-3- (2, 3, 6-tridedeuterium-4, 5-dihydroxyphenyl) propionic acid,

l-2-amino-2, 3, 3-tridedeuterium-3- (2, 3, 6-tridedeuterium-4, 5-dihydroxyphenyl) propionic acid methyl ester,

ethyl L-2-amino-2, 3, 3-tridedeuterium-3- (2, 3, 6-tridedeuterium-4, 5-dihydroxyphenyl) propionate,

cyclohexyl L-2-amino-2, 3, 3-tridedeuterium-3- (2, 3, 6-tridedeuterium-4, 5-dihydroxyphenyl) propionate,

l-2-amino-2, 3, 3-tridedeuterium-3- (2, 3, 6-tridedeuterium-4, 5-dihydroxyphenyl) propionic acid deuterium methyl ester,

l-2-amino-2, 3, 3-tridedeuterium-3- (2, 3, 6-tridedeuterium-4, 5-dihydroxyphenyl) propionic acid ethyl ester deuterium,

l-2-amino-2, 3, 3-tridedeuterium-3- (2, 3, 6-tridedeuterium-4, 5-dihydroxyphenyl) propanoic acid perhdeuterocyclohexyl ester,

l-2-amino-2, 3, 3-tridedeuterium-3- (2, 3, 6-tridedeuterium-4, 5-dideutereoxyphenyl) propanoic acid deuterium cyclohexyl ester,

l-2-amino-3, 3-dideuterio-3- (4, 5-dideuteryloxyphenyl) propionic acid perheuterucylcyclohexyl ester.

Another embodiment of the invention is the use of the deuterated catecholamine derivatives according to the invention and the physiologically compatible salts thereof for the treatment of dopamine deficient diseases or diseases caused by disturbed tyrosine transport or disturbed tyrosine decarboxylase, such as parkinson's disease, restless leg syndrome, dystonia, for inhibiting prolactin secretion, for stimulating growth hormone release, for the treatment of neurological symptoms of chronic manganese intoxication, amyotrophic lateral sclerosis and multiple systemic atrophy (systematrophi).

Preferred herein are the use of deuterated catecholamine derivatives and their physiologically compatible salts in combination with one or more enzyme inhibitors for the treatment of dopamine deficiency diseases or diseases which are caused by disturbed tyrosine transport or disturbed tyrosine decarboxylase, such as parkinson's disease, restless leg syndrome, dystonia, for inhibiting prolactin secretion, for stimulating the release of growth hormone, for the treatment of the neurological symptoms of chronic manganese intoxication, amyotrophic lateral sclerosis and multiple systemic atrophy.

It is advantageous if the one or more enzyme inhibitors are decarboxylase inhibitors and/or catechol-O-methyltransferase inhibitors and/or monoamine oxidase inhibitors and/or beta-hydroxylase inhibitors.

It is particularly advantageous if the decarboxylase inhibitor is selected from the group consisting of D, L-serine-2- (2, 3, 4-trihydroxybenzyl) hydrazide (benserazide), (-) -L-alpha-hydrazino-3, 4-dihydroxy-alpha-methyl hydrocinnamic acid (carbidopa), L-serine-2- (2, 3, 4-trihydroxybenzyl) hydrazide, glycine-2- (2, 3, 4-trihydroxybenzyl) hydrazide and L-tyrosine-2- (2, 3, 4-trihydroxybenzyl) hydrazide and physiologically compatible salts thereof.

Furthermore, it is particularly advantageous if the catechol-O-methyltransferase inhibitor is selected from entacapone and cabergoline and physiologically compatible salts thereof.

It is also preferred if the monoamine oxidase inhibitor is selected from selegiline, moclobemide and tranylcypromine and the physiologically compatible salts thereof.

It is further particularly preferred if the beta-hydroxylase inhibitor is selected from the group consisting of calcium 5-butylpyridinecarboxylate and calcium 5-pentylpicolinate, and their physiologically compatible salts.

Another object of the present invention is the use of the deuterated catecholamine derivatives according to the invention and the physiologically compatible salts thereof for the preparation of a medicament for the treatment of dopamine deficiency diseases or diseases which are caused by a disturbed tyrosine transport or a disturbed tyrosine decarboxylase, such as parkinson's disease, restless leg syndrome, dystonia, for inhibiting prolactin secretion, for stimulating growth hormone release, for the treatment of the neurological symptoms of chronic manganese intoxication, amyotrophic lateral sclerosis and multiple systemic atrophy.

Another object of the present invention is a pharmaceutical composition comprising, in addition to pharmaceutically compatible adjuvants and additives, deuterated catecholamines according to the invention and their physiologically compatible salts for the treatment of dopamine deficiency diseases or diseases due to disturbed tyrosine transport or disturbed tyrosine decarboxylase like parkinson's disease, restless leg syndrome, dystonia, for inhibiting prolactin secretion, for stimulating growth hormone release, for the treatment of neurological symptoms of chronic manganese intoxication, amyotrophic lateral sclerosis and multiple systemic atrophy.

Particularly advantageous here are pharmaceutical compositions which, in addition to pharmaceutically compatible auxiliaries and additives, contain the deuterated catecholamines compounds of the invention and their physiologically compatible salts for the treatment of parkinson's disease, restless leg syndrome, dystonia, for inhibiting prolactin secretion, for stimulating growth hormone release, for the treatment of the neurological symptoms of chronic manganese intoxication, amyotrophic lateral sclerosis and multiple systemic atrophy, and one or more enzyme inhibitors.

Particularly preferred are pharmaceutical compositions wherein the one or more enzyme inhibitors are decarboxylase inhibitors and/or catechol-O-methyltransferase inhibitors and/or monoamine oxidase inhibitors and/or beta-hydroxylase inhibitors.

Further preferred are pharmaceutical compositions wherein the decarboxylase inhibitor is selected from the group consisting of D, L-serine-2- (2, 3, 4-trihydroxybenzyl) hydrazide (benserazide), (-) -L- α -hydrazino-3, 4-dihydroxy- α -methylhydrocinnamic acid (carbidopa), L-serine-2- (2, 3, 4-trihydroxybenzyl) hydrazide, glycine-2- (2, 3, 4-trihydroxybenzyl) hydrazide and L-tyrosine-2- (2, 3, 4-trihydroxybenzyl) hydrazide and physiologically compatible salts thereof.

Of particular interest are pharmaceutical compositions wherein the catechol-O-methyltransferase inhibitor is selected from entacapone and cabergoline and physiologically compatible salts thereof.

Further advantageous are pharmaceutical compositions wherein the monoamine oxidase inhibitor is selected from selegiline, moclobemide and tranylcypromine and the physiologically compatible salts thereof.

Furthermore, preferred are pharmaceutical compositions wherein the beta-hydroxylase inhibitor is selected from the group consisting of calcium 5-butylpyridinecarboxylate and calcium 5-pentylpicolinate, and physiologically compatible salts thereof.

Another object of the present invention is the use of the deuterated catecholamine derivatives and the physiologically compatible salts thereof according to the invention for the prevention of psychotic disorders, in particular in susceptible patients, for the prevention of relapse, and in particular also for the treatment of acute psychotic disorders, for example with negative symptoms.

Particularly preferred here is the use of the deuterated catecholamine derivatives according to the invention and the physiologically compatible salts thereof in combination with one or more enzyme inhibitors for the prophylaxis of psychotic disorders, and for acute psychotic disorders, preferably with negative symptomatic characteristics.

The use of the deuterated catecholamine derivatives according to the invention and their physiologically compatible salts is further preferred if the one or more enzyme inhibitors are decarboxylase inhibitors and/or catechol-O-methyltransferase inhibitors and/or monoamine oxidase inhibitors and/or β -hydroxylase inhibitors.

The use of deuterated catecholamine derivatives and their physiologically compatible salts according to the invention is particularly preferred if the decarboxylase inhibitor is selected from the group consisting of D, L-serine-2- (2, 3, 4-trihydroxybenzyl) hydrazide (benserazide), (-) -L- α -hydrazino-3, 4-dihydroxy- α -methyl hydrocinnamic acid (carbidopa), L-serine-2- (2, 3, 4-trihydroxybenzyl) hydrazide, glycine-2- (2, 3, 4-trihydroxybenzyl) hydrazide and L-tyrosine-2- (2, 3, 4-trihydroxybenzyl) hydrazide as physiologically compatible salts thereof.

The use of the deuterated catecholamine derivatives and the physiologically compatible salts thereof according to the invention is advantageous if the catechol-O-methyltransferase inhibitor is selected from entacapone and cabergoline and the physiologically compatible salts thereof.

The use of the deuterated catecholamine derivatives and their physiologically compatible salts according to the invention is further advantageous here if the monoamine oxidase inhibitor is selected from selegiline, moclobemide and tranylcypromine and their physiologically compatible salts.

The use of the deuterated catecholamine derivatives and the physiologically compatible salts thereof according to the invention is particularly advantageous if the β -hydroxylase inhibitor is selected from calcium 5-butylpyridinecarboxylate and calcium 5-pentylpicolinate and the physiologically compatible salts thereof.

Another object of the present invention is the use of the deuterated catecholamine derivatives according to the invention and the physiologically compatible salts thereof for the preparation of a medicament for use in the prevention of psychiatric disorders.

Another object of the present invention is a pharmaceutical composition comprising the deuterated catecholamines of the present invention and their physiologically compatible salts for the prevention of psychiatric disorders and for the treatment of acute psychiatric disorders, in addition to pharmaceutically compatible adjuvants and additives.

Of particular interest here are pharmaceutical compositions which, in addition to the pharmaceutically compatible adjuvants and additives, also contain the deuterated catecholamines according to the invention and their physiologically compatible salts for the prophylaxis of psychotic disorders and for the treatment of acute psychotic disorders, and one or more enzyme inhibitors.

Particularly preferred are pharmaceutical compositions wherein the one or more enzyme inhibitors are decarboxylase inhibitors and/or catechol-O-methyltransferase inhibitors and/or monoamine oxidase inhibitors and/or beta-hydroxylase inhibitors.

Further preferred are pharmaceutical compositions wherein the decarboxylase inhibitor is selected from the group consisting of D, L-serine-2- (2, 3, 4-trihydroxybenzyl) hydrazide (benserazide), (-) -L- α -hydrazino-3, 4-dihydroxy- α -methylhydrocinnamic acid (carbidopa), L-serine-2- (2, 3, 4-trihydroxybenzyl) hydrazide, glycine-2- (2, 3, 4-trihydroxybenzyl) hydrazide and L-tyrosine-2- (2, 3, 4-trihydroxybenzyl) hydrazide and physiologically compatible salts thereof.

Of particular interest are pharmaceutical compositions wherein the catechol-O-methyltransferase inhibitor is selected from entacapone and cabergoline and physiologically compatible salts thereof.

Of particular interest are pharmaceutical compositions wherein the monoamine oxidase inhibitor is selected from selegiline, moclobemide and tranylcypromine and the physiologically compatible salts thereof.

Particularly preferred are pharmaceutical compositions wherein the beta-hydroxylase inhibitor is selected from the group consisting of calcium 5-butylpyridinecarboxylate and calcium 5-pentylpicolinate, and physiologically compatible salts thereof.

The preparation of the L-2-amino-3, 3-dideutero-3- (3, 4-dihydroxyphenyl) propionic acid according to the invention is carried out according to Binns et al, J.chem.Soc. (C), 1970, page 1134. 1138, in which the preparation of racemic 2-amino-3, 3-dideutero-3- (3, 4-dihydroxyphenyl) propionic acid is described inter alia. Didehydro- (3, 4-dimethoxyphenyl) methane was prepared by reaction with lithium aluminum deuteride starting from ethyl 3, 4-dimethoxybenzoate. Whereby 4- (chlorodideuteromethyl) -1, 2-dimethoxybenzene is produced by reaction with thionyl chloride, which reacts with the sodium salt of diethyl acetylaminomalonate to produce deuterated diethyl 3, 4-dimethoxybenzylacetylaminomalonate, which is converted to D, L-2-acetylamino-3, 3-dideuterio-3- (3, 4-dimethoxyphenyl) propionic acid by treatment with an ethanolic solution of potassium hydroxide. The object of the present invention, i.e. the preparation of the L-enantiomer of a dideuterated amino acid in the β, β -position, can be achieved by carrying out the racemate resolution in these positions in a manner analogous to that disclosed in patent document CH 59098. It was also found that L-2-acetamido-3, 3-didedeuterium-3- (3, 4-dimethoxyphenyl) propionic acid could also be very well isolated from the solution by crystal formation with (R) - (+) -1-phenylethylamine. L-2-amino-3, 3-didehydro-3- (3, 4-dihydroxyphenyl) propionic acid according to the invention is then obtained from L-2-acetamido-3, 3-didehydro-3- (3, 4-dimethoxyphenyl) propionic acid by a mild ether cleavage reaction analogously to Jung et al, J.Org.chem., 42, 23, 1977, 3761-propan 3764. The esters of the dideuterated compounds of the invention in the beta position are then prepared from this amino acid at low temperature by reaction with thionyl chloride and a deuterated or non-deuterated alcohol.

It is particularly advantageous here that the residual D-2-acetylamino-3, 3-dideuterio-3- (3, 4-dimethoxyphenyl) propionic acid can be separated off from the mother liquor of the racemate resolution, which after the ether cleavage reaction can be used as starting material for the preparation of further compounds according to the invention.

In addition, L-2-amino-3, 3-didehydro-3- (3, 4-dihydroxyphenyl) propionic acid can also be used as a starting material for further deuteration in the phenyl ring of the amino acid by a method similar to that of Vining et al, Journal of laboratory Compounds and RadiopharmaThe compounds were prepared in an autoclave at 190 ℃ and D by the method described in pharmaceuticals, volume XVIII, No. 11, 1981, page 1683-1692₂And O reaction. The obtained L-2-amino-3, 3-dideutero-3- (2, 3, 6-trideutero-4, 5-dihydroxyphenyl) propanoic acid is then converted to the ester of the invention as described above. According to EP 610595, the stability of the obtained esters can be increased by adding antioxidants during the preparation or isolation of the esters.

D-2-acetamido-3, 3-didehydro-3- (3, 4-dimethoxyphenyl) propionic acid obtained by the above-described racemate resolution is converted into a dihydroxyamino acid in analogy to the L-compound and then used to form the compound of the invention deuterated at the alpha-position by racemization and simultaneous deuteration in analogy to Chen et al, Biotechnology Letters, Vol.14, No. 4, 1992, page 269-274. For this purpose, D-2-acetamido-3, 3-dideutero-3- (3, 4-dihydroxyphenyl) propionic acid is reacted with benzaldehyde in deuterated acetic acid. D-and L-2-acetamido-3, 3-dideutero-3- (3, 4-dihydroxyphenyl) propionic acid, deuterated in the alpha-position, present as racemate are converted into the corresponding methyl esters and are isolated with the aid of Alcalase by enzymatically hydrolyzing methyl L-2-acetamido-3, 3-dideutero-3- (3, 4-dihydroxyphenyl) propionate to the carboxylic acid and leaving methyl D-2-acetamido-3, 3-dideutero-3- (3, 4-dihydroxyphenyl) propionate unreacted. The separation of the compounds is carried out by means of HPLC.

The isolated L-2-acetamido-2, 3, 3-trideutero-3- (3, 4-dihydroxyphenyl) propionic acid is converted into the ester of the invention, or is additionally deuterated on the benzene ring according to the above-described method to obtain the L-2-amino-2, 3, 3-trideutero-3- (2, 3, 6-trideutero-4, 5-dihydroxyphenyl) propionic acid of the invention, and the carboxylic acid is converted again into the ester of the invention. Multiple passes of H/D exchange on phenolic hydroxyl and on amino from D₂Recrystallization in O.

For the preparation of the physiologically compatible salts of the deuterated catecholamine derivatives of the invention, it is possible to use the customary physiologically compatible inorganic and organic acids, for example hydrochloric acid, hydrobromic acid, phosphoric acidSulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid, and benzoic acid. Other acids which may be used are described, for example, in Fortschrite derArzneimitelforschung, volume 10, page 224-,publishers, Basel and Stuttgart (1966), and Journal of Pharmaceutical Sciences, Vol.66, pages 1-5 (1977).

Acid addition salts are usually obtained in a manner known per se by mixing the free base or a solution thereof with the corresponding acid or a solution thereof in an organic solvent, for example a lower alcohol such as methanol, ethanol, n-propanol or isopropanol, or a lower ketone such as acetone, methyl-ethyl ketone or methyl-isobutyl ketone, or an ether such as diethyl ether, tetrahydrofuran or dioxane. Mixtures of the solvents mentioned can also be used in order to obtain better crystal precipitation. Furthermore, physiologically compatible aqueous solutions of the acid addition salts of the compounds used according to the invention can also be prepared in aqueous acid solutions.

The acid addition salts of the compounds of the invention can be converted into the free bases in a manner known per se, for example using bases or ion exchangers. Other salts may be obtained from the free base by reaction with an inorganic or organic acid, particularly an acid suitable for forming a therapeutically useful salt. This or other salts of the novel compounds, such as picric acid salts, can also be used to purify the free base by converting the free base into a salt, isolating the salt, and releasing the base from the salt again.

The invention also relates to medicaments for oral, buccal, sublingual, nasal, rectal, subcutaneous, intravenous or intramuscular administration, and for inhalation, which contain, as active substance, in addition to the usual carriers and diluents, a compound of the general formula I or an acid addition salt thereof.

The medicaments according to the invention are prepared in a known manner in suitable doses from the usual solid or liquid carrier substances or diluents and the usual pharmaceutical technical auxiliaries corresponding to the type of administration desired. Preferred formulations are in a form suitable for oral administration. Such administration forms are, for example, tablets, sucking tablets, film-coated tablets, dragees, capsules, pills, powders, solutions, aerosols or suspensions or depot forms.

It goes without saying that parenteral preparations such as injection solutions are also conceivable. Further, examples of the preparation include suppositories. Corresponding tablets may be obtained, for example, by mixing the active substances with known auxiliaries, for example inert diluents such as glucose, sucrose, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents for achieving a long-acting effect such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also be made of multiple layers.

Accordingly, dragees (also including dragees in the form of preparations for controlled or delayed release) can be prepared by coating cores prepared analogously to tablets with agents customarily used in dragee coatings, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sucrose. The dragee shells can also be composed of a plurality of layers, in which case the auxiliaries described above for the tablets can be used.

The solutions or suspensions with the active substances used according to the invention may additionally contain taste improvers, such as saccharin, cyclamate or sucrose, and, for example, aromatics, such as vanillin or orange extract. In addition, they may contain suspension aids such as sodium carboxymethylcellulose, or preservatives such as p-hydroxybenzoate. Capsules containing the active substance can be prepared, for example, by mixing the active substance with an inert carrier, such as lactose or sorbitol, and then encapsulating in gelatin capsules. Suitable suppositories may be prepared, for example, by mixing with carriers intended for suppository, such as neutral fats or polyethylene glycols or derivatives thereof.

The preparation of the pharmaceutical preparations of the invention is known per se and is described in handbooks known to the skilled worker, for example Hager's Handbuch (5.)2, 622-; list et al, Arzneiformenlehre, Stuttgart: boss press 1985; sucker et al, Pharmazeutische technology, Stuttgart: thieme 1991; ullmann' s(5.)A 19，241-271；Voigt，Pharmazeutische Technologie，Berlin：Ullstein Mosby 1995。

The following examples illustrate the invention:

example 1

Preparation of L-2-acetamido-3, 3-dideuterio-3- (3, 4-dimethoxyphenyl) propionic acid

In analogy to the procedure used for the non-deuterated compound, 50ml of acetone were added to 3.85g D, L-2-acetylamino-3, 3-didehydro-3- (3, 4-dimethoxyphenyl) propionic acid and the solution was heated. To this warm solution was added 0.865g of (R) - (+) -1-phenylethylamine dissolved in 5ml of acetone. The precipitated salt was redissolved in solution by the addition of a small amount of methanol. Methanol was removed by multiple concentrations of the reaction mixture and the volume of the solution was made up to 50ml by addition of acetone. To crystallize the salt formed from L-2-acetamido-3, 3-dideuterio-3- (3, 4-dimethoxyphenyl) propionic acid and (R) - (+) -1-phenylethylamine, the reaction mixture was rubbed with a glass rod and left to stand at room temperature for 12 hours after the start of crystallization. The crystals formed were separated off, washed with cold acetone and diethyl ether and dried.

2.6g of salt was isolated.

The solvent was distilled off from the remaining mother liquor and the residue consisting of D-2-acetamido-3, 3-dideuterio-3- (3, 4-dimethoxyphenyl) propionic acid was saved until further processing.

Yield: 93 percent

Melting point: 185 ℃ C., 187 ℃ C

[α]_D ²⁵56.4 ° (c 1 in methanol)

The salt was further worked up without further purification by dissolving 2.5g of the salt in 15ml of 5% sodium hydroxide solution. The liberated (R) - (+) -1-phenylethylamine is removed from the solution by extraction with petroleum ether. After acidification of the aqueous phase with hydrochloric acid, saturated sodium chloride solution was added and the solution was extracted with ethyl acetate. The organic phase was dried and the solvent was removed. The residue was crystallized overnight to obtain L-2-acetylamino-3, 3-dideuterio-3- (3, 4-dimethoxyphenyl) propionic acid. 1.48g of product was obtained.

Yield: 86 percent of the total weight

Melting point: 135 ℃ 137 DEG C

[α]_D ²⁵Not at +45.5 ° (c not at 1 in methanol)

Calculated values:

C：57.98％ H：7.11％ N：5.20％

measurement value:

C：57.89％ H：7.19％ N：5.30％

¹H-NMR(400MHz，d6-DMSO)：δ6.48(s，1H)；6.60(s，1H)；6.54(s，1H)；7.8(s，1H)；4.60(s，1H)；3.70(s，6H)；2.20(s，3H)。

example 2

Preparation of L-2-amino-3, 3-dideuterio-3- (3, 4-dihydroxyphenyl) propionic acid

1.35g L-2-acetylamino-3, 3-dideuterio-3- (3, 4-dimethoxyphenyl) propionic acid was dissolved in 17ml chloroform and then 26.3ml iodotrimethylsilane was added. The reaction mixture was heated to 60 ℃ and the progress of the reaction was monitored by means of NMR. After 30 hours the reaction was terminated, the mixture was filtered and 15ml methanol was added to the filtrate. After 30 hours the solvent was removed and 0.96g of product was isolated.

Yield: 96 percent

Melting point: 287-290 deg.C (decomposition)

[α]_D ²⁵11.7 ° (c 5.27 in 1M HCl)

Calculated values:

C：54.27％ H：6.58％ N：7.03％

measurement value:

C：54.10％ H：6.60％ N：7.11％

¹H-NMR(400MHz，d6-DMSO)：δ6.49(s，1H)；6.59(s，1H)；6.54(s，1H)；7.8(s，1H)；4.28(s，1H)。

example 3

D-2-amino-3, 3-dideuterio-3- (3, 4-dihydroxyphenyl) propionic acid

D-2-acetylamino-3, 3-dideutero-3- (3, 4-dimethoxyphenyl) propionic acid obtained in example 1 was converted in analogy to example 2 into D-2-amino-3, 3-dideutero-3- (3, 4-dihydroxyphenyl) propionic acid. Starting from 1.2g of the starting compound, 0.82g of deuterated dihydroxyamino acid is isolated.

Yield: 92 percent of

Melting point: 287-290 deg.C (decomposition)

[α]_D ²⁵11.5 ° (c 5.27 in 1M HCl)

Calculated values:

C：54.27％ H：6.58％ N：7.03％

measurement value:

C：54.31％ H：6.55％ N：7.10％

¹³C-NMR (200MHz, d 6-DMSO): δ 41.0 (quintuple); 62.50(s); 116.20(s); 117.30(s); 121.70(s); 133.80(s); 141.40(s); 144.40(s); 176.40(s).

Example 4

Preparation of D, L-2-amino-2, 3, 3-trideutero-3- (3, 4-dihydroxyphenyl) propionic acid

To 1.99g D-2-acetamido-3, 3-didehydro-3- (3, 4-dihydroxyphenyl) propionic acid was admixed 50ml of monodeuterated acetic acid (CH)₃COOD) and 0.2ml benzaldehyde are added. The reaction mixture was rinsed with nitrogen and then heated to reflux for 1 hour. After the end of the reaction time, the solvent was removed and the residue was admixed with 20ml of ethanol. The precipitated solid was filtered to isolate 1.74g D, L-2-amino-2, 3, 3-trideutero-3- (3, 4-dihydroxyphenyl) propionic acid.

Yield: 87 percent of

Melting point: 287-290 deg.C (decomposition)

Calculated values:

C：53.99％ H：7.05％ N：7.00％

measurement value:

C：53.90％ H：7.12％ N：7.04％

¹H-NMR(400MHz，d6-DMSO)：δ6.47(s，1H)；6.59(s，1H)；6.52(s，1H)；7.8(s，1H)。

example 5

Preparation of D, L-2-amino-2, 3, 3-trideutero-3- (3, 4-dihydroxyphenyl) propionic acid methyl ester

2g D, L-2-amino-2, 3, 3-trideuterio-3- (3, 4-dihydroxyphenyl) propionic acid in 30ml of methanol was cooled to-10 ℃ and 1ml of thionyl chloride was added dropwise. The reaction mixture was then heated to 40 ℃ and held for 15 hours. The reaction mixture was freed of volatiles in vacuo and 10ml of water and 15ml of a solution consisting of 0.8g of sodium bicarbonate, 1g of sodium sulfate and 1mg of ascorbic acid were added. The pH of the solution was adjusted to 7 by adding dilute sodium hydroxide solution. The product was transferred to the organic phase by extraction with oxygen-free ethyl acetate containing 0.01% 2, 6-di-tert-butyl-4-methoxyphenol. The organic phase is dried and subsequently the solvent is distilled off. To the residue was added 50ml of oxygen-free diethyl ether, and after standing overnight, methyl D, L-2-amino-2, 3, 3-trideuterio-3- (3, 4-dihydroxyphenyl) propionate precipitated. After recrystallization from an oxygen-free methanol/ether mixture with 2, 6-di-tert-butyl-4-methoxyphenol incorporated, 1.8g of product were isolated.

Yield: 85 percent of

Calculated values:

C：56.06％ H：7.53％ N：6.54％

measurement value:

C：56.20％ H：7.48％ N：6.55％

¹H-NMR(400MHz，d6-DMSO)：δ6.48(s，1H)；6.59(s，1H)；6.54(s，1H)；7.8(s，1H)；3.80(s，3H)。

example 6

L-2-amino-2, 3, 3-trideuterio-3- (3, 4-dihydroxyphenyl) propionic acid

1.07g D methyl L-2-amino-2, 3, 3-trideuterio-3- (3, 4-dihydroxyphenyl) propanoate was dissolved in 30ml of a 0.2 molar sodium bicarbonate solution (pH 8.2). 200. mu.l of Alcalase were added and the pH of the solution was kept at this value with the aid of a carbonate-bicarbonate buffer. The course of the reaction was controlled by means of HPLC and stopped by adding hydrochloric acid when the ester concentration had decreased to half. The trideuterated amino acids contained in the solution were separated from the trideuterated methyl esters by chromatography using a developing solvent mixture acetonitrile/0.1% aqueous trifluoroacetic acid (15: 85) to isolate 1.04g L-2-amino-2, 3, 3-trideuterio-3- (3, 4-dihydroxyphenyl) propionic acid.

Yield: 97 percent

Melting point: 287-290 deg.C (decomposition)

[α]_D ²⁵11.6 ° (c 5.27 in 1M HCl)

Calculated values:

C：53.99％ H：7.05％ N：7.00％

measurement value:

C：53.83％ H：7.12％ N：6.91％

¹³C-NMR (200MHz, d 6-DMSO): δ 41.0 (quintuple); 62.40 (triplet); 116.20(s); 117.30(s); 121.70(s); 133.80(s); 141.40(s); 144.40(s); 176.40(s).

Example 7

Preparation of L-2-amino-2, 3, 3-trideutero-3- (2, 3, 6-trideutero-4, 5-dihydroxyphenyl) propionic acid

In an autoclave, 0.2g L-2-amino-2, 3, 3-tridedeuterium-3- (3, 4-dihydroxyphenyl) propionic acid was admixed with 10ml of D₂And O. The autoclave was evacuated and heated at a temperature of 190 ℃ for 24 hours. After the reaction was completed, the solvent was removed, ethyl acetate was added to the residue, and the solvent was distilled off in vacuo. The residue was washed with cold acetone, thereby isolating 0.17g of the product.

Yield: 84 percent

Melting point: 287-290 deg.C (decomposition)

[α]_D ²⁵11.5 ° (c 5.27 in 1M HCl)

Calculated values:

C：53.19％ H：8.43％ N：6.89％

measurement value:

C：53.30％ H：8.31％ N：7.00％

¹³C-NMR (200MHz, d 6-DMSO): δ 41.0 (quintuple); 62.40 (t); 116.30 (t); 117.20 (t); 121.70 (t); 133.80(s); 141.30(s); 144.40(s); 176.40(s).

Claims (19)

1. A deuterated catecholamine derivative of the general formula I:

formula I

Wherein R is¹Is H or D, R²Is H or D, R³Is H, D, C₁-C₆Alkyl or C₅-C₆Cycloalkyl, deuterated C₁-C₆Alkyl or deuteratedC₅-C₆Cycloalkyl radical, R⁴Is H or D, and R⁵Is H or D.

2. The deuterated catecholamine derivative of claim 1, wherein R¹Is H or D, R²Is H or D, R³Is H, D, C₁-C₆Alkyl or C₅-C₆Cycloalkyl, deuterated C₁-C₆Alkyl or deuterated C⁵-C⁶Cycloalkyl radical, R⁴Is H or D, and R⁵Is D.

3. The deuterated catecholamine derivative of claim 1, wherein R¹Is H or D, R²Is D, R³Is D, C₁-C₆Alkyl or C₅-C₆Cycloalkyl, deuterated C₁-C₆Alkyl or deuterated C₅-C₆Cycloalkyl radical, R⁴Is H or D, and R⁵Is D.

4. The deuterated catecholamine derivative of claim 1, wherein R¹Is H or D, R²Is D, R³Is H, D, C₁-C₆Alkyl or C₅-C₆Cycloalkyl, deuterated C₁-C₆Alkyl or deuterated C₅-C₆Cycloalkyl radical, R⁴Is H or D, and R⁵Is D.

5. Deuterated catecholamine derivatives of the general formula I, wherein R¹Is H or D, R²Is D, R³Is C₁-C₆Alkyl or C₅-C₆Cycloalkyl radical, R⁴Is H or D, and R⁵Is D.

6. The deuterated catecholamine derivative of claim 1, wherein R¹Is H or D, R²Is D, R³Is methyl, R⁴Is H or D, and R⁵Is D.

7. The deuterated catecholamine derivative of claim 1, wherein R¹Is H or D, R²Is D, R³Is ethyl, R⁴Is H or D, and R⁵Is D.

8. The deuterated catecholamine derivative of claim 1, wherein R¹Is H or D, R²Is D, R³Being an all-deuterium ethyl group, R⁴Is H or D, and R⁵Is D.

9. The deuterated catecholamine derivative of claim 1, wherein R¹Is H or D, R²Is H or D, R³Being an all-deuterium ethyl group, R⁴Is H or D, and R⁵Is D.

10. The deuterated catecholamine derivative of claim 1, wherein R¹Is H or D, R²Is H or D, R³Being an all-deuterium ethyl group, R⁴Is D, and R⁵Is H or D.

11. Deuterated catecholamine derivatives according to claim 1, which are:

l-2-amino-3, 3-dideuterio-3- (3, 4-dihydroxyphenyl) propionic acid,

l-2-amino-2, 3, 3-tridedeuterium-3- (3, 4-dihydroxyphenyl) propionic acid,

l-2-amino-2, 3, 3-trideutero-3- (2, 3, 6-trideutero-4, 5-dihydroxyphenyl) propionic acid.

12. Use of deuterated catecholamine derivatives as claimed in any one of claims 1 to 11, and physiologically compatible salts thereof, for the preparation of a medicament for the treatment of parkinson's disease, restless leg syndrome, amyotrophic lateral sclerosis and multiple systemic atrophy.

13. Pharmaceutical composition containing, in addition to pharmaceutically compatible adjuvants and additives, deuterated catecholamines compounds according to any one of claims 1 to 11 and their physiologically compatible salts for the treatment of parkinson's disease, restless leg syndrome, dystonia, for inhibiting prolactin secretion, for stimulating growth hormone release, for the treatment of the neurological symptoms of chronic manganese intoxication, amyotrophic lateral sclerosis and multiple systemic atrophy.

14. Pharmaceutical composition containing, in addition to pharmaceutically compatible adjuvants and additives, deuterated catecholamines compounds according to any one of claims 1 to 11 and their physiologically compatible salts, and one or more enzyme inhibitors for the treatment of parkinson's disease, restless leg syndrome, dystonia, for inhibiting prolactin secretion, for stimulating growth hormone release, for the treatment of the neurological symptoms of chronic manganese intoxication, amyotrophic lateral sclerosis and multiple systemic atrophy.

15. Pharmaceutical composition according to claim 14, characterized in that the one or more enzyme inhibitors are decarboxylase inhibitors and/or catechol-O-methyltransferase inhibitors and/or monoamine oxidase inhibitors and/or β -hydroxylase inhibitors.

16. Pharmaceutical composition according to claim 14, characterized in that the decarboxylase inhibitor is selected from the group consisting of D, L-serine-2- (2, 3, 4-trihydroxybenzyl) hydrazide, (-) -L- α -hydrazino-3, 4-dihydroxy- α -methylhydrocinnamic acid, L-serine-2- (2, 3, 4-trihydroxybenzyl) hydrazide, glycine-2- (2, 3, 4-trihydroxybenzyl) hydrazide and L-tyrosine-2- (2, 3, 4-trihydroxybenzyl) hydrazide and physiologically compatible salts thereof.

17. Pharmaceutical composition according to claim 14, characterized in that the catechol-O-methyltransferase inhibitor is selected from entacapone and cabergoline and physiologically compatible salts thereof.

18. Pharmaceutical composition according to claim 14, characterized in that the monoamine oxidase inhibitor is selected from selegiline, moclobemide and tranylcypromine and the physiologically compatible salts thereof.

19. Pharmaceutical composition according to claim 14, characterized in that the β -hydroxylase inhibitor is selected from the group consisting of calcium 5-butylpyridinoate and calcium 5-pentylpicolinate and the physiologically compatible salts thereof.