Deuterated catecholamine derivatives and medicaments comprising 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 acceptable 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## R.sup.1 is H or D, or a group that is easily hydrolytically or enzymatically cleavable under physiological conditions, R.sup.2 indicates D, R.sup.3 is H, D, C.sub.1 to C.sub.6 alkyl or C.sub.1 to C.sub.6-cycloalkyl, deuterated to C.sub.1 to C.sub.6 wherein alkyl or C.sub.1 to C.sub.6-cycloalkyl, or a group that is easily hydrolytically or enzymatically cleavable under physiological conditions, R.sup.4 indicates H or D, or a group that is easily hydrolytically or enzymatically cleavable under physiological conditions, R.sup.5 is H or D, and one of R.sup.6 is H and the other R.sup.6 is D, as well as their physiologically acceptable salts and their stereoisomers, enantiomeres or diastereomers in optically pure form..].

.[.2. Deuterated catecholamine derivatives according to claim 1, wherein R.sup.1 is H or 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 D..].

.[.3. Deuterated catecholamine derivatives according to claim 1, wherein R.sub.1 is H or 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 D..].

.[.4. Deuterated catecholamine derivatives according to claim 1, wherein R.sub.1 is H or 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 D..].

.[.5. Deuterated catecholamine derivatives according to the general formula I, wherein R.sub.1 is H or 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 D..].

.[.6. Deuterated catecholamine derivatives according to claim 1, wherein R.sub.1 is H or D, R.sup.3 is methyl, R.sup.4 indicates H or D, and R.sup.5 is D..].

.[.7. Deuterated catecholamine derivatives according to claim 1, wherein R.sup.1 is H or D, R.sup.3 is ethyl, R.sup.4 indicates H or D, and R.sup.5 is D..].

.[.8. Deuterated catecholamine derivatives according to claim 1, wherein R.sup.1 is H or D, R.sup.3 is perdeuteroethyl, R.sup.4 indicates H or D, and R.sup.5 is D..].

.[.9. Deuterated catecholamine derivatives according to claim 1, wherein R.sup.1 is H or D, R.sup.3 is perdeuteroethyl, R.sup.4 indicates H or D, and R.sup.5 is D..].

.[.10. Deuterated catecholamine derivatives according to claim 1, wherein R.sup.1 is H or D, R.sup.3 is perdeuteroethyl, R.sup.4 indicates D, and R.sup.5 is H or D..].

.[.11. Deuterated catecholamine derivatives according to claim 1, namely R/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid, R/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid methyl ester, R/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid ethyl ester, R/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid, R/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid methyl ester, R/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid ethyl ester, S/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid, S/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid methyl ester, S/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid ethyl ester, S/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid, S/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid methyl ester, S/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid ethyl ester, 2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl) propionic acid, 2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl) propionic acid methyl ester, 2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl) propionic acid ethyl ester, R/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl) propionic acid, R/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl) propionic acid methyl ester, R/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl) propionic acid ethyl ester, R/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl) propionic acid, R/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl) propionic acid methyl ester, R/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl) propionic acid ethyl ester, S/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl) propionic acid, S/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl) propionic acid methyl ester, S/R-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl) propionic acid ethyl ester, S/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl) propionic acid, S/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl) propionic acid methyl ester, and S/S-2-amino-2,3-dideutero-3-(2,3,6-trideutero-4,5- dihydroxyphenyl) propionic acid ethyl ester..].

12. A pharmaceutical composition.[., which contains.]. .Iadd.comprising a .Iaddend.deuterated .[.catecholamines according to claim 1 as well as.]. .Iadd.catecholamine that is R/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid, R/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid, S/R-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid, or S/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid, or a .Iaddend.physiologically acceptable .[.salts.]. .Iadd.salt .Iaddend.thereof, for .[.the treatment of.]. .Iadd.treating .Iaddend.Parkinson's disease, .[.of.]. .Iadd.treating .Iaddend.restless leg syndrome, .[.of.]. .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.[., in addition to.]. .Iadd.and further comprising a .Iaddend.pharmaceutically acceptable .[.adjuvants and additives.]. .Iadd.adjuvant or additive.Iaddend..

13. .[.A.]. .Iadd.The .Iaddend.pharmaceutical composition.[., which contains deuterated catecholamines according to.]. .Iadd.of .Iaddend.claim .[.1 as well as physiologically acceptable salts thereof, for the treatment of 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, as well as.]. .Iadd.12, further comprising .Iaddend.one or more enzyme inhibitors.[., in addition to pharmaceutically acceptable adjuvants and additives.]..

14. The pharmaceutical composition .[.according to.]. .Iadd.of .Iaddend.claim 13, .[.further characterized in that.]. .Iadd.wherein .Iaddend.the enzyme inhibitor .[.or the enzyme inhibitors involve.]. .Iadd.is a .Iaddend.decarboxylase .[.inhibitors.]. .Iadd.inhibitor, .Iaddend.and/or .Iadd.a .Iaddend.catechol-.[.0.]..Iadd.O.Iaddend.-methyltransferase .[.inhibitors.]. .Iadd.inhibitor, .Iaddend.and/or .Iadd.a .Iaddend.monoamine oxidase .[.inhibitors.]. .Iadd.inhibitor, .Iaddend.and/or .Iadd.a .Iaddend.β-hydroxylase .[.inhibitors.]. .Iadd.inhibitor.Iaddend..

15. The pharmaceutical composition .[.according to.]. claim .[.13.]. .Iadd.14.Iaddend., .[.further characterized in that.]. .Iadd.wherein .Iaddend.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.Iadd.-.Iaddend.dihydroxy-α-methylhydrocinnamic acid (carbidopa), L.Iadd.-.Iaddend.serine.Iadd.-.Iaddend.2-(2,3,4-trihydroxybenzyl) hydrazide, glycine 2-(2,3,4-trihydroxybenzyl) hydrazide and L-tyrosine 2.Iadd.-.Iaddend.(2,3,4-trihydroxybenzyl) hydrazide .[.as well as.]. .Iadd.or a .Iaddend.physiologically acceptable .[.salts.]. .Iadd.salt .Iaddend.thereof.

16. The pharmaceutical composition .[.according to.]. .Iadd.of .Iaddend.claim 14, .[.further characterized in that.]. .Iadd.wherein .Iaddend.the .[.catechol-0-methyltransferase.]. .Iadd.catechol-O-methyltransferase .Iaddend.inhibitor is .[.selected from.]. entacapone .[.and.]. .Iadd.or .Iaddend.cabergoline .[.as well as.]. .Iadd.or a .Iaddend.physiologically acceptable .[.salts.]. .Iadd.salt .Iaddend.thereof.

17. The pharmaceutical composition .[.according to.]. .Iadd.of .Iaddend.claim 14, .[.further characterized in that.]. .Iadd.wherein .Iaddend.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 acceptable .[.salts.]. .Iadd.salt .Iaddend.thereof.

18. The pharmaceutical composition .[.according to.]. .Iadd.of .Iaddend.claim 14, .[.further characterized in that.]. .Iadd.wherein .Iaddend.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 acceptable .[.salts.]. .Iadd.salt .Iaddend.thereof.

.Iadd.19. The pharmaceutical composition of claim 12, for treating Parkinson's disease..Iaddend.

.Iadd.20. The pharmaceutical composition of claim 12, for treating restless leg syndrome..Iaddend.

.Iadd.21. The pharmaceutical composition of claim 12, for treating dystonia..Iaddend.

.Iadd.22. The pharmaceutical composition of claim 12, for treating chronic manganese intoxication..Iaddend.

.Iadd.23. The pharmaceutical composition of claim 12, for treating amyotrophic lateral sclerosis..Iaddend.

.Iadd.24. The pharmaceutical composition of claim 12, for treating multiple system atrophy..Iaddend.

.Iadd.25. The pharmaceutical composition of any one of claims 19 to 24, wherein the deuterated catecholamine is S/S-2-amino-2,3-dideutero-3-(3,4-dihydroxyphenyl)propionic acid..Iaddend.

Description

(1) The following examples are given to explain the present invention in more detail but shall not be understood to limit the scope of the invention.

EXAMPLE 1

D,L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid

(2) 2.5 g Levodopa are dissolved in 60 mL CH.sub.3CO.sub.2D under argon and then reacted with 0.25 mL benzaldehyde under reflux. Following elimination of acetic acid and benzaldehyde by distillation in vacuum, 2 mL of methanol are added. The product is precipitated slowly with 10 mL ethyl acetate/toluene (1:1). After drying under vacuum, 2.2 g D,L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid are isolated.

(3) Yield: 87.6%

EXAMPLE 2

D,L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl) methyl propionate

(4) 2.0 g of D,L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid are dissolved in 30 mL methanol and 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 acetate, which contains 0.01% 2,6-ditert-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-deutero-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.

(5) Yield: 84.9%

EXAMPLE 3

L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid

(6) 1.15 g of D,L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl)methyl propionate are 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 carbonate-bicarbonate buffer. The course of the reaction is monitored by 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 deuterated amino acid contained in the solution is separated from the deuterated methyl ester chromatographically by use of the solvent system of acetonitrile/0.1% aqueous trifluoroacetic acid (15:85) and 0.51 g of L-2-amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid is isolated.

(7) Yield: 95% (based on the proportion of L-enantiomer)

(8) Melting point: 287-290° C.

(9) C.sub.9H.sub.10NO.sub.4D:

(10) calc. C, 54.54%; H, 5.09%; N, 7.07%; O, 32.29%; D, 1.02%.

(11) found C, 54.45%; H+D, 6.08; N, 7.02.

(12) .sup.1H-NMR (400 MHz, d6-DMSO): 6.58 (d, 1H); 6.54 (s, 1H); 6.47 (d, 1H); 3.07 (d, 1H); 2.90 (d, 1H)

EXAMPLE 4

L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl)methyl propionate

(13) 2.0 g of L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid are dissolved in 30 mL 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 acetate, which contains 0.01% 2,6-ditert-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 the material is left to stand overnight, the L-2-amino-2-deutero-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, 1.9 g of product is isolated.

(14) Yield: 89.6%

(15) C.sub.10H.sub.12NO.sub.4D:

(16) calc. C, 56.60%; H, 5.70%; N, 6.60%: O, 30.16%; D, 0.95%.

(17) found C, 56.65%; H+D, 6.63%; N, 6.54%.

(18) .sup.1H-NMR (400 MHz, d6-DMSO): 6.58 (d, 1H); 6.54 (s, 1H); 6.47 (d, 1H); 3.81 (s, 3H); 3.07 (d, 1H); 2.90 (d, 1H)

EXAMPLE 5

L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl)ethyl propionate

(19) 2.0 g of L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid are dissolved in 30 mL ethanol 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 acetate, which contains 0.01% 2,6-ditert-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 the material is left to stand overnight, the L-2-amino-2-deutero-3-(3,4-dihydroxyphenyl)ethyl propionate precipitates. After recrystallization from an oxygen-free ethanol/diethyl ether mixture, which is combined with 2,6-ditert-butyl-4-methoxyphenol, 2 g of product is isolated.

(20) Yield: 88.5%

(21) C.sub.11H.sub.14NO.sub.4D:

(22) calc. C, 58.40%; H, 6.24%; N, 6.19%; O, 28.29%; D, 0.89%.

(23) found C, 58.32%; H+D, 7.03%; N, 6.12%.

(24) .sup.1H-NMR (400 MHz, d6-DMSO): 6.58 (d, 1H); 6.54 (s, 1H); 6.47 (d, 1H); 4.15 (q, 2H); 3.07 (d, 1H); 2.90 (d, 1H); 1.21 (t, 3H)

EXAMPLE 6

L-2-Amino-2,3(S)-dideutero-3-(3,4-dihydroxyphenyl) propionic acid

(25) 2.5 g of N-acetyl-3-methoxy-4-acetoxy cinnamic acid are dissolved in 30 mL methanol containing 0.027 g sodium hydroxide and placed into an autoclave. The oxygen is replaced by nitrogen before the reactor is filled with deuterium gas. At the same time 0.5 g of Monsanto catalyst are prepared in 2.5 mL toluene by treating with deuterium gas. After addition of the catalyst to the autoclave, the “hydrogenation” is started at 60° C. and 4-5 bar. After 4 hours, the excess of deuterium gas is removed and the solvent is distilled of. The sodium salt of the deuterated product is isolated and recrystallized.

(26) Yield: 2.4 g (94%)

(27) 0.9 g of the sodium salt are dissolved in 2.5 mL of hydrobromic acid (23%) and heated to reflux at about 105-110° C. Afterwards, the reaction mixture is cooled to 25-30° C. and the pH is adjusted to 3 by addition of concentrated sodium hydroxide solution to start the precipitation of L-2-Amino-2,3(S)-dideutero-3-(3,4-dihydroxyphenyl) propionic acid. The precipitate is washed with cold water and recrystallized in hot water under protective gas. After recrystallization, 0.51 g of the product are isolated.

(28) Yield: 85.1%

(29) Melting point: 286-299° C.

(30) C.sub.9H.sub.9NO.sub.4D.sub.2:

(31) calc. C, 54.27%; H, 4.55%; N, 7.03%; O, 32.13%; D, 2.02%.

(32) found C, 54.15%; H+D, 6.50%; N, 7.08%.

(33) .sup.1H-NMR (400 MHz, d6-DMSO): 6.59 (d, 1H); 6.54 (s, 1H); 6.48 (d, 1H); 2.74 (m, 1H)

EXAMPLE 7

(34) L-2-Amino-2,3(S)-dideutero-3-(3,4-dihydroxyphenyl)methyl propionate

(35) The compound is produced according to the description for the mono-deuterated compound (cf. example 4).

(36) Yield: 91%

(37) C.sub.10H.sub.11D.sub.2NO.sub.4:

(38) calc. C, 56.33%; H, 5.20%; N, 6.57%; O, 30.01%; D, 1.89%.

(39) found C, 56.22%; H+D, 7.01; N, 6.45.

(40) .sup.1H-NMR. (400 MHz, d6.-DMSO): 6.59 (d, 1H); 6.54 (S, 1H); 6.48 (d, 1H); 2.72 (m, 1H); 3.81 (s, 3H).

EXAMPLE 8

L-2-Amino-2,3(S)-dideutero-3-(3,4-dihydroxyphenyl)ethyl propionate

(41) The compound is produced according to the description for the mono-deuterated compound (cf. example 5).

(42) Yield: 93%,

(43) C.sub.11H.sub.13D.sub.2NO.sub.4:

(44) calc. C, 58.14%; H, 5.77%; N, 6.16%; O, 28.16%; D, 1.77%.

(45) found C, 58.10%; H+D, 7.48%; N, 6.10%.

(46) .sup.1H-NMR (400 MHz, d6-DMSO): 6.59 (d, 1H); 6.54 (s, 1H); 6.48 (d, 1H); 2.72 (m, 1H); 4.17 (q, 2H); 1.22 (t, 3H).

EXAMPLE 9

L-2-Amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl) propionic acid

(47) 0.2 g of L-2-Amino-2-deutero-3-(3,4 dihydroxyphenyl) propionic acid are placed into an autoclave and 10 mL of D.sub.2O are added. The autoclave is evacuated and heated to 190° C. for 24 hours. The solvent is eliminated and acetic acid ethyl ester is added. The solvent is distilled of and the residue washed with cold acetone. Thereafter, 0.17 g of the product are isolated.

(48) Yield: 84%

(49) C.sub.9H.sub.7NO.sub.4D.sub.4:

(50) calc. C, 53.72%; H, 3.51%: N, 6.96%; O, 31.81%; D, 4.00%.

(51) found C, 53.65%; H+D, 7.45%; N, 6.90%.

(52) .sup.1H-NMR (400 MHz, d6-DMSO): 3.06 (d, 1H); 2.88 (d, 1H)

EXAMPLE 10

L-2-Amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)methyl propionate

(53) The compound is produced according to the description for the mono-deuterated compound (cf. example 4).

(54) Yield: 89%.

(55) C.sub.10H.sub.9NO.sub.4D.sub.4:

(56) calc. C, 55.80%; H, 4.21%; N, 6.51%; O, 29.73%; D, 3.74%.

(57) found C, 55.71%; H+D, 7.89%; N, 6.53%.

(58) .sup.1H-NMR (400 MHz, d6-DMSO): 3.81 (s, 3H); 3.08 (d, 1H); 2.88 (d, 1H)

EXAMPLE 11

L-2-Amino-2-deutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)ethyl propionate

(59) The compound is produced according to the description for the mono-deuterated compound (cf. example 5).

(60) Yield: 92%.

(61) C.sub.11H.sub.11NO.sub.4D.sub.4:

(62) calc. C, 57.63%; H, 4.84%; N, 6.11%; O, 27.91%; D, 3.51%.

(63) found C, 57.57%; H+D, 8.31%; N, 6.15%.

(64) .sup.1H-NMR (400 MHz, d6-DMSO): 4.17 (q, 2H); 3.06 (d, 1H); 2.88 (d, 1H); 1.21 (t, 3H)

EXAMPLE 12

L-2-Amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl) propionic acid

(65) 0.2 g of L-2-Amino-2-deutero-3-(3,4-dihydroxyphenyl) propionic acid are placed into an autoclave and 10 mL of D.sub.2O are added. The autoclave is evacuated and heated to 190° C. for 24 hours. The solvent is eliminated and acetic acid ethyl ester is added. The solvent is distilled of and the residue washed with cold acetone. Thereafter, 0.16 g of the product are isolated.

(66) Yield: 79.2%

(67) C.sub.9H.sub.6NO.sub.4D.sub.5:

(68) calc. C, 53.46%; H, 2.99%; N, 6.93%; O, 31.65%; D, 4.98%.

(69) found C, 53.49%; H+D, 7.92%; N, 6.88%.

(70) .sup.1H-NMR (400 MHz, d6-DMSO): 2.76 (m, 1H)

EXAMPLE 13

L-2-Amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)methyl propionate

(71) The compound is produced according to the description for the mono-deuterated compound (cf. example 4).

(72) Yield: 90%

(73) C.sub.11H.sub.8D.sub.5NO.sub.4:

(74) calc. C, 55.54%; H, 3.73%; N, 6.48%; O, 29.59%; D, 4.66%.

(75) found C, 55.50%; H+D, 8.31; N, 6.45%.

(76) .sup.1H-NMR (400 MHz, d6-DMSO): 3.80 (s, 3H); 2.74 (m, 1H)

EXAMPLE 14

L-2-Amino-2,3-dideutero-3-(2,3,6-trideutero-4,5-dihydroxyphenyl)ethyl propionate

(77) The compound is produced according to the description for the mono-deuterated compound (cf. example 5).

(78) Yield: 93%

(79) C.sub.11H.sub.10D.sub.5NO.sub.4:

(80) calc. C, 57.38%; H, 4.38%; N, 6.08%; O, 27.79%; D, 4.37%.

(81) found C, 57.34%; H+D, 8.71%; N, 6.04%.

(82) .sup.1H-NMR (400 MHz, d6-DMSO): 4.15 (q, 2H); 2.75 (m, 1H); 1.21 (t, 3H)

EXAMPLE 15

Striatal Dopamine Output Measured by Microdialysis

(83) The striatal output of dopamine was measured in Male Wistar rats following intraperitoneal administration of 50 mg/kg L-2-Amino-3-(3,4-dihydroxyphenyl) propionic acid (L-DOPA), L-2-Amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid (WO-A 2004/056724, Example 6) and L-2-Amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid (Example 6), respectively. Male wistar rats (BK Universal, Sollentuna, Sweden) weighing about 300 g at the time of experiment were anaesthetized with a cocktail containing fentanyl citrate (0.39 mg/kg) and fluanisone (12.5 mg/kg, Hypnorm®, Janssen-Cilag) and midazolam (6.25 mg/kg, Dormicum®, Roche) diluted in distilled water (1:1:2; 5 ml/kg i.p.) and mounted in a stereotaxic frame. Dialysis probes were implanted in the dorsolateral striatum (AP: +0.6: ML+3.0: DV −6.2 relative to bregma and the dural surface according to the atlas of Paxinos and Watson (1998)). Dialysis occurs through a semipermeable membrane (Filtral AN69, Hospal Industrie, France) with an active surface length of 3.5 mm. Dialysis experiments were conducted approximately 48 h after surgery in freely moving rats. The rats received 30 min before administration of test items 10 mg/kg Carbidopa, (i.p.). The dialysis probe was perfused with a physiological perfusion solution (Apoteksbolaget, Sweden) at a rate of 2.5 ml/min set by a microinfusion pump (Harvard Apparatus, Holliston, Mass.). Dialysate was collected over 15 min intervals and automatically injected into a high performance liquid chromatography (HPLC) system. On-line quantification of dopamine in the dialysate was accomplished by electrochemical detection (ESA, Chelmsford, Mass.). The location of microdialysis probes was verified in slices of formalin-fixed tissue stained with neutral red. The baseline corrected concentrations (fmol/min) were plotted over the time.

(84) Comparison of AUC.sub.0-t (area under the curve) values revealed that the increase of dopamine in the striatum following administration of 50 mg/kg L-2-Amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) propionic acid was about twice as high compared to L-2-Amino-3-(3,4-dihydroxyphenyl) propionic acid (L-DOPA) as displayed in Table 1. The increase of striatal dopamine following administration of 50 mg/kgL-2-Amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) propionic acid (Example 6) was even threefold higher than that measured after administration of L-DOPA.

(85) TABLE-US-00001 TABLE 1 Baseline corrected dopamine output in the striatum AUC.sub.0-t Compound [fmol/min * min] L-2-Amino-3-(3,4-dihydroxyphenyl) propionic acid 228 L-2-Amino-2,3,3-trideutero-3-(3,4-dihydroxyphenyl) 533 propionic acid L-2-Amino-2,3-dideutero-3-(3,4-dihydroxyphenyl) 685 propionic acid (Ex. 6)