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.

The invention claimed is: 
     
       1. Deuterated catecholamine derivatives of the general formula I 
       
         
           
           
               
               
           
         
         R 1  is H or D, or a group that is easily hydrolytically or enzymatically cleavable under physiological conditions, 
         R 2  indicates D, 
         R 3  is H, D, C 1  to C 6  alkyl or C 1  to C 6 -cycloalkyl, deuterated to C 1  to C 6  wherein alkyl or C 1  to C 6 -cycloalkyl, or a group that is easily hydrolytically or enzymatically cleavable under physiological conditions, 
         R 4  indicates H or D, or a group that is easily hydrolytically or enzymatically cleavable under physiological conditions, 
         R 5  is H or D, and 
         one of R 6  is H and the other R 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 1  is H or D,   R 3  is H, D, C 1  to C 6 -alkyl or C 5  to C 6 -cycloalkyl, deuterated C 1  to C 6 -alkyl or deuterated C 5  to C 6 -cycloalkyl,   R 4  indicates H or D, and   R 5  is D.   
     
     
       3. Deuterated catecholamine derivatives according to  claim 1 , wherein
 R 1  is H or D,   R 3  is D, C 1  to C 6 -alkyl or C 5  to C 6 -cycloalkyl, deuterated C 1  to C 6 -alkyl or deuterated C 5  to C 6 -cycloalkyl,   R 4  indicates H or D, and   R 5  is D.   
     
     
       4. Deuterated catecholamine derivatives according to  claim 1 , wherein
 R 1  is H or D,   R 3  is H, D, C 1  to C 6 -alkyl or C 5  to C 6 -cycloalkyl, deuterated C 1  to C 6 -alkyl or deuterated C 5  to C 6 -cycloalkyl,   R 4  indicates H or D, and   R 5  is D.   
     
     
       5. Deuterated catecholamine derivatives according to the general formula I, wherein
 R 1  is H or D,   R 3  is C 1  to C 6 -alkyl or C 5  to C 6 -cycloalkyl,   R 4  indicates H or D, and   R 5  is D.   
     
     
       6. Deuterated catecholamine derivatives according to  claim 1 , wherein
 R 1  is H or D,   R 3  is methyl,   R 4  indicates H or D, and   R 5  is D.   
     
     
       7. Deuterated catecholamine derivatives according to  claim 1 , wherein
 R 1  is H or D,   R 3  is ethyl,   R 4  indicates H or D, and   R 5  is D.   
     
     
       8. Deuterated catecholamine derivatives according to  claim 1 , wherein
 R 1  is H or D,   R 3  is perdeuteroethyl,   R 4  indicates H or D, and   R 5  is D.   
     
     
       9. Deuterated catecholamine derivatives according to  claim 1 , wherein
 R 1  is H or D,   R 3  is perdeuteroethyl,   R 4  indicates H or D, and   R 5  is D.   
     
     
       10. Deuterated catecholamine derivatives according to  claim 1 , wherein
 R 1  is H or D,   R 3  is perdeuteroethyl,   R 4  indicates D, and   R 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 comprising a deuterated catecholamines according to  claim 1  as well as 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 physiologically acceptable salts salt thereof, for the treatment of treating Parkinson's disease, of treating restless leg syndrome, of treating dystonia, for inhibiting prolactin secretion, for stimulating the release of growth hormone, for the treatment of treating neurological symptoms of chronic manganese intoxications intoxication, of treating amyotrophic lateral sclerosis and of, or treating multiple system atrophy, in addition to and further comprising a pharmaceutically acceptable adjuvants and additives adjuvant or additive. 
     
     
       13. A The pharmaceutical composition, which contains deuterated catecholamines according to of 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 12, further comprising one or more enzyme inhibitors, in addition to pharmaceutically acceptable adjuvants and additives. 
     
     
       14. The pharmaceutical composition according to of  claim 13 , further characterized in that wherein the enzyme inhibitor or the enzyme inhibitors involve is a decarboxylase inhibitors inhibitor, and/or a catechol-0O-methyltransferase inhibitors inhibitor, and/or a monoamine oxidase inhibitors inhibitor, and/or a β-hydroxylase inhibitors inhibitor. 
     
     
       15. The pharmaceutical composition according to claim  13  14, further characterized in that 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 as well as or a physiologically acceptable salts salt thereof. 
     
     
       16. The pharmaceutical composition according to of  claim 14 , further characterized in that wherein the catechol-0-methyltransferase catechol-O-methyltransferase inhibitor is selected from entacapone and or cabergoline as well as or a physiologically acceptable salts salt thereof. 
     
     
       17. The pharmaceutical composition according to of  claim 14 , further characterized in that wherein the monoamine oxidase inhibitor is selected from the group consisting of selegiline, moclobemide and, or tranylcypromine as well as or a physiologically acceptable salts salt thereof. 
     
     
       18. The pharmaceutical composition according to of  claim 14 , further characterized in that wherein the β-hydroxylase inhibitor is selected from calcium 5-butyl picolinate and or calcium 5-pentyl picolinate as well as or a physiologically acceptable salts salt thereof. 
     
     
       19. The pharmaceutical composition of claim 12, for treating Parkinson's disease. 
     
     
       20. The pharmaceutical composition of claim 12, for treating restless leg syndrome. 
     
     
       21. The pharmaceutical composition of claim 12, for treating dystonia. 
     
     
       22. The pharmaceutical composition of claim 12, for treating chronic manganese intoxication. 
     
     
       23. The pharmaceutical composition of claim 12, for treating amyotrophic lateral sclerosis. 
     
     
       24. The pharmaceutical composition of claim 12, for treating multiple system atrophy. 
     
     
       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.