Deuterated catecholamine derivatives and medicaments compromising said compounds

Abstract

The present invention concerns deuterated catecholamine derivatives as well as pharmaceuticals containing these compounds. In addition, the invention concerns the use of deuterated catecholamine derivatives as well as physiologically compatible salts thereof, and also pharmaceutical compositions, which contain these compounds, also in combination with enzyme inhibitors, for the treatment of dopamine deficiency diseases or diseases which are based on disrupted tyrosine transport or disrupted tyrosine decarboxylase, as well as other disorders.

Claims

.[.1. Deuterated catecholamine derivatives of the general formula I ##STR00002## wherein R.sup.1 is H or D, R2 indicates D, R.sup.3 is H, D, C.sub.1 to C.sub.6-alkyl or C.sub.5 to C.sub.6-cycloalkyl, deuterated C.sub.1 to C.sub.6-alkyl or deuterated C.sub.5 to C.sub.6-cycloalkyl, R.sup.4 indicates H or D and R.sup.5 is H or hhD..].

.[.2. Deuterated catecholamine derivatives of the general formula I ##STR00003## wherein R.sup.1 is H or D, R.sup.2 indicates D, R.sup.3 is D, C.sub.1 to C.sub.6-alkyl or C.sub.5 to C.sub.6-cycloalkyl, deuterated C.sub.1 to C.sub.6-alkyl or deuterated C.sub.5 to C.sub.6-cycloalkyl, R.sup.4 indicates H or D and R.sup.5 is H or D..].

.[.3. Deuterated catecholamine derivatives of the general formula I ##STR00004## wherein R.sup.1 is H or D, R.sup.2 indicates D, R.sup.3 is H, D, C.sub.1 to C.sub.6-alkyl or C.sub.5 to C.sub.6-cycloalkyl, deuterated C.sub.1 to C.sub.6-alkyl or deuterated C.sub.5 to C.sub.6-cycloalkyl, R.sup.4 indicates H or D and R.sup.5 is H or D..].

.[.4. Deuterated catecholamine derivatives of the general formula I ##STR00005## wherein R.sup.1 is H or D, R.sup.2 indicates D, R.sup.3 is C.sub.1 to C.sub.6-alkyl or C.sub.5 to C.sub.6-cycloalkyl, R.sup.4 indicates H or D and R.sup.5 is H or D..].

.[.5. Deuterated catecholamine derivatives of the general formula I ##STR00006## wherein R.sup.1 is H or D, R.sup.2 indicates D, R.sup.3 is methyl, R.sup.4 indicates H or D and R.sup.5 is H or D..].

.[.6. Deuterated catecholamine derivatives of the general formula I ##STR00007## wherein R.sup.1 is H or D, R.sup.2 indicates D, R.sup.3 is ethyl, R.sup.4 indicates H or D and R.sup.5 is H or D..].

.[.7. Deuterated catecholamine derivatives of the general formula I ##STR00008## wherein R.sup.1 is H or D, R.sup.2 indicates D, R.sup.3 is perdeuteroethyl, R.sup.4 indicates H or D and R.sup.5 is H or D..].

.[.8. Deuterated catecholamine derivatives of the general formula I ##STR00009## wherein R.sup.1 is H or D, R2 indicates D, R.sup.3 is perdeuteroethyl, R.sup.4 indicates H or D and R.sup.5 is H or D..].

.[.9. Deuterated catecholamine derivatives of the general formula I ##STR00010## wherein R.sup.1 is H or D, R.sup.2 indicates D, R.sup.3 is perdeuteroethyl, R.sup.4 indicates D and R.sup.5 is H or D..].

10. A method for .[.the treatment of.]. .Iadd.treating a .Iaddend.dopamine deficiency .[.diseases or diseases.]. .Iadd.disease, treating a disease .Iaddend.which .[.are.]. .Iadd.is .Iaddend.based on disrupted tyrosine transport or disrupted tyrosine decarboxylase, .[.or.]. .Iadd.treating .Iaddend.Parkinson's disease, .Iadd.treating .Iaddend.restless leg syndrome, .Iadd.treating .Iaddend.dystonia, .[.for.]. inhibiting prolactin secretion, .[.for.]. stimulating the release of growth hormone, .[.for the treatment of.]. .Iadd.treating .Iaddend.neurological symptoms of chronic manganese .[.intoxications.]. .Iadd.intoxication.Iaddend., .[.of.]. .Iadd.treating .Iaddend.amyotrophic lateral sclerosis .[.and of.]..Iadd., or treating .Iaddend.multiple system atrophy, .[.said method.]. comprising administering to a patient in need thereof an effective amount of .[.a compound of general formula I ##STR00011## wherein R.sup.1 is H or D, R.sup.2 indicates D, R.sup.3 is H, D, C.sub.1-C.sub.6- alkyl or C.sub.5 to C.sub.6-cycloalkyl, deuterated C.sub.1 to C.sub.6-alkyl or C.sub.5 to C.sub.6-cycloalkyl, R.sup.4 indicates H or D and R.sup.5 is H or D, and wherein the compound is selected from the group consisting of,.]. L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)propionic acid.[.;.]..Iadd., .Iaddend. .[.L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)methyl propionate; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) ethyl propionate; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)cyclohexyl propionate; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)perdeuteromethyl propionate; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)perdeuteroethyl propionate; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)perdeuterocyclohexyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)propionic acid; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)methyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)ethyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)cyclohexyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)perdeuteromethyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)perdeuteroethyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)perdeuterocyclohexyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dideuteroxyphenyl)perdeuterocyclohexyl propionate; and, as well as.]. .Iadd.or a .Iaddend.physiologically compatible .[.salts.]. .Iadd.salt .Iaddend.thereof.

11. The method of claim 10, wherein the .[.compound as well as.]. .Iadd.L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)propionic acid or the .Iaddend.physiologically compatible .[.salts.]. .Iadd.salt .Iaddend.thereof is administered in combination with an enzyme inhibitor or several enzyme inhibitors.

12. The method .[.as claimed in.]. .Iadd.of .Iaddend.claim 11.Iadd., .Iaddend.wherein the enzyme inhibitor or the .Iadd.several .Iaddend.enzyme inhibitors .[.involve.]. are decarboxylase inhibitors and/or catechol-O-methyltransferase inhibitors and/or monoamine oxidase inhibitors and/or β-hydroxylase inhibitors.

13. The method .[.as claimed in.]. .Iadd.of .Iaddend.claim 12.Iadd., .Iaddend.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.]..Iadd., or .Iaddend.L-tyrosine 2-(2,3,4-trihydroxybenzyl)hydrazide .[.as well as.]..Iadd., or a .Iaddend.physiologically compatible .[.salts.]. .Iadd.salt .Iaddend.thereof.

14. The method .[.as claimed in.]. .Iadd.of .Iaddend.claim 12.Iadd., .Iaddend.wherein the catechol-O-methyltransferase inhibitor is .[.selected from.]. entacapone .[.and.]. .Iadd.or .Iaddend.cabergoline .[.as well as.]. .Iadd.or a .Iaddend.physiologically compatible .[.salts.]. .Iadd.salt .Iaddend.thereof.

15. The method .[.as claimed in.]. .Iadd.of .Iaddend.claim 12.Iadd., .Iaddend.wherein the monoamine oxidase inhibitor is .[.selected from the group consisting of.]. selegiline, moclobemide .[.and.]..Iadd., or .Iaddend.tranylcypromine .[.as well as.]. .Iadd.or a .Iaddend.physiologically compatible .[.salts.]. .Iadd.salt .Iaddend.thereof.

16. The method .[.as claimed in.]. .Iadd.of .Iaddend.claim 12.Iadd., .Iaddend.wherein the β-hydroxylase inhibitor is .[.selected from.]. calcium 5-butyl picolinate .[.and.]. .Iadd.or .Iaddend.calcium 5-pentyl picolinate .[.as well as.]. .Iadd.or a .Iaddend.physiologically compatible .[.salts.]. .Iadd.salt .Iaddend.thereof.

.[.17. A method for the production of pharmaceuticals for treatment of dopamine deficiency diseases or diseases which are based on disrupted tyrosine transport or disrupted tyrosine decarboxylase, or Parkinson's disease, restless leg syndrome, dystonia, for inhibiting prolactin secretion, for stimulating the release of growth hormone, for the treatment of neurological symptoms of chronic manganese intoxications, of amyotrophic lateral sclerosis and of multiple system atrophy, said method comprising the steps of providing a compound of general formula I ##STR00012## wherein R.sup.1 is H or D, R.sup.2 indicates D, R.sup.3 is H, D, C.sub.1-C.sub.6 alkyl or C.sub.5 to C.sub.6-cycloalkyl, deuterated C.sub.1 to C.sub.6-alkyl or C.sub.5 to C.sub.6-cycloalkyl, R.sup.4 indicates H or D and R.sup.5 is H or D, and wherein the compound is selected from the group consisting of L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)propionic acid; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)methyl propionate; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) ethyl propionate; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)cyclohexyl propionate; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)perdeuteromethyl propionate; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)perdeuteroethyl propionate; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)perdeuterocyclohexyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)propionic acid; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)methyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)ethyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)cyclohexyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)perdeuteromethyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)perdeuteroethyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)perdeuterocyclohexyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dideuteroxyphenyl)perdeuterocyclohexyl propionate; and as well as physiologically compatible salts thereof and combining said compound and physiologically compatible salts with pharmaceutically compatible adjuvants and additives..].

18. A pharmaceutical composition .[.for the treatment of Parkinson's disease, of restless leg syndrome, of dystonia, for inhibiting prolactin secretion, for stimulating the release of growth hormone, for the treatment of neurological symptoms of chronic manganese intoxications, of amyotrophic lateral sclerosis and of multiple system atrophy, which pharmaceutical composition comprises a compound of general formula I ##STR00013## wherein R.sup.1 is H or D, R.sup.2 indicates D, R.sup.3 is H, D, C.sub.1-C.sub.6 alkyl or C.sub.5 to C.sub.6-cycloalkyl, deuterated C.sub.1 to C.sub.6-alkyl or C.sub.5 to C.sub.6-cycloalkyl, R.sup.4 indicates H or D and R.sup.5 is H or D, and wherein the compound is selected from the group consisting of.]. .Iadd.comprising .Iaddend. L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)propionic acid.[.; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)methyl propionate; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) ethyl propionate; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)cyclohexyl propionate; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)perdeuteromethyl propionate; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)perdeuteroethyl propionate; L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl)perdeuterocyclohexyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)propionic acid; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)methyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)ethyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)cyclohexyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)perdeuteromethyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)perdeuteroethyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)perdeuterocyclohexyl propionate; L-2-amino-2,3,3-trideutero-3-(2,3,6-trideutero-4,5-dideuteroxyphenyl)perdeuterocyclohexyl propionate; and as well as.]. .Iadd.or a .Iaddend.physiologically compatible .[.salts.]. .Iadd.salt .Iaddend.thereof, .[.in addition to.]. .Iadd.for treating Parkinson's disease, treating restless leg syndrome, treating dystonia, inhibiting prolactin secretion, stimulating the release of growth hormone, treating neurological symptoms of chronic manganese intoxication, treating amyotrophic lateral sclerosis, or treating multiple system atrophy, and a .Iaddend.pharmaceutically compatible .[.adjuvants and additives.]. .Iadd.adjuvant or additive.Iaddend..

19. The pharmaceutical composition of claim 18 further comprising one or more enzyme inhibitors.

.[.20. The pharmaceutical composition according to claim 19, further characterized in that the enzyme inhibitor or the enzyme inhibitors involve decarboxylase inhibitors and/or catechol-O-methyltransferase inhibitors and/or monoamine oxidase inhibitors and/or β-hydroxylase inhibitors..].

.[.21. The pharmaceutical composition according to claim 19, further characterized in that 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 as well as physiologically compatible salts thereof..].

.[.22. The pharmaceutical composition according to claim 19, further characterized in that the catechol-O-methyltransferase inhibitor is selected from entacapone and cabergoline as well as physiologically compatible salts thereof..].

.[.23. The pharmaceutical composition according to claim 19, further characterized in that the monoamine oxidase inhibitor is selected from the group consisting of selegiline, moclobemide and tranylcypromine as well as physiologically compatible salts thereof..].

.[.24. The pharmaceutical composition according to claim 19, further characterized in that the β-hydroxylase inhibitor is selected from calcium 5-butyl picolinate and calcium 5-pentyl picolinate as well as physiologically compatible salts thereof..].

.Iadd.25. The method of claim 10 for treating Parkinson's disease. .Iaddend.

.Iadd.26. The method of claim 10 for treating restless leg syndrome. .Iaddend.

.Iadd.27. The method of claim 10 for treating dystonia. .Iaddend.

.Iadd.28. The method of claim 10 for treating neurological symptoms of chronic manganese intoxication. .Iaddend.

.Iadd.29. The method of claim 10 for treating amyotrophic lateral sclerosis. .Iaddend.

.Iadd.30. The method of claim 10 for treating multiple system atrophy. .Iaddend.

.Iadd.31. The pharmaceutical composition of claim 18, for treating Parkinson's disease. .Iaddend.

.Iadd.32. The pharmaceutical composition as recited in claim 18, for treating restless leg syndrome. .Iaddend.

.Iadd.33. The pharmaceutical composition of claim 18, for treating dystonia. .Iaddend.

.Iadd.34. The pharmaceutical composition of claim 18, for treating neurological symptoms of chronic manganese intoxication. .Iaddend.

.Iadd.35. The pharmaceutical composition of claim 18, for treating amyotrophic lateral sclerosis. .Iaddend.

.Iadd.36. The pharmaceutical composition of claim 18, for treating multiple system atrophy. .Iaddend.

Description

EXAMPLE 1

Production of L-2-acetylamino-3,3-dideutero-3-(3,4-dimethoxyphenyl) propionic acid

(1) Analogously to the method for the undeuterated compound, 50 ml of acetone are added to 3.85 g of D,L-2-acetylamino-3,3-dideutero-3-(3,4-dimethoxyphenyl) propionic acid and the solution is heated. 0.865 g of (R)-(+)-1-phenylethylamine, dissolved in 5 ml of acetone, are added to this warm solution. The precipitated salt is again dissolved by addition of a small amount of methanol. The methanol is removed by repeated concentration of the reaction batch and the volume of the solution is brought to 50 ml by the addition of acetone. For crystallization of the salt formed from L-2-acetylamino-3,3-dideutero-3-(3,4-dimethoxyphenyl) propionic acid and (R)-(+)-1-phenylethylamine, the reaction batch is triturated with a glass rod and then after crystallization has begun, it is left to stand for 12 hours at room temperature. The crystals that form are separated, washed with cold acetone and diethyl ether and dried. 2.6 g of the salt are isolated.

(2) The solvent is distilled off from the remaining mother liquor and the residue of D-2-acetylamino-3,3-dideutero-3-(3,4-dimethoxyphenyl) propionic acid is stored until further processing.

(3) Yield: Melting point: 185-187° C.

(4) [α].sub.D.sup.25=+56.4° (c=1 in methanol)

(5) The salt is further processed without additional purification by dissolving 2.5 g in 15 ml of a 5% sodium hydroxide solution. The released (R)-(+)-1-phenylethylamine is removed from the solution by extraction with petroleum ether. After acidifying the aqueous phase with hydrochloric acid, a saturated sodium chloride solution is added and the solution is extracted with ethyl acetate. The organic phase is dried and the solvent is removed. The residue crystallizes overnight and L-2-acetylamino-3,3-dideutero-3-(3,4-dimethoxyphenyl) propionic acid is obtained. 1.48 g of product is obtained.

(6) Yield: 86%

(7) Melting point 135-137° C.

(8) [α].sub.D.sup.25=+45.5° (c=1 in methanol)

(9) TABLE-US-00001 Theoretical: C: 57.98% H: 7.11% N: 5.20% Experimentally found: C: 57.89% H: 7.19% N: 5.30%

(10) .sup.1H-NMR (400 MHz, d6-DMSO): δ 6.48 (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

Production of L-2-amino-3,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid

(11) 1.35 g of L-2-acetylamino-3,3-dideutero-3-(3,4-dimethoxyphenyl) propionic acid are dissolved in 17 ml of chloroform and then reacted with 26.3 ml of iodotrimethylsilane. The reaction batch is heated to 60° C. and the course of the reaction is followed by means of NMR. After 30 hours, the reaction is terminated, the batch is filtered and 15 ml of methanol are added to the filtrate. After 30 hours, the solvent is removed and 0.96 g of product is isolated.

(12) Yield: 96%

(13) Melting point 287-290° C. (decomp.)

(14) [α].sub.D.sup.25=−11.7° (c=5.27 in 1 M HCl)

(15) TABLE-US-00002 Theoretical: C: 54.27% H: 6.58% N: 7.03% Experimentally found: C: 54.10% H: 6.60% N: 7.11%

(16) .sup.1H-NMR (400 MHz, d6-DMSO): δ 6.49 (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-dideutero-3-(3,4-dihydroxyphenyl) propionic acid

(17) The D-2-acetylamino-3,3-dideutero-3-(3,4-dimethoxyphenyl) propionic acid obtained in Example 1 is converted to the D-2-amino-3,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid analogously to Example 2. 0.82 g of the deuterated dihydroxy amino acid is isolated from 1.2 g of the initial compound.

(18) Yield: 92%

(19) Melting point: 287-290° C. (decomp.)

(20) [α].sub.D.sup.25=+11.5° (c=5.27 in 1 M HCl)

(21) TABLE-US-00003 Theoretical: C: 54.27% H: 6.58% N: 7.03% Experimentally found: C: 54.31% H: 6.55% N: 7.10%

(22) .sup.13C-NMR (200 MHz, d6-DMSO): δ 41.0 (quint); 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

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

(23) 1.99 g of D-2-acetylamino-3,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid are reacted with 50 ml of singly deuterated acetic acid (CH.sub.3COOD) and 0.2 ml of benzaldehyde is added. The reaction batch is rinsed with nitrogen and then heated to reflux for one hour. After the end of the reaction time, the solvent is removed and the residue is reacted with 20 ml of ethanol. The precipitated solid is filtered off and 1.74 g of D,L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid is isolated.

(24) Yield: 87%

(25) Melting point: 287-290° C. (decomp.)

(26) TABLE-US-00004 Theoretical: C: 53.99% H: 7.05% N: 7.00% Experientally found: C: 53.90% H: 7.12% N: 7.04%

(27) .sup.1H-NMR (400 MHz, d6-DMSO): δ 6.47 (s, 1H); 6.59 (s, 1H); 6.52 (s, 1H); 7.8 (s, 1H).

EXAMPLE 5

Production of D,L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) methyl propionate

(28) 2 g of D,L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) proponic acid in 30 ml of methanol are cooled to −10° C. and reacted dropwise with 1 ml of thionyl chloride. The reaction batch is then heated to 40° C. for 15 hours. The volatile substances in the reaction batch are eliminated in vacuum and 10 ml of water and 15 ml of a solution of 0.8 g of sodium hydrogen carbonate, 1 g of sodium sulfate and 1 mg of ascorbic acid are added. The pH of the solution is adjusted to a value of 7 by addition of a dilute sodium hydroxide solution. The product is transferred to the organic phase by extraction with oxygen-free ethyl aectate, which contains 0.01% 2,6-di-tert-butyl-4-methoxyphenol. The organic phase is dried and then the solvent is distilled off. 50 ml of oxygen-free diethyl ether are added to the residue and after this material is left to stand overnight, the D,L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) methyl propionate precipitates. After recrystallization from an oxygen-free methanol/diethyl ether mixture which is combined with 2,6-di-tert-butyl-4-methoxyphenol, 1.8 g of product is isolated.

(29) Yield: 85%

(30) TABLE-US-00005 Theoretical: C: 56.06% H: 7.53% N: 6.54% Experientally found: C: 56.20% H: 7.48% N: 6.55%

(31) .sup.1H-NMR (400 MHz, d6-DMSO): δ 6.48 (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-trideutero-3-(3,4-dihydroxyphenyl) propionic acid

(32) 1.07 g of D,L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) methyl propionate is dissolved in 30 ml of a 0.2-molar sodium bicarbonate solution (pH 8.2). 200 μl of alcalase are added and the pH of the solution is kept at this value by means of a carbonate-bicarbonate buffer. The course of the reaction is monitored by means of HPLC and the reaction is terminated by the addition of hydrochloric acid when the concentration of the propionate ester has been reduced to one-half. The trideuterated amino acid contained in the solution is separated from the trideuterated methyl ester chromatographically with the use of the solvent system of acetonitrile/0.1% aqueous trifluoroacetic acid (15:85) and 1.04 g of L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid is isolated.

(33) Yield: 97%

(34) Melting point: 287-290° C. (decomp.)

(35) [α].sub.D.sup.25=−11.6° (c=5.27 in 1 M HCl)

(36) TABLE-US-00006 [Theoretical]: C: 53.99% H: 7.05% N: 7.00% Experientally found: C: 53.83% H: 7.12% N: 6.91%

(37) .sup.13C-NMR (200 MHz, d6-DMSO): δ 41.0 (quint); 62.40 (trip.); 116.20 (s); 117.30 (s); 121.70 (s); 133.80 (s); 141.40 (s); 144.40 (s); 176.40 (s).

EXAMPLE 7

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

(38) 0.2 g of L-2-amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid are reacted with 10 ml of D.sub.2O in an autoclave. The autoclave is evacuated and heated to a temperature of 190° C. for 24 hours. After the reaction has terminated, the solvent is removed, the residue is mixed with ethyl acetate and the solvent is distilled off in vacuum. The residue is washed with cold acetone and 0.17 g of product is isolated.

(39) Yield: 84%

(40) Melting point: 287-290° C. (decomp.)

(41) [α].sub.D.sup.25=−11.5° (c=5.27 in 1 M HCl)

(42) TABLE-US-00007 [Theoretical]: C: 53.19% H: 8.43% N: 6.89% Experientally found: C: 53.30% H: 8.31% N: 7.00%

(43) .sup.13C-NMR (200 MHz, d6-DMSO): 41.0 (quint); 62.40 (t); 116.30 (t); 117.20 (t); 121.70 (t); 133.80 (s); 141.30 (s); 144.40 (s); 176.40 (s).