IP Library › Granted Patent US 46,629

Granted Patent E1

US 46,629 · App. 14/464,444 · Granted Dec 12, 2017

Deuterated catecholamine derivatives and medicaments compromising said compounds

Inventor: Rudolf-Giesbert Alken (Neuenhagen, DE)

Assignee: Teva Pharmaceuticals International GmbH

C07C229/36 C07B59/001

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Quick Facts

Patent No.: US 46,629
App. No.: 14/464,444
Granted: Dec 12, 2017
Kind: E1

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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 (96)

1. Deuterated catecholamine derivatives of the general formula I

wherein R 1 is H or D, R2 indicates 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 H or hhD.

2. Deuterated catecholamine derivatives of the general formula I

wherein R 1 is H or D, R 2 indicates 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 H or D.

3. Deuterated catecholamine derivatives of the general formula I

wherein R 1 is H or D, R 2 indicates 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 H or D.

4. Deuterated catecholamine derivatives of the general formula I

wherein R 1 is H or D, R 2 indicates 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 H or D.

5. Deuterated catecholamine derivatives of the general formula I

wherein R 1 is H or D, R 2 indicates D, R 3 is methyl, R 4 indicates H or D and R 5 is H or D.

6. Deuterated catecholamine derivatives of the general formula I

wherein R 1 is H or D, R 2 indicates D, R 3 is ethyl, R 4 indicates H or D and R 5 is H or D.

7. Deuterated catecholamine derivatives of the general formula I

wherein R 1 is H or D, R 2 indicates D, R 3 is perdeuteroethyl, R 4 indicates H or D and R 5 is H or D.

8. Deuterated catecholamine derivatives of the general formula I

wherein R 1 is H or D, R2 indicates D, R 3 is perdeuteroethyl, R 4 indicates H or D and R 5 is H or D.

9. Deuterated catecholamine derivatives of the general formula I

wherein R 1 is H or D, R 2 indicates D, R 3 is perdeuteroethyl, R 4 indicates D and R 5 is H or D.

10. A method for the treatment of treating a dopamine deficiency diseases or diseases disease, treating a disease which are is based on disrupted tyrosine transport or disrupted tyrosine decarboxylase, or treating Parkinson's disease, treating restless leg syndrome, 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, said method comprising administering to a patient in need thereof an effective amount of a compound of general formula I

wherein R 1 is H or D, R 2 indicates D, R 3 is H, D, C 1 -C 6 - alkyl or C 5 to C 6 -cycloalkyl, deuterated C 1 to C 6 -alkyl or C 5 to C 6 -cycloalkyl, R 4 indicates H or D and R 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 or a physiologically compatible salts salt thereof.

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

12. The method as claimed in of claim 11 , wherein the enzyme inhibitor or the several 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 of claim 12 , 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, or L-tyrosine 2-(2,3,4-trihydroxybenzyl)hydrazide as well as, or a physiologically compatible salts salt thereof.

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

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

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

wherein R 1 is H or D, R 2 indicates D, R 3 is H, D, C 1 -C 6 alkyl or C 5 to C 6 -cycloalkyl, deuterated C 1 to C 6 -alkyl or C 5 to C 6 -cycloalkyl, R 4 indicates H or D and R 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;