Deuterated catecholamine derivatives and medicaments comprising said compounds

Patent metadata

Field	Value
Publication number	US-RE46555-E
Application number	US-200714464568-A
Country	US
Kind code	E1
Filing date	Feb 16, 2007
Priority date	Feb 17, 2006
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

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.

First claim

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

Assignees

• Teva Pharmaceuticals Int Gmbh

Inventors

• Alken Rudolf-Giesbert
• Schneider Frank

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title